A method for synthesizing diaryl acetylenes

Abstract

The application belongs to the field of organic synthesis, and particularly relates to a synthesis method of diaryl acetylene. A toluene compound shown in formula 1 and a methyl benzoate compound shown in formula 2 are mixed with an organic solvent (toluene or dimethyl tetrahydrofuran) in the presence of a strong base (lithium bis(trimethylsilyl)amide), a cesium salt additive (cesium fluoride), an amidine additive (DBU) and an activating agent (Nf-F), and then reacted to synthesize the diaryl acetylene shown in formula 3. The raw material used in the application is simple and easy to obtain, a one-pot synthesis method of the diaryl acetylene 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 diaryl acetylene. BACKGROUND

[0002] As a precursor in many organic reactions, acetylene is a key motif in chemistry, which is mainly used for the synthesis of bioactive compounds, polymers and new materials. The method for synthesizing terminal acetylene with an extended carbon skeleton is harsh. The further derivation of terminal acetylene to diaryl acetylene also mainly depends on Sonogashira coupling. This cross-coupling method is very useful, but it needs to use expensive Pd catalyst, phosphine ligand and toxic copper co-catalyst, which produces heavy metal waste and other problems. Therefore, it is necessary to continuously explore various more economical and effective synthesis routes of acetylene derivatives. SUMMARY

[0003] The present application provides a one-pot synthesis of diaryl acetylene from toluene and methyl benzoate, which is expected to simplify the synthesis of acetylene, reduce the production cost of these valuable building blocks, and increase the sustainability of acetylene synthesis, thereby complementing the most advanced technology. The specific scheme is as follows:

[0004]

[0005] A synthesis method of diaryl acetylene compound, which adopts toluene 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 diaryl acetylene shown in formula 3;

[0006] wherein R 1 is selected from methyl, methoxy, pyridyl, halogen, etc., and R2 is selected from methoxy, tert-butyl, phenoxy, N, N-dimethyl, etc.

[0007] The method of the present application can realize one-pot synthesis of diaryl acetylene compound, reduce the reaction steps, and thus improve the yield of product; the raw materials used in the synthesis method are simple and economical; R 1 , R 2 in the present application can be selected in a variety of ways, and has wider applicability.

[0008] Preferably, R 1 is selected from methyl, methoxy, pyridyl, halogen, etc., and R 2 is selected from methoxy, tert-butyl, phenoxy, N, N-dimethyl, etc.

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

[0010] Preferably, the synthesis is carried out 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 toluene, dimethyltetrahydrofuran.

[0014] Preferably, the molar ratio of the toluene derivative of formula 1, the methyl benzoate derivative of formula 2, and the catalyst in the reaction is 5-6:1-2:1-4, and the reaction temperature is 50-130°C.

[0015] Preferably, the method of the present application can be used to synthesize a diaryl acetylene having the following structure:

[0016]

[0017]

[0018] The toluene and methyl benzoate are reacted in the presence of a strong base (lithium bis(trimethylsilyl)amide) and a cesium salt additive (cesium fluoride) in an organic solvent (toluene) to synthesize a diaryl acetylene.

[0019] The technical solution of the present application can achieve at least one of the following beneficial effects:

[0020] The raw materials used in the synthesis method of the present application are inexpensive and readily available.

[0021] The synthesis method of the present application does not use a transition metal catalyst, and is green and environmentally friendly.

[0022] The synthesis method of the present application uses a one-pot method, which has fewer reaction steps, reduces the loss of raw materials, and improves the yield of the product.

[0023] The operation steps required by the present application are relatively simple, do not require extreme heating or cooling, and can be reacted at normal pressure, which is safe and convenient.

[0024] In the present application, R 1 , R 2 may be selected in a variety of ways, so the method of the present application is more widely applicable and can be used to synthesize a variety of diaryl acetylene compounds.

[0025] Drawings

[0026] The drawings are the hydrogen spectrum and carbon spectrum nuclear magnetic resonance spectra of the products of the examples, the serial numbers of the drawings correspond to the serial numbers of the examples, Figure A is the hydrogen spectrum nuclear magnetic resonance spectrum, and Figure B is the carbon spectrum nuclear magnetic resonance spectrum, as shown inFigure 1A hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 1, Figure 1B carbon nuclear magnetic resonance spectrum of the product obtained in Example 1; Figure 2A hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 2, Figure 2B carbon nuclear magnetic resonance spectrum of the product obtained in Example 2; Figure 3A hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 3, Figure 3B carbon nuclear magnetic resonance spectrum of the product obtained in Example 3; Figure 4A hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 4, Figure 4B carbon nuclear magnetic resonance spectrum of the product obtained in Example 4; Figure 5A hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 5, Figure 5B carbon nuclear magnetic resonance spectrum of the product obtained in Example 5; Figure 6A hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 6, Figure 6B carbon nuclear magnetic resonance spectrum of the product obtained in Example 6; Figure 7A hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 7, Figure 7B carbon nuclear magnetic resonance spectrum of the product obtained in Example 7; Figure 8A hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 8, Figure 8B carbon nuclear magnetic resonance spectrum of the product obtained in Example 8; Figure 9A hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 9, Figure 9B carbon nuclear magnetic resonance spectrum of the product obtained in Example 9; Figure 10A hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 10, Figure 10B carbon nuclear magnetic resonance spectrum of the product obtained in Example 10. Specific embodiments

[0027] 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 simply synthesized, and other drugs are purchased from Anjieji, Bide, Sigma-Aldrich, Acros, Alfa Aesar, Adamas-beta or J&K. The nuclear magnetic resonance spectrometer is Bruker 400M and JEOL 400M of Japan.

[0028] Example 1

[0029] 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), toluene (0.6 mL) sequentially, and reacted at 110 °C for 4 h. Then cooled to 50 °C, added methyl benzoate (12.5 μL, 0.1 mmol, 1 equiv) and stirred for 4 h, cooled to 0 °C, added Nf-F (1.6 equiv) and DBU (1 equiv), kept 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 (94% yield). 1 H NMR (400 MHz, CDC13) δ 7.62-7.52 (m, 4H), 7.42-7.31 (m, 6H) ppm. 13 C{ 1 H} NMR (101 MHz, CDC13) δ 131.8, 128.5, 128.4, 123.4, 89.5 ppm.

[0030] The starting materials in Example 1 were changed to design the following 10 groups of experimental examples, wherein the first group of experiments is Example 1, and the nuclear magnetic resonance spectrum of the corresponding product is Figure 1. The nuclear magnetic resonance spectrum of the product of each of the remaining 2-10 groups corresponds to the serial number of the corresponding example.

[0031] The structural formula of the product in each of Examples 1-10 is listed in the table, and the last column lists the yield of the product 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.

[0032]

[0033]

[0034] Example 2

[0035] In a nitrogen filled glove box, 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), 2-methoxy-1,4-dimethylbenzene (40.8 mg, 0.3 mmol, 3 equiv) dissolved in 2Me-THF (5 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, 0 °C for 30 min, then warmed to 50 °C for 6 h, 130 °C for 6 h, cooled to room temperature, reaction was complete. The crude product was purified by flash chromatography on silica gel to give the product (64% yield). 13 C{ 1 H}NMR (101 MHz, CDC13) δ 159.5, 131.8, 129.5, 128.5, 128.4, 124.4, 124.3, 123.3, 116.4, 115.1, 89.4, 89.3, 55.4 ppm.

[0036] Example 3

[0037] In a nitrogen filled glove box, 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), 2-methoxy-1,4-dimethylbenzene (40.8 mg, 0.3 mmol, 3 equiv) dissolved in 2Me-THF (5 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, 0 °C for 30 min, then warmed to 50 °C for 6 h, 130 °C for 6 h, cooled to room temperature, reaction was complete. The crude product was purified by flash chromatography on silica gel to give the product (64% yield). 1H NMR (400 MHz, CDCI3) δ 7.56-7.52 (m, 2H), 7.38-7.32 (m, 3H), 7.12-7.04 (m, 2H), 6.99 (d, j == 1.4 Hz, 1H), 3.86 (s, 3H), 2.24 (s, 3H) ppm. 13 C{ 1 H} NMR (101 MHz, CDCI3) δ 157.4, 131.6, 130.5, 128.3, 128.1, 127.7, 123.9, 123.4, 121.4, 112.9, 89.8, 88.5, 55.4, 16.3 ppm.

[0038] Example 4

[0039] In a glove box filled with nitrogen, a dry microwave tube with a magnet was added with LiN(SiMe3)2(50.2 mg, 0.3 mmol), CsF (30.4 mg, 0.2 mmol), o-chlorotoluene (37.9 mg, 0.3 mmol, 3 equiv) dissolved in 2Me-THF (5 mL) sequentially, and reacted at 110 °C for 4 h. Then cooled to 50 °C, added methyl benzoate (12.5 μL, 0.1 mmol, 1 equiv) and stirred for 4 h, cooled to 0 °C, added Nf-F (1.6 equiv) and DBU (1 equiv), 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 chromatography to obtain the product (78% yield). 1 H NMR (400 MHz, CDCI3) δ 7.60-7.55 (m, 3H), 7.45-7.42 (m, 1H), 7.39-7.34 (m, 3H), 7.29-7.22 (m, 2H) ppm. 13 C{ 1 H} NMR (101 MHz, CDCI3) δ 136.0, 133.2, 131.8, 129.3, 129.3, 128.7, 128.4, 126.5, 123.2, 122.9, 94.5, 86.2 ppm.

[0040] Example 5

[0041] 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), 2-(4-methylphenyl)pyridine (50.8 mg, 0.3 mmol, 3 equiv) dissolved in 2Me-THF (5 mL) sequentially, and reacted at 110 °C for 4 h. Then cooled to 50 °C, added methyl benzoate (12.5 μL, 0.1 mmol, 1 equiv) and stirred for 4 h, cooled to 0 °C, added Nf-F (3 equiv) and DBU (1 equiv), 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 (89% yield). 1 H NMR (400 MHz, CDC13) δ 8.71 (dt, J = 4.8, 1.4 Hz, 1H), 8.06 (d, J = 8.6 Hz, 2H), 7.79-7.71 (m, 2H), 7.68-7.61 (m, 2H), 7.61-7.52 (m, 2H), 7.36 (m, 3H), 7.24 (m, 1H) ppm. 13 C{ 1 H} NMR (101 MHz, CDC13) δ 156.5, 149.8, 139.0, 136.9, 132.0, 131.7, 128.4, 126.8, 123.9, 123.2, 122.4, 120.6, 90.7, 89.3 ppm.

[0042] Example 6

[0043] 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), toluene (0.6 mL) sequentially, and reacted at 110 °C for 4 h. Then cooled to 50 °C, added methyl p-tert-butylbenzoate (19.3 μL, 0.1 mmol, 1 equiv) and stirred for 4 h, cooled to 0 °C, added Nf-F (1.6 equiv) and DBU (1 equiv), 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 (90% yield). 1 H NMR (400 MHz, CDC13) δ 8.71 (dt, J = 4.8, 1.4 Hz, 1H), 8.06 (d, J = 8.6 Hz, 2H), 7.79-7.71 (m, 2H), 7.68-7.61 (m, 2H), 7.61-7.52 (m, 2H), 7.36 (m, 3H), 7.24 (m, 1H) ppm. 13 C{ 1H NMR (101 MHz, CDC13) δ 151.7, 131.7, 131.5, 128.5, 128.2, 125.5, 123.6, 120.4, 89.7, 88.9, 34.9, 31.3 ppm.

[0044] Example 7

[0045] 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), toluene (0.6 mL) and heated at 110 °C for 4 h. Then cooled to 50 °C, charged with methyl o-methoxybenzoate (14.4 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), 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 (78% yield). 1 H NMR (400 MHz, CDC13) δ 7.63-7.56 (m, 2H), 7.52 (dd, J = 7.5, 1.7 Hz, 1H), 7.38-7.29 (m, 4H), 6.99-6.88 (m, 2H), 3.91 (s, 3H) ppm. 13 C{ 1 H NMR (101 MHz, CDC13) δ 160.0, 133.7, 131.8, 129.9, 128.4, 128.3, 123.7, 120.6, 112.5, 110.8, 93.6, 85.9, 55.9 ppm.

[0046] Example 8

[0047] 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), toluene (0.6 mL) and heated at 110 °C for 4 h. Then cooled to 50 °C, charged with methyl 4-phenoxybenzoate (22.824 mg, 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), 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 (70% yield). 1H NMR (400 MHz, CDCI3) δ 7.58 - 7.47 (m, 4H), 7.42 - 7.31 (m, 5H), 7.21 - 7.11 (m, 1H), 7.06 (d, J = 8.6 Hz, 2H), 6.98 (d, J = 8.3 Hz, 2H) ppm. 13 C{ 1 H} NMR (101 MHz, CDCI3) δ 157.7, 156.5, 133.4, 131.7, 130.0, 128.5, 128.3, 124.0, 123.5, 119.6, 118.5, 117.9, 89.1, 88.9 ppm.

[0048] Example 9

[0049] 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), toluene (0.6 mL) sequentially, and reacted at 110 °C for 4 h. Then cooled to 50 °C, added methyl-m-tolylamide (16.3 μL, 0.1 mmol, 1 equiv) and stirred for 4 h, cooled to 0 °C, added Nf-F (1.6 equiv) and DBU (1 equiv), and kept at 0 °C for 30 min, then warmed to 50 °C for 6 h, and 130 °C for 6 h, and cooled to room temperature, and the reaction was completed. The crude product was purified by silica gel column flash chromatography to obtain the product (87% yield). 1 H NMR (400 MHz, CDCI3) δ 7.58 - 7.47 (m, 4H), 7.42 - 7.31 (m, 5H), 7.21 - 7.11 (m, 1H), 7.06 (d, J = 8.6 Hz, 2H), 6.98 (d, J = 8.3 Hz, 2H) ppm. 13 C{ 1 H} NMR (101 MHz, CDCI3) δ 157.7, 156.5, 133.4, 131.7, 130.0, 128.5, 128.3, 124.0, 123.5, 119.6, 118.5, 117.9, 89.1, 88.9 ppm.

[0050] Example 10

[0051] 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), 2-(4-methylphenyl)pyridine (50.8 mg, 0.3 mmol, 3 equiv) dissolved in 2Me-THF (5 mL) sequentially, and reacted at 110 °C for 4 h. Then cooled to 50 °C, added methyl 4-methoxybenzoate (16.6 mg, 0.1 mmol, 1 equiv) and stirred for 4 h, cooled to 0 °C, added Nf-F (1.6 equiv) and DBU (1 equiv), kept 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 (82% yield). 1 H NMR (400 MHz, CDC13) δ 8.70 (d, J = 4.9 Hz, 1H), 8.00 (d, J = 8.1 Hz, 2H), 7.78 - 7.72 (m, 2H), 7.62 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H), 7.27 - 7.20 (m, 1H), 6.89 (d, J = 8.7 Hz, 2H), 3.83 (s, 3H) ppm. 13 C{ 1 H}NMR (101 MHz, CDC13) δ 159.8, 156.6, 149.7, 138.6, 136.8, 133.1, 131.9, 126.8, 124.3, 122.3, 120.5, 115.3, 114.1, 90.8, 88.1, 55.3 ppm.

Claims

1. A method for synthesizing diarylacetylene, characterized in that: The diarylacetylene of Formula 3 was synthesized by reacting a toluene derivative shown in Formula 1 and a methyl benzoate derivative shown in Formula 2 with an organic solvent in the presence of a strong base, a cesium salt additive, an amidine additive, and an activator Nf-F; the strong base was lithium di(trimethylsilyl)amino. Where R 1 Selected from methyl, methoxy, pyridyl, halogen, R 2 Selected from methoxy, tert-butyl, phenoxy, and N,N-dimethyl.

2. The synthesis method according to claim 1, characterized in that, The cesium salt additive is cesium fluoride, and the amidine additive is DBU.

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 dimethyltetrahydrofuran.

5. The synthesis method according to claim 1, characterized in that, In the reaction, the molar ratio of the toluene derivative shown in Formula 1, the methyl benzoate derivative shown in Formula 2, and the catalyst is 5-6:1-2:1-4; the reaction temperature is 50-130℃.

6. A method for synthesizing diarylacetylene, characterized in that, Diarylacetylene was synthesized by reacting a toluene derivative and a methyl benzoate derivative, as shown below, with an organic solvent in the presence of a strong base, a cesium salt additive, an amidine additive, and the activator Nf-F; wherein the strong base was lithium di(trimethylsilyl)amino; and R 1 and R 2 The limitations are shown in the following figure:

7. The synthesis method according to claim 6, characterized in that, The cesium salt additive is cesium fluoride, and the amidine additive is DBU.

8. The synthesis method according to claim 6, characterized in that, The reaction is carried out under the protection of an inert gas, namely nitrogen.

9. The synthesis method according to claim 6, characterized in that, The organic solvent is toluene or dimethyltetrahydrofuran.

10. The synthesis method according to claim 6, characterized in that, The molar ratio of toluene derivative, methyl benzoate derivative and catalyst in the reaction is 5-6:1-2:1-4; the reaction temperature is 50-130℃.

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