A method for the synthesis of 1,4-diarylbut-1-ene-3-yne

Abstract

The application belongs to the field of organic synthesis, and particularly relates to a synthesis method of 1,4-diarylbut-1-ene-3-yne. Allylbenzene compounds shown in formula 1 and methyl benzoate compounds shown in formula 2 are mixed with organic solvents (toluene or tetrahydrofuran) in the presence of strong base (lithium bis(trimethylsilyl)amide), cesium salt additive (cesium fluoride), amidine additive (DBU) and activating agent (Nf-F), and then reacted to synthesize 1,4-diarylbut-1-ene-3-yne shown in formula 3. The raw materials used in the application are simple and easy to obtain, a one-pot synthesis method of 1,4-diarylbut-1-ene-3-yne is constructed, and the application has the advantages of simple synthesis method, economy, environmental protection and wide application range.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of organic synthesis, and particularly relates to a synthesis method of 1,4-diarylbut-1-ene-3-yne. BACKGROUND

[0002] Enynes as a basic part of organic synthesis have a wide range of applications in chemistry, and 1,4-diarylbut-1-ene-3-yne has wide practical applicability in pharmaceuticals, materials and lighting applications. The method for synthesizing enynes with extended carbon skeletons is harsh. The further derivatization of enynes also mainly depends on the Sonogashira coupling. This cross-coupling method is very effective, but requires the use of expensive Pd catalysts, phosphine ligands and toxic copper co-catalysts, and generates heavy metal waste and other problems. Therefore, it is necessary to continuously explore various more economically beneficial synthesis routes for enyne derivatives. SUMMARY

[0003] The present application provides a one-pot synthesis of 1,4-diarylbut-1-ene-3-yne from allylbenzene and methyl benzoate, which is expected to simplify the synthesis of enynes, reduce the production cost of these valuable building blocks, and increase the sustainability of enyne synthesis, thereby complementing the most advanced technology. The specific scheme is as follows:

[0004]

[0005] A synthesis method of 1,4-diarylbut-1-ene-3-yne compound, which adopts allylbenzene compound shown in formula 1 and methyl benzoate compound shown in formula 2 in the presence of strong base, cesium salt additive, and organic solvent mixture to react and synthesize 1,4-diarylbut-1-ene-3-yne shown in formula 3;

[0006] Wherein R is selected from methyl, n-butyl, aryl, halogen, etc.

[0007] The method of the present application can realize one-pot synthesis of 1,4-diarylbut-1-ene-3-yne compound, reduce the reaction steps, and thus improve the yield of the product; the raw materials used in the synthesis method are simple and economical; R in the present application can be selected from a variety of options, and the applicability is wider.

[0008] Preferably, R is selected from methyl, n-butyl, aryl, halogen, etc.

[0009] Preferably, the reaction is carried out under inert gas protection, and preferably the inert gas is nitrogen.

[0010] Preferably, the synthesis occurs in the presence of strong base, cesium salt additive, amidine additive and organic solvent.

[0011] Preferably, the strong base is lithium bis(trimethylsilyl)amide; the cesium salt additive is cesium fluoride; and the amidine additive is DBU.

[0012] Preferably, the reaction is carried out in the presence of an activating agent, and preferably the activating agent is Nf-F.

[0013] Preferably, the organic solvent is tetrahydrofuran or toluene.

[0014] Preferably, the molar ratio of the allylbenzene derivative of formula 1, the methyl benzoate of formula 2 and the catalyst in the reaction is 2-4:1-3:2-5, and the reaction temperature is 50-130 DEG C.

[0015] Preferably, the method of the present application can be used to synthesize 1,4-diarylbut-1-ene-3-yne with the following structure:

[0016]

[0017] The method of the present application can be used to synthesize 1,4-diarylbut-1-ene-3-yne by reacting allylbenzene and methyl benzoate in the presence of a strong base (lithium bis(trimethylsilyl)amide) and a cesium salt additive (cesium fluoride) and in an organic solvent (toluene).

[0018] The method of the present application can achieve at least one of the following beneficial effects:

[0019] The raw materials used in the method of the present application are inexpensive and readily available.

[0020] The method of the present application does not use a transition metal catalyst, and is environmentally friendly.

[0021] The one-pot synthesis method of the present application has fewer reaction steps, reduces the loss of raw materials, and improves the yield of the product.

[0022] The method of the present application requires relatively simple operation steps, does not require extreme heating or cooling, and can be reacted at normal pressure, which is safe and convenient.

[0023] The R in the present application can be selected in a variety of ways, and therefore the method of the present application is more widely applicable and can be used to synthesize a variety of 1,4-diarylbut-1-ene-3-yne compounds. BRIEF DESCRIPTION OF DRAWINGS

[0024] Figure 1A Figure 2 is a hydrogen spectrum of the product obtained in Example 1, Figure 1B Figure 3 is a carbon spectrum of the product obtained in Example 1;

[0025] Figure 2A Figure 5 is a hydrogen spectrum of the product obtained in Example 2, Figure 2BThe carbon spectrum nuclear magnetic resonance spectrum of the product obtained in Example 2;

[0026] Figure 3A The hydrogen spectrum nuclear magnetic resonance spectrum of the product obtained in Example 3, Figure 3B The carbon spectrum nuclear magnetic resonance spectrum of the product obtained in Example 3;

[0027] Figure 4A The hydrogen spectrum nuclear magnetic resonance spectrum of the product obtained in Example 4, Figure 4B The carbon spectrum nuclear magnetic resonance spectrum of the product obtained in Example 4;

[0028] Figure 5A The hydrogen spectrum nuclear magnetic resonance spectrum of the product obtained in Example 5, Figure 5B The carbon spectrum nuclear magnetic resonance spectrum of the product obtained in Example 5;

[0029] Figure 6A The hydrogen spectrum nuclear magnetic resonance spectrum of the product obtained in Example 6, Figure 6B The carbon spectrum nuclear magnetic resonance spectrum of the product obtained in Example 6;

[0030] Figure 7A The hydrogen spectrum nuclear magnetic resonance spectrum of the product obtained in Example 7, Figure 7B The carbon spectrum nuclear magnetic resonance spectrum of the product obtained in Example 7:

[0031] Figure 8A The hydrogen spectrum nuclear magnetic resonance spectrum of the product obtained in Example 8, Figure 8B The carbon spectrum nuclear magnetic resonance spectrum of the product obtained in Example 8;

[0032] Figure 9A The hydrogen spectrum nuclear magnetic resonance spectrum of the product obtained in Example 9, Figure 9B The carbon spectrum nuclear magnetic resonance spectrum of the product obtained in Example 9. Specific embodiments

[0033] In order to facilitate the understanding of those skilled in the art, the concept of the present application is further illustrated below in conjunction with examples. The specific description of the following examples is not a limitation of the present application, but is only for the convenience of those skilled in the art to understand the technical solution. The various raw materials involved in the specification are purchased from the market or synthesized simply, and other drugs are purchased from Anjie, Bide, Sigma-Aldrich, Acros, Alfa Aesar, Adamas-beta or J&K. The nuclear magnetic resonance spectrometer is Bruker 400M and JEOL 400M of Japan.

[0034] Example 1

[0035] In a glove box filled with nitrogen, a dry microwave tube with a magnet was charged with LiN(SiMe3)2(50.2 mg, 0.3 mmol), CsF (30.4 mg, 0.2 mmol), tetrahydrofuran (0.6 mL) sequentially, and reacted at 110 °C for 4 h. Then cooled to 50 °C, methyl benzoate (12.5 μL, 0.1 mmol, 1 equiv) was added and stirred for 4 h, cooled to 0 °C, Nf-F (1.6 equiv) and DBU (1 equiv) were added, stirred at 0 °C for 30 min, then warmed to 50 °C for 6 h, 130 °C for 6 h, cooled to room temperature, and the reaction was completed. The crude product was purified by silica gel column flash chromatography to obtain the product (86% yield). 1 H NMR (400 MHz, CDC13) δ 7.51-7.46 (m, 2H), 7.45-7.41 (m, 2H), 7.40-7.27 (m, 6H), 7.06 (d, J = 16.3 Hz, 1H), 6.40 (d, J = 16.2 Hz, 1H). 13 C{ 1 H} NMR (101 MHz, CDC13) 141.4, 136.4, 131.7, 128.9, 128.8, 128.5, 128.3, 126.4, 123.5, 108.2, 91.9, 89.0 ppm.

[0036] The starting materials in Example 1 were changed, and the following 8 groups of experimental examples were designed, in which the first group of experiments was Example 1, and the nuclear magnetic resonance spectrum of the corresponding product was Figure 1. The serial numbers of the nuclear magnetic resonance spectra of the products of the remaining 2-8 groups correspond to the serial numbers of the corresponding examples.

[0037] The structural formulas of the products in Examples 1-8 are listed in the table, and the last column lists the yields of the products of each example, and the specific implementation conditions of each example are indicated. The specific meanings of the implementation conditions of each example are shown below the table.

[0038]

[0039] Example 2

[0040] In a glove box under nitrogen, a dry microwave tube with a magnet was charged with LiN(SiMe3)2(50.2 mg, 0.3 mmol), CsF (30.4 mg, 0.2 mmol), tetrahydrofuran (0.6 mL), and heated at 110 °C for 4 h. Then cooled to 50 °C, methyl benzoate (12.5 μL, 0.1 mmol, 1 equiv) was added and stirred for 4 h, cooled to 0 °C, Nf-F (1.6 equiv) and DBU (1 equiv) were added, stirred at 0 °C for 30 min, then warmed to 50 °C for 6 h, 130 °C for 6 h, cooled to room temperature, reaction was finished. The crude product was purified by flash chromatography on silica gel to give the product (64% yield). 1 H NMR (400 MHz, CDC13) δ 7.51 - 7.42 (m, 2H), 7.37 - 7.29 (m, 5H), 7.15 (d, J = 7.9 Hz, 2H), 7.02 (d, J = 16.2 Hz, 1H), 6.34 (d, J = 16.2 Hz, 1H), 2.35 (s, 3H) ppm. 13 C{ 1 H} NMR (101 MHz, CDC13) δ 141.4, 138.9, 133.7, 131.6, 129.6, 128.5, 128.2, 126.4, 123.6, 107.1, 91.5, 89.2, 21.5 ppm.

[0041] Example 3

[0042] In a glove box under nitrogen, a dry microwave tube with a magnet was charged with LiN(SiMe3)2(50.2 mg, 0.3 mmol), CsF (30.4 mg, 0.2 mmol), tetrahydrofuran (0.6 mL), and heated at 110 °C for 4 h. Then cooled to 50 °C, methyl benzoate (12.5 μL, 0.1 mmol, 1 equiv) was added and stirred for 4 h, cooled to 0 °C, Nf-F (1.6 equiv) and DBU (1 equiv) were added, stirred at 0 °C for 30 min, then warmed to 50 °C for 6 h, 130 °C for 6 h, cooled to room temperature, reaction was finished. The crude product was purified by flash chromatography on silica gel to give the product (64% yield). 1 H NMR (400 MHz, CDC13) δ 7.51 - 7.42 (m, 2H), 7.37 - 7.29 (m, 5H), 7.15 (d, J = 7.9 Hz, 2H), 7.02 (d, J = 16.2 Hz, 1H), 6.34 (d, J = 16.2 Hz, 1H), 2.35 (s, 3H) ppm. 13 C{ 1H} NMR (101 MHz, CDC13) δ 141.6, 138.5, 136.4, 131.6, 129.6, 128.8, 128.5, 128.3, 127.1, 123.6, 123.6, 108.0, 91.7, 89.1, 21.5 ppm.

[0043] Example 4

[0044] In a dry microwave tube with a magnet, LiN(SiMe3)2(50.2 mg, 0.3 mmol), CsF (30.4 mg, 0.2 mmol), tetrahydrofuran (0.6 mL) were added successively at 110 °C for 4 h. Then cooled to 50 °C, methyl benzoate (12.5 μL, 0.1 mmol, 1 equiv) was added and stirred for 4 h, cooled to 0 °C, Nf-F (1.6 equiv) and DBU (1 equiv) were added, stirred for 30 min at 0 °C, then warmed to 50 °C for 6 h, 130 °C for 6 h, cooled to room temperature, the reaction was finished. The crude product was purified by silica gel column flash chromatography to obtain the product (62% yield). 1 H NMR (400 MHz, CDC13) δ 7.53-7.47 (m, 3H), 7.37-7.32 (m, 3H), 7.30 (d, J = 16.2 Hz, 1H), 7.22-7.16 (m, 3H), 6.31 (d, J = 16.1 Hz, 1H), 2.41 (s, 3H) ppm. 13 C{ 1 H} NMR (101 MHz, CDC13) δ 139.2, 136.0, 135.4, 131.7, 130.7, 128.7, 128.5, 128.3, 126.4, 125.0, 123.5, 109.2, 91.5, 89.3, 20.0 ppm.

[0045] Example 5

[0046] In a dry microwave tube with a magnet, LiN(SiMe3)2(50.2 mg, 0.3 mmol), CsF (30.4 mg, 0.2 mmol), tetrahydrofuran (0.6 mL) were added successively at 110 °C for 4 h. Then cooled to 50 °C, methyl benzoate (12.5 μL, 0.1 mmol, 1 equiv) was added and stirred for 4 h, cooled to 0 °C, Nf-F (1.6 equiv) and DBU (1 equiv) were added, stirred for 30 min at 0 °C, then warmed to 50 °C for 6 h, 130 °C for 6 h, cooled to room temperature, the reaction was finished. The crude product was purified by silica gel column flash chromatography to obtain the product (62% yield).1 H NMR (400 MHz, CDC13) δ 7.51 - 7.45 (m, 2H), 7.37 (s, 4H), 7.35 - 7.29 (m, 3H), 7.04 (d, J = 16.2 Hz, 1H), 6.36 (d, J = 16.2 Hz, 1H), 1.33 (s, 9H) ppm. 13 C{ 1 H} NMR (101 MHz, CDC13) δ 152.1, 141.3, 133.7, 131.6, 128.5 128.2, 126.2, 125.8, 123.6, 107.3, 91.5, 89.3, 34.8, 31.3 ppm.

[0047] Example 6

[0048] In a dry microwave tube with a magnet, LiN(SiMe3)2(50.2 mg, 0.3 mmol), CsF (30.4 mg, 0.2 mmol), tetrahydrofuran (0.6 mL) were added successively in a nitrogen filled glovebox, and reacted at 110 °C for 4 h. Then cooled to 50 °C, methyl benzoate (12.5 μL, 0.1 mmol, 1 equiv) was added and stirred for 4 h, cooled to 0 °C, Nf-F (1.6 equiv) and DBU (1 equiv) were added, stirred at 0 °C for 30 min, then warmed to 50 °C for 6 h, 130 °C for 6 h, cooled to room temperature, reaction was finished. The crude product was purified by silica gel column flash chromatography to give the product (67% yield). 1 H NMR (400 MHz, CDC13) δ 7.51 - 7.45 (m, 2H), 7.37 (s, 4H), 7.35 - 7.29 (m, 3H), 7.04 (d, J = 16.2 Hz, 1H), 6.36 (d, J = 16.2 Hz, 1H), 1.33 (s, 9H) ppm. 13 C{ 1 H} NMR (101 MHz, CDC13) δ 152.1, 141.3, 133.7, 131.6, 128.5 128.2, 126.2, 125.8, 123.6, 107.3, 91.5, 89.3, 34.8, 31.3 ppm.

[0049] Example 7

[0050] In a dry microwave tube with a magnet, LiN(SiMe3)2(50.2 mg, 0.3 mmol), CsF (30.4 mg, 0.2 mmol), tetrahydrofuran (0.6 mL) were added successively at 110 °C for 4 h. Then cooled to 50 °C, methyl benzoate (12.5 μL, 0.1 mmol, 1 equiv) was added and stirred for 4 h, cooled to 0 °C, Nf-F (1.6 equiv) and DBU (1 equiv) were added, stirred at 0 °C for 30 min, then warmed to 50 °C for 6 h, 130 °C for 6 h, cooled to room temperature, the reaction was completed. The crude product was purified by silica gel column flash chromatography to obtain the product (70% yield). 1 H NMR (400 MHz, CDC13) δ 8.23 - 8.14 (m, 1H), 7.90 - 7.82 (m, 3H), 7.70 (d, J = 7.2 Hz, 1H), 7.58 - 7.46 (m, 5H), 7.41 - 7.34 (m, 3H), 6.48 (d, J = 15.9 Hz, 1H) ppm. 13 C{ 1 H} NMR (101 MHz, CDC13) δ 138.45, 133.86, 133.79, 131.73, 130.98, 129.16, 128.8, 128.6, 128.4, 126.6, 126.2, 125.7, 123.7, 123.6, 123.5, 110.9, 91.7, 89.3 ppm.

[0051] Example 8

[0052] In a dry microwave tube with a magnet, LiN(SiMe3)2(50.2 mg, 0.3 mmol), CsF (30.4 mg, 0.2 mmol), tetrahydrofuran (0.6 mL) were added successively at 110 °C for 4 h. Then cooled to 50 °C, methyl benzoate (12.5 μL, 0.1 mmol, 1 equiv) was added and stirred for 4 h, cooled to 0 °C, Nf-F (1.6 equiv) and DBU (1 equiv) were added, stirred at 0 °C for 30 min, then warmed to 50 °C for 6 h, 130 °C for 6 h, cooled to room temperature, the reaction was completed. The crude product was purified by silica gel column flash chromatography to obtain the product (75% yield). 1 H NMR (400 MHz, CDC13) δ 7.49 - 7.44 (m, 2H), 7.41 - 7.37 (m, 2H), 7.35 - 7.29 (m, 3H), 7.05 - 6.97 (m, 3H), 6.29 (d, J = 16.2 Hz, 1H) ppm. 13 C{1 H} NMR (101 MHz, CDC13) δ 163.0 (d, J = 248.7 Hz), 140.1, 132.7 (d, J = 3.4 Hz), 131.6, 128.5, 128.4, 128.0 (d, J = 8.1 Hz), 123.4, 115.9 (d, J = 21.9 Hz), 108.0 (d, J = 2.6 Hz), 91.82, 88.75 ppm. 1 C-F H} NMR (101 MHz, CDC13) δ 163.0 (d, J = 248.7 Hz), 140.1, 132.7 (d, J = 3.4 Hz), 131.6, 128.5, 128.4, 128.0 (d, J = 8.1 Hz), 123.4, 115.9 (d, J = 21.9 Hz), 108.0 (d, J = 2.6 Hz), 91.82, 88.75 ppm. 4 C-F H} NMR (101 MHz, CDC13) δ 163.0 (d, J = 248.7 Hz), 140.1, 132.7 (d, J = 3.4 Hz), 131.6, 128.5, 128.4, 128.0 (d, J = 8.1 Hz), 123.4, 115.9 (d, J = 21.9 Hz), 108.0 (d, J = 2.6 Hz), 91.82, 88.75 ppm. 3 C-F H} NMR (101 MHz, CDC13) δ 163.0 (d, J = 248.7 Hz), 140.1, 132.7 (d, J = 3.4 Hz), 131.6, 128.5, 128.4, 128.0 (d, J = 8.1 Hz), 123.4, 115.9 (d, J = 21.9 Hz), 108.0 (d, J = 2.6 Hz), 91.82, 88.75 ppm. 2 C-F H} NMR (101 MHz, CDC13) δ 163.0 (d, J = 248.7 Hz), 140.1, 132.7 (d, J = 3.4 Hz), 131.6, 128.5, 128.4, 128.0 (d, J = 8.1 Hz), 123.4, 115.9 (d, J = 21.9 Hz), 108.0 (d, J = 2.6 Hz), 91.82, 88.75 ppm. 4 C-F H} NMR (101 MHz, CDC13) δ 163.0 (d, J = 248.7 Hz), 140.1, 132.7 (d, J = 3.4 Hz), 131.6, 128.5, 128.4, 128.0 (d, J = 8.1 Hz), 123.4, 115.9 (d, J = 21.9 Hz), 108.0 (d, J = 2.6 Hz), 91.82, 88.75 ppm.

[0053] Example 9

[0054] In a glove box under nitrogen, a dry microwave tube with a magnet was charged with LiN(SiMe3)2(50.2 mg, 0.3 mmol), CsF (30.4 mg, 0.2 mmol), tetrahydrofuran (0.6 mL) sequentially, and reacted at 110 °C for 4 h. Then cooled to 50 °C, charged with methyl benzoate (12.5 μL, 0.1 mmol, 1 equiv) and stirred for 4 h, cooled to 0 °C, charged with Nf-F (1.6 equiv) and DBU (1 equiv), stirred at 0 °C for 30 min, then warmed to 50 °C for 6 h, 130 °C for 6 h, cooled to room temperature, and the reaction was completed. The crude product was purified by silica gel column flash chromatography to obtain the product (70% yield). 1 H NMR (400 MHz, CDC13) δ 7.50 - 7.45 (m, 2H), 7.38 - 7.28 (m, 7H), 6.98 (d, J = 16.2 Hz, 1H), 6.35 (d, J = 16.2 Hz, 1H) ppm. 13 C{ 1 H} NMR (101 MHz, CDC13) δ 163.0 (d, J = 248.7 Hz), 140.1, 132.7 (d, J = 3.4 Hz), 131.6, 128.5, 128.4, 128.0 (d, J = 8.1 Hz), 123.4, 115.9 (d, J = 21.9 Hz), 108.0 (d, J = 2.6 Hz), 91.82, 88.75 ppm.

Claims

1. A method for synthesizing 1,4-diarylbut-1-ene-3-yne, characterized in that: 1,4-Diarylbut-1-en-3-yne (Formula 3) was synthesized by reacting an allylbenzene derivative of Formula 1 and methyl benzoate of Formula 2 with an organic solvent in the presence of a strong base, a cesium salt additive, an amidine additive, and an activator; the strong base was lithium di(trimethylsilyl)amino, the amidine additive was DBU, and the activator was Nf-F; the allylbenzene derivative, methyl benzoate, and the product 1,4-diarylbut-1-en-3-yne were listed in one of the following tables: 。 2. The synthesis method according to claim 1, characterized in that, The cesium salt additive mentioned is cesium fluoride.

3. The synthesis method according to claim 1, characterized in that, The reaction is carried out under the protection of an inert gas, namely nitrogen.

4. The synthesis method according to claim 1, characterized in that, The organic solvent is toluene or tetrahydrofuran.

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