A method for synthesizing 3-methylbenzofuran structure compounds using calcium carbide as an alkynyl source

Abstract

The invention discloses a method for synthesizing a 3-methylbenzofuran skeleton structure compound, using a series of substituted 2-(2-bromophenoxy)-1-phenylethane-1-ketone compounds and calcium carbide as raw materials, metal palladium and metal copper as catalysts, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), toluene (Tolune), dichloromethane (DCM) as solvents, potassium carbonate and potassium phosphate as alkalis, water as additives, reacting for 4 to 12 hours under 80 to 160 ° C, and synthesizing a series of 3-methylbenzofuran compounds. The present invention utilizes calcium carbide as a green alkynyl source to replace traditional alkyne derivatives to synthesize 3-methylbenzofuran structure compounds, fully demonstrating the concept of green chemistry, greatly shortening the route of traditionally synthesizing 3-methylbenzofuran derivative-related drugs, and the synthesis method is concise and effective, with a good yield, and meets the requirements of atom economy.

Description

Technical Field

[0001] The invention relates to a method for synthesizing a 3-methylbenzofuran structure compound by using calcium carbide as an alkynyl source. Technical Background

[0002] Benzofuran derivatives are an extremely important class of heterocyclic compounds in organic chemistry. They are widely present in nature and are a class of compounds with good pharmaceutical and biological activities. In particular, 2-methylbenzofuran compounds can be used as glucokinase activators, thrombin inhibitors, etc., and are an indispensable class of drugs for humans today.

[0003] In recent years, the synthesis methods of benzofuran compounds have been widely reported, but 2-methylbenzofuran compounds have been rarely reported. The only reports used alkyne compounds, which have high production costs, high commercial prices, and are difficult to store. Therefore, it is still necessary to explore a new, low-cost method for preparing 2-methylbenzofuran compounds. For example, the invention patent with the authorization announcement number CN105646414B discloses a method for synthesizing 6-hydroxy-2-methylbenzofuran compounds, which uses resorcinol compounds as starting materials, and sequentially undergoes Friedel-Crafts reaction, ring closure, and reduction to obtain a target product. For example, the invention patent with the authorization announcement number CN110590722B discloses a method for synthesizing 2-trifluoromethylbenzofuran derivatives. The present invention relates to a method for synthesizing 2-trifluoromethylbenzofuran derivatives, comprising the following steps: using 1-bromo-2-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)benzene as a reaction substrate, potassium hydroxide as an oxygen source, potassium phosphate as a base, cuprous iodide as a catalyst, 1,10-phenanthroline as a ligand, and dimethyl sulfoxide as a solvent, stirring the reaction at 80-100°C under nitrogen conditions for 10-12 hours to obtain a product.

[0004] However, there is no report on the efficient and low-cost synthesis of 2-methylbenzofuran structure compounds. With the development of green chemistry, calcium carbide has entered people's field of vision as a cheap green alkyne source. Calcium carbide is not only easy to store and easy to operate, but also can solve the problems of high production cost and high market price of alkyne compounds. Summary of the invention

[0005] In view of the shortcomings of the prior art, the object of the present invention is to provide a method for synthesizing 3-methylbenzofuran structure compounds using calcium carbide as an alkynyl source.

[0006] The technical solution of the present invention is summarized as follows:

[0007] A method for synthesizing a 3-methylbenzofuran structure compound using calcium carbide as an alkynyl source comprises the following steps:

[0008]

[0009] S1: Add 2-(2-bromophenoxy)-1-phenylethane-1-one compound A, calcium carbide, catalyst and base into a Xulink reaction bottle in sequence, then quickly add distilled water and organic solvent mixed into the system, seal it and place it in a metal bath at 80-160°C to react for 4-12 hours;

[0010] S2: After the reaction is cooled, 2-3 mL of water is added to quench the excess calcium carbide; the reaction solution is then filtered with diatomaceous earth, the mother liquor is washed with ethyl acetate 2-3 times, dried over anhydrous sodium sulfate, and vacuum distilled, mixed, and separated with a silica gel column to obtain a white solid or colorless oily liquid 3-methylbenzofuran structure compound B.

[0011] Preferably, the calcium carbide is a solid alkynyl source.

[0012] Preferably, the catalyst is a metal palladium catalyst or a metal copper catalyst, including copper acetate, palladium acetate, etc.

[0013] Preferably, the organic solvent includes one or more of dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), toluene, and dichloromethane (DCM).

[0014] Preferably, the organic solvent is tetrahydrofuran (THF).

[0015] Preferably, the water is an additive.

[0016] Preferably, the reaction temperature is 120°C.

[0017] Preferably, the reaction time is 6 to 8 hours.

[0018] Beneficial effects of the present invention:

[0019] 1. Make full use of calcium carbide, a resource in Ningxia, as a green alkynyl source to synthesize 3-methylbenzofuran structure compounds. Calcium carbide is used as a solid alkynyl source to replace traditional alkyne derivatives, making the reaction system more green, environmentally friendly and safe, and the solid calcium carbide raw material is easy to transport. The entire reaction conditions are mild and the cost is relatively low.

[0020] 2. The use of water as an additive in this reaction system fully demonstrates the concept of green chemistry. A new synthesis route for 3-methylbenzofuran derivatives has been developed, which greatly shortens the traditional route for synthesizing 3-methylbenzofuran derivative-related drugs. The synthesis method is simple and effective, meeting the requirements of atom economy. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 The invention provides a method for synthesizing a 3-methylbenzofuran structure compound, wherein R1 is selected from Me, OMe, Cl, Br, I and the like; and R2 is selected from Me, OMe, Cl, Br, I and the like. DETAILED DESCRIPTION

[0022] The present invention is further described in detail below in conjunction with embodiments so that those skilled in the art can implement the invention with reference to the description.

[0023] The method for synthesizing the 3-methylbenzofuran structure compound of this embodiment comprises the following steps:

[0024]

[0025] S1: Add 2-(2-bromophenoxy)-1-phenylethane-1-one compound A, calcium carbide, catalyst and base into a Xulink reaction bottle in sequence, then quickly add distilled water and organic solvent mixed into the system, seal it and place it in a metal bath at 80-160°C to react for 4-12 hours;

[0026] S2: After the reaction is cooled, 2-3 mL of water is added to quench the excess calcium carbide; the reaction solution is then filtered with diatomaceous earth, the mother liquor is washed with ethyl acetate 2-3 times, dried over anhydrous sodium sulfate, and vacuum distilled, mixed, and separated with a silica gel column to obtain a white solid or colorless oily liquid 3-methylbenzofuran structure compound B.

[0027] The organic solvent includes one or more of dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), toluene (Tolune), and dichloromethane (DCM), preferably tetrahydrofuran (THF); the reaction temperature is preferably 120° C.; and the reaction time is preferably 6 to 8 hours.

[0028] Example 1

[0029] Synthesis of (3-methylbenzofuran-2-yl)(phenyl)methanone

[0030]

[0031] S1: Weigh 100 mg of compound A, 88 mg of calcium carbide, 9 mg of palladium acetate, and 146 mg of potassium phosphate, and add them into a 25 mL Xulink reaction bottle in sequence. Mix 186 mg of distilled water with 1 mL of tetrahydrofuran and quickly add them into the system. After sealing, place the mixture in a 120°C metal bath and heat for 8 hours. TLC detection shows that the reaction is complete (PE:EA=20:1), and the raw material point disappears;

[0032] S2: After the reaction is cooled, open the bottle cap and add 2-3 mL of water to quench the excess calcium carbide; then filter the reaction solution with diatomaceous earth, wash the mother liquor with ethyl acetate three times, dry with anhydrous sodium sulfate, perform reduced pressure distillation, mix the sample, and separate on a silica gel column (PE:EA=30:1) to obtain 97 mg of a white solid (3-methylbenzofuran-2-yl)(phenyl)ketone, with a yield of 82%, mp=201-204°C.

[0033] 1 H NMR (400MHz, CDCl3) δ8.11-8.09 (dd, J=8, 0.8Hz, 2H), 7.71-7.69 (dd, J=8, 0.8 Hz,1H),7.63-7.59(m,1H),7.55-7.47(m,4H),7.36-7.32(m,1H),2.65(s,3H); 13 C NMR (150MHz, CDCl3) δ185.9,154.3,148.4,137.9,132.6,129.8,129.3.2,128.3,128.2,126.9,123.3,121.5,112.2,10.0ppm; HRMS (ESI): m / z (M+H) + Calculate for C 16 H 12 O2:237.0905;Found:237.0906.

[0034] Example 2

[0035] Synthesis of [1,1'-biphenyl]-4-yl(3-methylbenzofuran-2-yl)methanone

[0036]

[0037] The reaction conditions were the same as those in Example 1 to obtain 134 mg of the title compound as a colorless oily liquid with a yield of 86%.

[0038] 1 H NMR (400MHz, CDCl3) δ8.22-8.20 (dd, J=8, 0.8Hz, 2H), 7.77-7.75 (m, 2H), 7.73-7.71 (dd, J=8, 0.8Hz, 1H), 7.70-7. 68(m,2H),7.58-7.56(dd,J=8,0.8Hz,1H),7.53-7.48(m,3H),7.44-7.40(m,1H),7.38-7.34(m,1H),2.69(s,3H); 13C NMR (150MHz, CDCl3) δ185.4,154.3,148.5,145.4,140.1,136.6,130.4,129.3,129. 9,128.2,127.4,127.0,126.9,123.64,121.5,112.2,10.0ppm; HRMS(ESI):m / z(M+H) + Calculate for C 22 H 16 O2:313.1223;Found:313.1215.

[0039] Example 3

[0040] Synthesis of (3-methoxyphenyl)(3-methylbenzofuran-2-yl)methanone

[0041]

[0042] The reaction conditions were the same as those in Example 1 to obtain 101 mg of the title compound as a white solid. The yield was 76%, mp = 232-235°C.

[0043] 1 H NMR (400MHz, CDCl3) δ8.07-8.05 (dd, J=8, 0.8Hz, 2H), 7.59-7.49 (m, 4H), 7.00-63.95 (m, 2H), 3.87 (s, 3H), 2.61 (s, 3H) 13 C NMR (150MHz, CDCl3) δ185.3,161.2,155.8,148.2,138.2,132.3,129.6,128.2,127.7,122.7,121.8,113.7,95.4,55.7,10.2ppm; HRMS (ESI): m / z (M+H) + Calculate for C 17 H 14 O3:267.1015;Found:267.1005.

[0044] Example 4

[0045] Synthesis of (4-fluorophenyl)(3-methylbenzofuran-2-yl)methanone

[0046]

[0047] The reaction conditions were the same as those in Example 1 to obtain 93 mg of the title compound as a colorless oily liquid with a yield of 73%.

[0048] 1H NMR (400MHz, CDCl3) δ8.11-8.07 (m, 2H), 7.64-7.62 (dd, J = 8, 0.8Hz, 1H), 7.47-7.40 (m,2H),7.29-7.25(t,J=8,0.8Hz,1H),7.14-7.10(t,J=8,0.8Hz,1H),2.58(s,3H); 13 C NMR (150MHz, CDCl3) δ184.2,166.8,164.2,154.3,148.2,134.1,134.0,132.5,132.4,1 29.2,128.3,127.2,123.4,121.5,115.6,115.4,112.2,10.0ppm; HRMS(ESI):m / z(M+H) + Calculate for C 16 H 11 FO2:255.0815; Found:255.0812.

[0049] Example 5

[0050] Synthesis of (3-methylbenzofuran-2-yl)(p-tolyl)methanone

[0051]

[0052] The reaction conditions were the same as those in Example 1 to obtain 111 mg of the title compound as a white solid. The yield was 89%, and the mp was 222-224°C.

[0053] 1 H NMR (400MHz, CDCl3) δ8.04-8.02 (dd, J=8, 0.8Hz, 2H), 7.70-7.69 (dd, J=8, 0.8Hz, 1H), 7.55-7.53 (dd, J= 8,0.8Hz,1H),7.50-7.46(t,J=8,0.8Hz,1H),7.35-7.32(dd,J=8,0.8Hz,3H),2.64(s,3H),2.46(s,3H). 13 C NMR (150MHz, CDCl3) δ185.6,154.2,148.5,143.4,135.3,129.4,129.3,129.1,128.0,126.4,123.3,121.4,112.2,21.7,10.0ppm; HRMS (ESI): m / z (M+H) + Calculate for C 17 H 14O2:251.1066;Found:251.1023.

[0054] Example 6

[0055] Synthesis of (3,5-dimethylbenzofuran-2-yl)(phenyl)methanone

[0056]

[0057] The reaction conditions were the same as those in Example 1 to obtain 114 mg of the title compound as a white solid with a yield of 92% and mp = 216-221°C.

[0058] 1 H NMR (400MHz, CDCl3) δ8.09-8.07 (dd, J=8, 0.8Hz, 2H), 7.62-7.58 (m, 1H), 7.54-7.50 (t, J=8, 0.8Hz, 2H), 7.47(s,1H),7.42-7.40(dd,J=8,0.8Hz,1H),7.31-7.29(dd,J=8,0.8Hz,1H),2.60(s,3H),2.49(s,3H). 13 C NMR (150MHz, CDCl3) δ185.9,152.8,148.4,137.9,132.9,129.8,129.7,129.2,128.2,126.7,120.9,111.7,21.3,10.0ppm; HRMS (ESI): m / z (M+H) + Calculate for C 17 H 14 O2:251.1065;Found:251.1062.

[0059] Example 7

[0060] Synthesis of (5-chloro-3-methylbenzofuran-2-yl)(phenyl)methanone

[0061]

[0062] The reaction conditions were the same as those in Example 1 to obtain 116 mg of the title compound as a white solid. The yield was 86%, mp = 253-255°C.

[0063] 1 H NMR (400MHz, CDCl3) δ8.08-8.06 (dd, J=8, 0.8Hz, 2H), 7.67-7.58 (m, 2H), 7.55-7.51 (t, J=8, 0.8Hz, 2H), 7.48-7.40 (m, 2H), 2.60 (s, 3H).13 C NMR (150MHz, CDCl3) δ185.8,154.5,149.3,137.5,132.9,130.5,129.7,129.1,128.5,128.4,126.0,120.9,113.4,9.9ppm; HRMS (ESI): m / z (M+H) + Calculate for C 16 H 11 ClO2:271.0520; Found:271.0516.

[0064] Example 8

[0065] Synthesis of (3,6-dimethylbenzofuran-2-yl)(phenyl)methanone

[0066]

[0067] The reaction conditions were the same as those in Example 1 to obtain 94 mg of the title compound as a white solid. The yield was 75%, and the mp was 216-218°C.

[0068] 1 H NMR (400MHz, CDCl3) δ8.08-8.06 (dd, J=8, 0.8Hz, 2H), 7.60-7.56 (m, 2H), 7.53-7.50 (t, J=8,0.8Hz,2H),7.34(s,1H),7.17-7.15(dd,J=8,0.8Hz,1H),2.62(s,3H),2.51(s,3H). 13 C NMR (150MHz, CDCl3) δ139.1,137.98,132.4,129.6,128.4,127.2,126.7,125.0,120.9,112.2,22.1,10.2ppm; HRMS (ESI): m / z (M+H) + Calculate for C 15 H 10 ClNO:251.1066; Found:251.1061.

[0069] Example 9

[0070] Synthesis of (6-methoxy-3-methylbenzofuran-2-yl)(phenyl)methanone

[0071]

[0072] The reaction conditions were the same as those in Example 1 to obtain 90 mg of the title compound as a white solid with a yield of 68% and mp = 76-80°C.

[0073] 1 H NMR (400MHz, CDCl3) δ8.05 (dd, J=8, 0.8Hz, 2H), 7.66-7.49 (m, 4H), 7.01-6.96 (t, J=8, 0.8Hz, 2H), 3.88 (s, 3H), 2.61 (s, 3H). 13 C NMR (150MHz, CDCl3) δ185.5,161.2,155.8,148.1,138.1,132.4,129.6,128.3,127.9,122.7,121.9,113.8,95.3,55.8,10.3ppm; HRMS (ESI): m / z (M+H) + calcd for C17H14O3:267.1015; Found:267.1011.

[0074] Example 10

[0075] Synthesis of (3-methyl-5-(trifluoromethyl)benzofuran-2-yl)(phenyl)methanone

[0076]

[0077] The reaction conditions were the same as those in Example 1 to obtain 115 mg of the title compound as a colorless oily liquid with a yield of 76%.

[0078] 1 H NMR (400MHz, CDCl3) δ8.19 (dd, J=8, 0.8Hz, 2H), 7.80-7.72 (m, 3H), 7.53 (s, 2H), 7.36 (s, 2H), 2.69 (s, 3H). 13 C NMR (150MHz, CDCl3) δ154.4,147.8,140.7,130.0,129.0,128.8,125.4,125.3,123.6,121.7,112.3,10.2ppm; HRMS (ESI): m / z (M+H) + Calculate for C 17 H 11 F3O2:305.0783; Found:305.0780.

[0079] Although the embodiments of the present invention have been disclosed as above, they are not limited to the applications listed in the specification and the implementation modes. They can be fully applied to various fields suitable for the present invention. For those familiar with the art, additional modifications can be easily implemented. Therefore, without departing from the general concept defined by the claims and the scope of equivalents, the present invention is not limited to specific details.

Claims

1. A method for synthesizing compound B using calcium carbide as an alkynyl source, characterized in that: The following steps are involved: S1: Add 2-(2-bromophenoxy)-1-phenylethane-1-one compound A, calcium carbide, palladium acetate, Xantphos, and potassium phosphate into a Xulink reaction bottle in sequence, then quickly add a mixture of distilled water and tetrahydrofuran into the system, seal it, and place it in a metal bath at 80-160°C to react for 4-12 hours; S2: After the reaction is cooled, 2-3 mL of water is added to quench the excess calcium carbide; the reaction solution is then filtered through diatomaceous earth, the mother liquor is washed with ethyl acetate 2-3 times, dried over anhydrous sodium sulfate, and vacuum distilled, mixed, and separated by silica gel column to obtain a white solid or colorless oily liquid compound B; The chemical reaction formula is as follows: The R1 and R2 are each independently Me, OMe, Cl, Br, or I.

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