A method of electrochemically synthesizing 3-benzofuranmethanol and analogs thereof

Abstract

The application relates to the technical field of organic synthesis, in particular to a method for electrochemically synthesizing 3-benzofuran methanol and analogs thereof. An o-allyloxy phenyl diazonium salt is reacted in an electrolyte and a solvent under the condition of current to obtain 3-benzofuran methanol and analogs thereof. The preparation method of the application can construct a benzofuran molecular skeleton by using a free radical cyclization reaction under the condition of electric reduction without a catalyst, and can realize aromatization by electric oxidation, so that the two important conversion processes can occur only under the action of current, energy saving and economy are achieved; the free radical source used in the reaction is cheap and easy to obtain, and the cost is low; the reaction device is simple, and the operation is convenient; the product has high added value, and the reaction yield is as high as 85%.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for the electrochemical synthesis of 3-benzofuran methanol and its analogues. Background Technology

[0002] Benzofuran fragments are commonly found in natural products and drug molecules (see...) Figure 1 3-benzofuran-methanol (CAS No.: 4687-23-4), which is a heterocyclic skeleton of great interest in synthetic chemistry, is particularly noteworthy. In particular, the 3-benzofuran-methanol involved in this invention patent has a high market price (for example, at Anaiji Chemical Company, it costs 1645 yuan / gram). The most commonly used method in the literature for preparing 3-benzofuran-methanol is to reduce benzofuran-3-carboxaldehyde (CAS No.: 4687-25-6) with sodium borohydride (Reference: [reference missing]). Journal of Heterocyclic Chemistry (1978, 15(3), 481-483.). However, other substituted benzofuran-3-carboxaldehyde compounds remain expensive.

[0003] Clearly, designing a reaction to synthesize 3-benzofuran methanol and its analogues from inexpensive raw materials is a valuable and promising research endeavor, given the extremely high added value of the products. Summary of the Invention

[0004] To address the aforementioned technical problems, this invention provides a method for the electrochemical synthesis of 3-benzofuran methanol and its analogues. This preparation method utilizes readily available o-allyloxyaryl diazonium salts as reaction precursors under catalyst-free conditions to construct the benzofuran molecular skeleton during the reaction.

[0005] The present invention achieves its technical objective through the following scheme: a method for electrochemically synthesizing 3-benzofuran methanol and its analogues, comprising the following steps: reacting o-allyloxyphenyl diazonium salt in an electrolyte and a solvent under current conditions to obtain 3-benzofuran methanol and its analogues.

[0006] Furthermore, the structural formula of the o-allyloxyphenyl diazonium salt is shown below: Wherein, R is a hydrogen atom, an electron-withdrawing group, or an electron-donating group; Furthermore, the electron-withdrawing group is one of nitro, halogen atom, cyano, and acyl; the electron-donating group is one of phenyl, amino, alkyl, and alkoxy.

[0007] The o-allyloxyphenyl diazonium salt in this invention is a substituted o-allyloxyaryl diazonium salt. Under constant current and in the presence of an electrolyte, the substituted o-allyloxyaryl diazonium salt undergoes transformation in a solvent. During the reaction, the phenyl diazonium salt gains an electron at the cathode, generating a phenyl radical A. This radical A further undergoes intramolecular 5-exo-trig cyclization to generate a thermodynamically more stable alkyl radical B. Subsequently, radical B forms a carbocation intermediate C at the anode. C reacts with water molecules to give 3-benzofuran methanol (see [link to detailed reaction mechanism]). Figure 2 ).

[0008] Furthermore, R is substituted at any one or more of the 2, 3, 4, 5, and 6 positions on the benzene ring.

[0009] Further, the electrolyte is tetrabutylammonium tetrafluoroborate (n-Bu4BF4), tetrabutylammonium iodide (Bu4NI), tetrabutylammonium bromide (Bu4NBr), and tetraethylammonium perchlorate (Et4NClO4); the concentration of the electrolyte in the solvent is 0.05~1 mol / L; The solvent is water (H2O) or isopropanol. i At least one of PrOH and dimethyl sulfoxide (DMSO); The concentration of o-allyloxyphenyl diazonium salt in the solvent is 0.02~0.5 mol / L.

[0010] Furthermore, the electrolyte is tetrabutylammonium iodide, and its concentration in the solvent is 0.1 mol / L; The solvent is a mixture of dimethyl sulfoxide and water in a volume ratio of 3:1. Such a mixture is more suitable for the reaction in terms of solubility and conductivity.

[0011] Furthermore, the specific conditions for the reaction under the current-carrying condition are as follows: using graphite felt (GF) or platinum sheet (Pt) as the anode material, using platinum sheet as the cathode material, a constant current of 3~10 mA, a reaction temperature of 25~70 ℃, and a reaction time of 7~15 h.

[0012] Excessive reaction temperature, excessive current, or excessively low current will reduce the conversion rate of reactants. Too high a reaction temperature will cause unwanted side reactions such as free radical self-coupling reactions, which will reduce the product yield.

[0013] Furthermore, the specific reaction conditions under the current-current condition are as follows: using a platinum sheet as the anode material, using a platinum sheet as the cathode material, a constant current of 5 mA, a reaction temperature of 30 °C, a reaction time of 9 h, and a concentration of the reactant (o-allyloxyphenyl diazonium salt) in the reaction solution of 0.1 mol / L. Under these conditions, the product yield is the highest.

[0014] Furthermore, the reaction can be carried out without a catalyst under a nitrogen atmosphere, or in an open system. Protecting the reaction environment with an inert gas such as nitrogen can, to some extent, be more conducive to the conversion of the product.

[0015] As an example, when the structural formula of the o-allyloxyphenyl diazonium salt is as shown in (1), the present invention utilizes the reaction of the o-allyloxyphenyl diazonium salt with water molecules or alcohol molecules in the solvent in the electrolyte to generate 3-benzofuran methanol or 3-alkoxy-substituted benzofuran under the promotion of electricity. The reaction route is as follows: The present invention has the following beneficial effects: The reaction of this invention does not require the addition of transition metal catalysts, oxidants, or reductants; it can occur solely under the influence of an electric current (the gain and loss of electrons at the electrodes act as both reductants and oxidants), making it energy-efficient and economical. The reactants used in the reaction are easy to prepare and have low cost. The reaction apparatus is simple, easy to operate, and the reaction yield is as high as 85%. The 3-substituted benzofuran compounds prepared by this method are important organic chemical intermediates with extremely high added value, thus this invention has significant industrial transformation value. Attached Figure Description

[0016] The accompanying drawings, which form part of this invention, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an undue limitation of the invention. In the drawings: Figure 1 These are common benzofuran molecular fragments; Figure 2 This is a reaction mechanism diagram of Example 1 of the present invention; Figure 3 The product obtained in Example 1 1 HNMR spectrum; Figure 4 The product obtained in Example 1 13 CNMR spectrum; Figure 5 The product obtained in Example 2 1 HNMR spectrum; Figure 6 The product obtained in Example 2 13 CNMR spectrum; Figure 7 The product obtained in Example 3 1 HNMR spectrum; Figure 8 The product obtained in Example 3 13 CNMR spectrum; Figure 9 The product obtained in Example 41 HNMR spectrum; Figure 10 The product obtained in Example 4 13 CNMR spectrum. Detailed Implementation

[0017] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as a limitation of the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0018] It should be understood that the terminology used in this invention is merely for describing particular embodiments and is not intended to limit the invention. Furthermore, with respect to numerical ranges in this invention, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Any stated value or intermediate value within a stated range, as well as each smaller range between any other stated value or intermediate value within said range, is also included in this invention. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.

[0019] Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. While only preferred methods and materials have been described herein, any methods and materials similar or equivalent to those described herein may be used in the implementation or testing of this invention. All references to this specification are incorporated by way of citation to disclose and describe methods and / or materials associated with those references. In the event of any conflict with any incorporated reference, the content of this specification shall prevail.

[0020] Various modifications and variations can be made to the specific embodiments described in this specification without departing from the scope or spirit of the invention, as will be apparent to those skilled in the art. Other embodiments derived from this specification will also be apparent to those skilled in the art. This specification and embodiments are merely exemplary.

[0021] The terms “include,” “including,” “have,” “contain,” etc., used in this article are all open-ended terms, meaning that they include but are not limited to.

[0022] All raw materials used in this invention were obtained through purchase.

[0023] The purification process using silica gel column chromatography in this embodiment is a conventional technique in the field and is not the focus of this invention, so it will not be described in detail here.

[0024] All experimental operations in the embodiments of this invention that are not described in detail are conventional operating methods in the art.

[0025] In this embodiment of the invention, the English abbreviations have the following meanings: Bu4NI is tetrabutylammonium iodide; DMSO stands for dimethyl sulfoxide. CCE represents the current. PE is petroleum ether; EA stands for ethyl acrylate. Example 1 In a reaction tube, o-allyloxyphenyl diazonium salt 1a (75 mg, 0.3 mmol, 1.0 equiv.) and Bu4NI (238 mg, 0.9 mmol, 3.0 equiv.) were accurately added and dissolved in a mixed solvent DMSO / H2O (3:1, v / v, 4.0 mL). The anode was a platinum sheet electrode with dimensions of (10 mm × 15 mm × 0.25 mm), and the cathode was also a platinum sheet electrode with dimensions of (10 mm × 15 mm × 0.25 mm). The electrochemical reaction was carried out at 30 °C with a current maintained at 5.0 mA for 9 h. All solvent was transferred to a round-bottom flask. Silica was added to the flask, and the solvent was evaporated under vacuum. Purification was performed by silica gel column chromatography using PE / EA (v / v, petroleum ether / ethyl acrylate, 3:1) as the eluent to obtain the corresponding product 2a, with a mass of 37.5 mg and a yield of 85%. The reaction formula is as follows: The product 1 See the HNMR spectrum. Figure 3 , 13 See CNMR spectrum Figure 4 Product NMR data: 1 H MR (400 MHz, CDCl3) δ 7.68 (dd, J = 7.6, 1.2 Hz, 1H), 7.61 (s, 1H), 7.52 (dt, J = 8.0, 0.8 Hz,1H), 7.37–7.27 (m, 2H), 4.83 (d, J = 1.2 Hz, 2H); 13 C NMR (101 MHz, CDCl3) δ 155.7,142.4, 126.8, 124.7, 122.9, 120.5, 120.0, 111.7, 55.9. HR–MS (ESI) m / z calc.for C9H8O2[M+H] + : 149.0597, found: 149.0600. Example 2 In a reaction tube, o-allyloxyphenyl diazonium salt 1b (78 mg, 0.3 mmol, 1.0 equiv.) and Bu4NI (238 mg, 0.9 mmol, 3.0 equiv.) were accurately added and dissolved in a mixed solvent DMSO / H2O (3:1, v / v, 4.0 mL). The anode was a platinum sheet electrode with dimensions of (10 mm × 15 mm × 0.25 mm), and the cathode was also a platinum sheet electrode with dimensions of (10 mm × 15 mm × 0.25 mm). The electrochemical reaction was carried out at 30 °C with a current maintained at 5.0 mA for 9 h. All solvent was transferred to a round-bottom flask. Silica was added to the flask, and the solvent was evaporated under vacuum. Purification was performed by silica gel column chromatography using PE / EA (v / v, 3:1) as the eluent to obtain the corresponding product 2b, with a mass of 32 mg and a yield of 68%. The reaction formula is as follows: The product 1 See the HNMR spectrum. Figure 5 , 13 See CNMR spectrum Figure 6 Product NMR data: 1 H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 7.6 Hz, 2H), 7.32–7.32(m, 1H), 7.12 (dd, J = 7.6, 2.0 Hz, 1H), 4.84 (d, J = 1.2 Hz, 2H), 2.50 (s, 3H); 13 C NMR (101 MHz, CDCl3) δ 156.2,141.9, 135.1, 124.3, 124.3, 120.4, 119.5, 111.9, 56.2, 21.8. HR–MS (ESI) m / zcalc. for C 10 H 10 O2[M+H] + : 163.0754, found: 163.0750. Example 3 In a reaction tube, accurately add o-allyloxyphenyl diazonium salt 1a (75 mg, 0.3 mmol, 1.0 equiv.) and Bu4NI (238 mg, 0.9 mmol, 3.0 equiv.), dissolved in a mixed solvent of dimethyl sulfoxide (DMSO) / isopropanol (...). i -PrOH) (3:1, v / v, 4.0 mL). The anode was a platinum sheet electrode with dimensions of (10 mm × 15 mm × 0.25 mm), and the cathode was a platinum sheet electrode with dimensions of (10 mm × 15 mm × 0.25 mm). The electrochemical reaction was carried out at 30 °C with a current maintained at 5.0 mA for 9 h. All solvent was transferred to a round-bottom flask. Silica was added to the flask, and the solvent was evaporated under vacuum. Purification was performed by silica gel column chromatography using PE / EA (v / v, 3:1) as the eluent to obtain the corresponding product 2c, with a mass of 23.4 mg and a yield of 41%. The reaction formula is as follows: The product 1 See the HNMR spectrum. Figure 7 , 13 See CNMR spectrum Figure 8 Product NMR data: 1 H NMR (400 MHz, CDCl3) δ 7.74 (s, 1H), 7.70 (dd, J = 8.0, 2.4 Hz, 1H), 7.52 (dd, J = 8.0, 1.6 Hz,1H), 7.37–7.31 (m, 2H), 5.33 (d, J = 1.2 Hz, 2H), 4.95–4.89 (m, 1H), 1.32 (s, 3H), 1.31 (s, 3H); 13 C NMR (101 MHz, CDCl3) δ 155.6, 144.6, 126.7, 124.9, 123.2,120.0, 115.7, 111.8, 59.8, 29.9, 21.9. HR–MS (ESI) m / z calc. for C 12 H 14 O2[M+Na] + : 213.0886, found: 213.0891. Example 4 In a reaction tube, o-allyloxyphenyl diazonium salt 1c (98.1 mg, 0.3 mmol, 1.0 equiv.) and Bu4NI (238 mg, 0.9 mmol, 3.0 equiv.) were accurately added and dissolved in a mixed solvent of dimethyl sulfoxide (DMSO) / H2O (3:1, v / v, 4.0 mL). A platinum sheet electrode (10 mm × 15 mm × 0.25 mm) was used as both the anode and cathode. The electrochemical reaction was carried out at 30 °C with a current maintained at 5.0 mA for 9 h. All solvent was transferred to a round-bottom flask. Silica was added to the flask, and the solvent was evaporated under vacuum. Purification was performed using silica gel column chromatography with PE / EA (v / v, 3:1) as the eluent to obtain product 2d, with a mass of 28.2 mg, in a yield of 42%. The reaction formula is as follows: The product 1 See the HNMR spectrum. Figure 9 , 13 See CNMR spectrum Figure 10 Product NMR data: 1 H NMR (400MHz, CDCl3) δ 7.83 (d, J = 2.0 Hz, 1H), 7.62 (s, 1H), 7.43 (dd, J = 8.8, 2.0 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 4.82 (d, J = 1.2 Hz, 2H); 13 C NMR (101 MHz, CDCl3) δ 154.5, 143.6, 128.9, 127.7, 123.0, 120.2, 116.1, 113.2, 55.9. HR–MS (ESI) m / zcalc. for C9H7BrO2[M+H] + : 226.9702, found: 226.9708. The parameter optimization process and yield of the electrochemical synthesis of 3-benzofuran methanol and its analogues are shown in Table 1.

[0026] Table 1 Note: In Table 1, [a] indicates the product yield: Undivided cell, platinum anode, platinum cathode, constant current = 5.0 mA, 1 (0.30 mmol), product 3 (1.5 mmol, 5.0 equiv), solvent (4.0 mL), in air, 9 h. [b] CCE = 4 mA. [c] CCE = 6 mA. [d] N2 instead of air; NR indicates product not detected; trace indicates trace product.

[0027] The above are merely preferred embodiments of the present invention, but the scope of protection of the present invention is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the scope of the technology disclosed in the present invention should be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the scope of the claims.

Claims

1. A method for electrochemically synthesizing compound of formula 2, characterized in that, Includes the following steps: adjacent Allyloxyphenyl diazonium salt was reacted in an electrolyte and solvent under an electric current to give compound of formula 2; The structural formula of the o-allyloxyphenyl diazonium salt is shown below: ; The structure of the compound of formula 2 is as follows: ; Where R' is H or isopropyl, and R is a hydrogen atom, an electron-withdrawing group or an electron-donating group; The electrolyte is tetrabutylammonium iodide; the concentration of the electrolyte in the solvent is 0.05~1 mol / L; The solvent is at least one of water, isopropanol and dimethyl sulfoxide, and the solvent is not water alone, isopropanol alone, or dimethyl sulfoxide alone. The concentration of o-allyloxyphenyl diazonium salt in the solvent is 0.02~0.5 mol / L.

2. The method for electrochemical synthesis of compound 2 according to claim 1, characterized in that, The electron-withdrawing group is one of nitro, halogen atom, cyano, and acyl; the electron-donating group is one of phenyl, amino, alkyl, and alkoxy.

3. The method for electrochemical synthesis of compound 2 according to claim 1, characterized in that, The substitution position of R is any one or more of the 3, 4, 5 and 6 positions of the benzene ring.

4. The method for electrochemical synthesis of compound 2 according to claim 1, characterized in that, The concentration of the electrolyte in the solvent is 0.1 mol / L; The solvent is a mixture of dimethyl sulfoxide and water in a volume ratio of 3:

1.

5. The method for electrochemical synthesis of compound 2 according to claim 1, characterized in that, The specific conditions for the reaction under the current-carrying condition are as follows: using a platinum sheet or graphite felt as the anode material, a platinum sheet as the cathode material, a constant current of 3~10 mA, a reaction temperature of 25~70 ℃, and a reaction time of 7~15 h.

6. The method for electrochemical synthesis of compound 2 according to claim 5, characterized in that, The specific conditions for the reaction under the current-carrying condition are as follows: using a platinum sheet as the anode material, using a platinum sheet as the cathode material, using a constant current of 5 mA, using a reaction temperature of 30 °C, and using a reaction time of 9 h.

7. The method for electrochemical synthesis of compound 2 according to claim 1, characterized in that, The reaction was carried out without a catalyst under a nitrogen atmosphere.

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