A method for preparing a 3-alkynylbenzofuran compound

Abstract

The application provides a preparation method of a 3-alkynyl benzofuran compound and belongs to the technical field of heterocyclic compounds. A palladium catalyst, a ligand, a base, 2-alkynyl phenol and aryl alkynyl bromide are added into an organic solvent, and the mixture is stirred at 60-80 o After C reaction for 22-26 hours, a 3-alkynyl benzofuran compound is obtained through post-treatment. The preparation method is simple in operation, low in cost of starting materials, high in reaction efficiency and good in substrate compatibility, and can realize one-step efficient and rapid synthesis of the 3-alkynyl benzofuran compound.

Description

Technical Field

[0001] This application relates to a method for preparing a 3-ynylbenzofuran compound, belonging to the field of heterocyclic compound technology. Background Technology

[0002] Benzofuran compounds are an important structural framework, widely found in natural products and drug molecules, and possess various biological activities such as anti-tumor, anti-inflammatory, and antibacterial effects.

[0003] (Eur. J. Med. Chem., 2015, 97, 483-504; Eur. J. Med. Chem., 2019, 162, 266-276; Curr. Top. Med. Chem., 2022, 22, 64-82).

[0004] In addition, 3-alkynylbenzofuran compounds are also important intermediates for the synthesis of high-value complex molecules with benzofuran skeletons (J.Org.Chem.,2010,75,1652-1658).

[0005] Tandem reactions provide an important method for the direct and efficient synthesis of complex molecules (Chem.Rev., 1996, 96, 195-206).

[0006] However, there are few reports on the synthesis of 3-alkynylbenzofuran compounds based on tandem reactions, and their application is not widespread at present, but they have great application potential and need to be studied in depth. Summary of the Invention

[0007] In view of this, this application provides a method for preparing a 3-ynylbenzofuran compound. The preparation steps are simple, and the obtained 3-ynylbenzofuran compound can simultaneously accommodate multiple functional groups, has good substrate compatibility, and has excellent applicability.

[0008] Specifically, this application is implemented through the following scheme:

[0009] A method for preparing a 3-ynylbenzofuran compound involves adding a palladium catalyst, a ligand, a base, 2-ynylphenol, and arylynyl bromide to an organic solvent, reacting the mixture at 60–80 °C for 22–26 hours, and then performing post-treatment to obtain the 3-ynylbenzofuran compound.

[0010] The structure of the 2-alkynylphenol is shown in formula (II):

[0011]

[0012] The structure of the aryl alkynyl bromide is shown in formula (III):

[0013]

[0014] The structure of the 3-alkynylbenzofuran compound is shown in formula (Ⅰ):

[0015]

[0016] R 1 The phenyl group is either substituted or unsubstituted, wherein the substituent on the substituted phenyl group is selected from any one of C1-C6 alkyl groups or halogens; R 2 The phenyl group is either substituted or unsubstituted, wherein the substituent on the substituted phenyl group is selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, or trifluoromethyl groups; R 3 The substituent is selected from C1-C6 alkyl, C1-C6 alkoxy, or halogenated phenyl groups.

[0017] The reaction equation for the above process is expressed as follows:

[0018]

[0019] The above scheme uses 2-alkynylphenol and arylalkynylbromo as starting materials. Palladium (0) undergoes oxidative addition with arylalkynylbromo to obtain arylalkynylpalladium (II)bromo. The arylalkynylpalladium (II)bromo then coordinates with the triple bond of 2-alkynylphenol, and the hydroxyl group of 2-alkynylphenol attacks the triple bond to generate an alkynylpalladium (II) intermediate. Finally, the alkynylpalladium (II) intermediate undergoes reductive elimination to obtain a 3-alkynylbenzofuran compound.

[0020] Furthermore, as a preferred option:

[0021] The molar ratio of 2-alkynylphenol, arylalkynyl bromide, palladium catalyst, ligand, and base is 1.0:1.4–1.6:0.1–0.2:0.1–0.2:2.0–3.0. During the preparation of the materials, the amount of organic solvent used should be sufficient to dissolve the raw materials well. Therefore, it is preferable to control the amount of organic solvent used for 0.2 mmol of 2-alkynylphenol to around 1.0 mL.

[0022] The organic solvent is any one of acetonitrile, toluene, and tetrahydrofuran, with acetonitrile being the most effective. In this case, all raw materials can be converted into products with a high conversion rate.

[0023] The palladium catalyst is palladium acetate, which has a relatively high reaction efficiency among many palladium catalysts.

[0024] The ligand is 1,1′-ferrocenediyl-bis(diphenylphosphine).

[0025] When palladium acetate is selected as the palladium catalyst and 1,1′-ferrocene di-bis(diphenylphosphine) is selected as the ligand, the molar ratio of palladium acetate to 1,1′-ferrocene di-bis(diphenylphosphine) is 0.1:0.1.

[0026] The alkali is either potassium carbonate or sodium carbonate.

[0027] The reaction time is 24–26 hours to ensure complete reaction.

[0028] The post-processing procedure is as follows: the reaction product is filtered, mixed with silica gel, and finally purified by column chromatography to obtain the corresponding 3-alkynylbenzofuran compound. The column chromatography purification parameters can be set using conventional methods.

[0029] The 3-alkynylbenzofuran compound is any one of the following structural formulas:

[0030]

[0031] In the above preparation methods, palladium acetate, 1,1′-ferrocene di-bis(diphenylphosphine) and potassium carbonate are generally commercially available products that can be easily obtained from the market. 2-Alynylphenol can be rapidly synthesized by coupling the corresponding 2-iodophenol with a terminal alkyne. Aryl alkynyl bromide can be rapidly synthesized by the corresponding aryl alkynyl and N-bromosuccinimide.

[0032] Compared with the prior art, the beneficial effects of the present invention are as follows: the preparation method is easy to operate and the post-processing is simple; the starting materials are inexpensive and readily available, the substrate functional groups have a wide tolerance range, the reaction efficiency is high, and 3-alkynylbenzofuran compounds can be synthesized in one step efficiently and rapidly, making it highly practical. Detailed Implementation

[0033] To make the technical problems, technical solutions, and beneficial effects to be solved by this application clearer, the technical solutions of this application will be further described in detail below with reference to specific examples in the embodiments of this application. It should be understood that the specific embodiments described herein are only used to explain this application and are not intended to limit the technical solutions of this application. Based on the embodiments in this application, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this application.

[0034] Example 1

[0035] Following the raw material ratios in Table 1, palladium acetate, 1,1′-ferrocene di-bis(diphenylphosphine), potassium carbonate, 2-alkynylphenol (II), arylalkynyl bromide (III), and 1.0 mL of organic solvent were added to a 15 mL Schlenk tube. The mixture was stirred thoroughly and reacted at 70 °C for 24 hours, as shown in Table 1. After the reaction was complete, the mixture was filtered, mixed with silica gel, and purified by column chromatography to obtain the corresponding 3-alkynylbenzofuran compound (I).

[0036] The reaction equation for the above process is expressed as follows:

[0037]

[0038] Table 1: Raw material addition amounts for different implementation schemes

[0039]

[0040]

[0041] Table 2: Comparison of the effects of different implementation schemes

[0042]

[0043] In Tables 1 and 2, T represents the reaction temperature, t represents the reaction time, Me represents methyl, and OMe represents methoxy. n Pr is n-propyl t Bu is tert-butyl, Ph is phenyl, MeCN is acetonitrile, and dppf is 1,1′-ferrocenediyl-bis(diphenylphosphine).

[0044] Meanwhile, the applicant also confirmed the structure of the products obtained from the above reactions, using Examples 1 to 5 as examples, and the detection results are as follows:

[0045] Nuclear magnetic resonance (NMR) of the 3-alkynylbenzofuran compound (I-1) prepared in Example 1 1 H NMR, 13 The 12C NMR and high-resolution (HRMS) detection data are as follows:

[0046]

[0047] 1 H NMR (400MHz, CDCl3) δ8.32(d,J=7.4Hz,2H),7.85(d,J=7.3Hz,1H),7.71(d,J=2.0Hz,1H),7.57 (d,J=8.8Hz,2H),7.51(t,J=7.6Hz,2H),7.45-7.42(m,2H),6.95(d,J=8.8Hz,2H),3.87(s,3H). 13 C NMR (101MHz, CDCl3) δ160.0,157.2,151.9,133.2,131.5,129.6,128.9,126.1,125.6,125.1, 124.5,120.2,115.2,114.3,112.3,100.9,99.2,97.3,79.1,55.5.HRMS(ESI-TOF)Calcd.for C 23 H 16 ClO2 +[M+H] + :359.0833; found:359.0837.

[0048] Nuclear magnetic resonance (NMR) of the 3-alkynylbenzofuran compound (I-2) prepared in Example 2 1 H NMR, 13 The 12C NMR and high-resolution (HRMS) detection data are as follows:

[0049]

[0050] 1 H NMR (400MHz, CDCl3) δ8.30(d,J=8.5Hz,2H),7.82(d,J=8.4Hz,2H),7.59(d,J=6.7Hz,1H),7.54(d,J=8.5Hz,1H) ,7.49(d,J=8.4Hz,2H),7.36-7.31(m,1H),7.30-7.27(m,1H),6.95(d,J=8.7Hz,2H),3.87(s,3H),1.37(s,9H). 13 C NMR (101MHz, CDCl3) δ159.8,154.9,153.5,133.1,125.8,124.8,124.0,123.3,122.9,120.8 ,120.3,114.2,111.2,100.7,98.9,96.6,79.8,55.4,34.9,31.3.HRMS(ESI-TOF)Calcd.for C 27 H 25 O2 + [M+H] + :381.1849; found:381.1843.

[0051] Example 3 shows the nuclear magnetic resonance (NMR) analysis of the 3-alkynylbenzofuran compound (I-3) prepared in this study. 1 H NMR, 13 The 12C NMR and high-resolution (HRMS) detection data are as follows:

[0052]

[0053] 1H NMR (400MHz, CDCl3) δ8.35(d,J=7.4Hz,2H),7.76(dd,J=6.9,1.9Hz,1H),7.58(d,J=8.7Hz,2H),7.55-7.52( m,1H),7.51(t,J=6.0Hz,2H),7.41(t,J=7.4Hz,1H),7.38-7.31(m,2H),6.95(d,J=8.8Hz,2H),3.86(s,3H). 13 C NMR (101MHz, CDCl3) δ159.9,156.0,153.6,133.2,130.4,130.1,129.2,128.8,126.1,125 .4,123.4,120.5,115.6,114.3,111.3,99.6,96.9,79.9,55.5.HRMS(ESI-TOF)Calcd.For C 23 H 17 O2 + [M+H] + :325.1223; found:325.1218.

[0054] Nuclear magnetic resonance (NMR) of the 3-alkynylbenzofuran compound (I-4) prepared in Example 4 1 H NMR, 13 The 12C NMR and high-resolution (HRMS) detection data are as follows:

[0055]

[0056] 1 H NMR (400MHz, CDCl3) δ8.32(d,J=7.4Hz,2H),7.75(d,J=7.0Hz,1H),7.54(d,J=2.7Hz,1H),7.52( t,J=5.0Hz,2H),7.44(d,J=7.4Hz,1H),7.41-7.35(m,3H),7.35-7.30(m,2H),7.13-7.07(m,1H). 13 C NMR (101MHz, CDCl3) δ156.8, 153.6, 130.1 (d, J = 9.0Hz), 129.8, 129.4, 128.8, 127.4 (d, J = 2.9Hz), 126.1, 124.5 (d, J=198.1Hz),120.3,118.3(d,J=22.8Hz),115.8(d,J=21.2Hz),111.3,98.8,95.5,82.2.HRMS(ESI-TOF)Calcd.forC22 H 14 FO + [M+H] + :313.1023; found:313.1027.

[0057] Nuclear magnetic resonance (NMR) of the 3-alkynylbenzofuran compound (I-5) prepared in Example 5 1 H NMR, 13 The 12C NMR and high-resolution (HRMS) detection data are as follows:

[0058]

[0059] 1 H NMR (400MHz, CDCl3) δ8.39(d,J=7.3Hz,2H),7.78(d,J=6.8Hz,1H),7.63(d,J=7.2Hz,1H),7.55(dd,J=7.1,2.1Hz,1H),7 .54-7.50(m,2H),7.45-7.41(m,1H),7.40-7.34(m,2H),7.31(dd,J=5.1,1.1Hz,2H),7.26(t,J=3.8Hz,1H),2.65(s,3H). 13 C NMR (101MHz, CDCl3) δ156.1,153.7,140.0,132.1,130.3,130.2,129.8,129.3,128.8,128.6,126 .2,125.9,125.5,123.5,123.3,120.4,111.4,99.6,96.0,85.1,21.2; HRMS(ESI-TOF)Calcd.for C 23 H 17 O + [M+H] + :309.1274; found:309.1270.

[0060] The above-described embodiments are merely illustrative of several feasible implementations of the present invention, and their descriptions are relatively specific and detailed. However, they should not be construed as limiting the scope of the present invention, nor are the embodiments intended to limit the scope of protection in the claims of the present invention. For those skilled in the art, various modifications and improvements can be made without departing from the concept of the present invention. All equivalent implementations or changes that do not depart from the present invention should be included in the present invention.

Claims

1. A method for preparing a 3-alkynylbenzofuran compound, characterized in that: Palladium catalyst, ligand, base, 2-alkynylphenol (II) and arylalkynyl bromide (III) were added to an organic solvent and reacted at 60-80°C for 22-26 hours. After post-treatment, 3-alkynylbenzofuran compound (I) was obtained. The reaction formula is expressed as follows: ； The molar ratio of 2-alkynylphenol, arylalkynyl bromide, palladium catalyst, ligand, and base is 1.0:1.4~1.6:0.1~0.2:0.1~0.2:2.0~3.

0. R 1 R 2 R 3 It is any one of the following: ， The palladium catalyst is palladium acetate, the ligand is 1,1′-ferrocene di-bis(diphenylphosphine), the base is either potassium carbonate or sodium carbonate, and the organic solvent is either acetonitrile, toluene, or tetrahydrofuran.

2. The method for preparing a 3-alkynylbenzofuran compound according to claim 1, characterized in that: The reaction time is 24-26 hours.

3. The method for preparing a 3-alkynylbenzofuran compound according to claim 1, characterized in that: The post-processing procedure is as follows: the reaction product is filtered, mixed with silica gel, and finally purified by column chromatography to obtain the corresponding 3-alkynylbenzofuran compound.

4. The method for preparing a 3-alkynylbenzofuran compound according to claim 1, characterized in that: The molar ratio of palladium acetate to 1,1′-ferrocene di-bis(diphenylphosphine) is 0.1:0.

1.

5. A method for preparing a 3-ynylbenzofuran compound according to any one of claims 1 to 4, characterized in that, The 3-alkynylbenzofuran compound is any one of the following structural formulas: 。

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