A method for synthesizing terminal alkyne

Abstract

The application belongs to the field of organic synthesis, and particularly relates to a synthesis method of terminal alkyne. A 2-methylpyridine compound shown in formula 1 and N,N-dimethylformamide shown in formula 2 are mixed with an organic solvent (isopropyl ether or methyl tert-butyl ether) in the presence of a strong base (lithium bis(trimethylsilyl)amide and lithium tert-butoxide), a cesium salt additive (cesium fluoride) and an activating agent (Nf-F), and are reacted to synthesize terminal alkyne shown in formula 3. The raw materials used in the application are common chemicals in the market. The application has a wide range of applications, and not only can common terminal alkyne compounds be synthesized, but also a series of terminal alkyne derivatives can be synthesized according to the need of adjusting the reaction substrate. This provides certain support for the research in the fields of medicine, material science and the like.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of organic synthesis, and particularly relates to a synthesis method of terminal alkyne. BACKGROUND

[0002] As a precursor in many organic reactions, alkyne 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 alkyne with an extended carbon skeleton is harsh. There are two traditional methods for preparing terminal alkyne, the Corey-Fuchs reaction, which requires n-BuLi and other dangerous reagents at low temperature. The Seyferth-Gilbert reaction or the modified Bestmann-Ohira reaction is to form a terminal alkyne from an aldehyde and a phosphonate. These dangerous diazocompounds are difficult to handle, especially for large-scale production. It is of great significance to develop a new synthetic strategy to prepare aryl terminal alkyne. SUMMARY

[0003] The present application provides a one-pot synthesis of terminal alkyne from 2-methylpyridine compounds and N,N-dimethylformamide, which is expected to simplify the synthesis of alkyne, reduce the production cost of these valuable building blocks, and increase the sustainability of alkyne synthesis, thereby complementing the most advanced technology. The specific scheme is as follows:

[0004]

[0005] A synthesis method of terminal alkyne compound, which adopts 2-methylpyridine compound shown as formula 1 and N,N-dimethylformamide shown as formula 2 in the presence of strong base, cesium salt additive, and activating agent, and is mixed with organic solvent to react and synthesize terminal alkyne shown as formula 3:

[0006] wherein R is selected from methyl, methoxy, and quinoline ring.

[0007] The method of the present application can realize one-pot synthesis of terminal alkyne 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 in the present application can be selected from a variety of options, and the applicability is wider.

[0008] Preferably, R is selected from methyl, methoxy, and quinoline ring.

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

[0010] Preferably, the cesium salt additive is cesium fluoride.

[0011] Preferably, the reaction is carried out under an activating agent, preferably, the activating agent is Nf-F (perfluorobutylsulfonyl fluoride).

[0012] Preferably, the organic solvent is isopropyl ether or methyl tert-butyl ether.

[0013] Preferably, the molar ratio of 2-methylpyridine of formula 1, N,N-dimethylformamide of formula 2, lithium bis(trimethylsilyl)amide, cesium fluoride, Nf-F and potassium tert-butoxide in the reaction is 2-3: 1-2: 1.6-3.2: 3-6; the reaction temperature is 50-130℃.

[0014] Preferably, by using the method of the present application, the terminal alkyne with the following structure can be synthesized:

[0015]

[0016] The 2-methylpyridine compound and N,N-dimethylformamide are mixed with an organic solvent (isopropyl ether or methyl tert-butyl ether) in the presence of a strong base (lithium bis(trimethylsilyl)amide and lithium tert-butoxide), cesium salt additive (cesium fluoride), and activating agent Nf-F (perfluorobutylsulfonyl fluoride) to react, and finally synthesize the terminal alkyne.

[0017] The technical solution of the present application can at least achieve one of the following beneficial effects:

[0018] The raw materials used in the synthesis method of the present application are cheap and easy to obtain;

[0019] The synthesis method of the present application does not use transition metal catalysts, which is green and environmentally friendly;

[0020] The synthesis method of the present application uses one-pot method, which has fewer reaction steps, reduces the loss of raw materials, and improves the yield of products;

[0021] The operation steps required by the present application are relatively simple, do not require extreme heating or cooling, and only require normal pressure to react, which is safe and convenient;

[0022] In the present application, R can be selected in many ways, so the method of the present application is more widely applicable and can synthesize a variety of terminal alkyne compounds. BRIEF DESCRIPTION OF DRAWINGS

[0023] The drawings are the hydrogen spectrum and carbon spectrum nuclear magnetic resonance spectra of the products of each embodiment, the serial numbers of the drawings correspond to the serial numbers of the embodiments, Figure A is the hydrogen spectrum nuclear magnetic resonance spectrum, and Figure B is the carbon spectrum nuclear magnetic resonance spectrum, such as Figure 1A Figure A is the hydrogen spectrum nuclear magnetic resonance spectrum of the product obtained in Example 1, Figure 1B Figure B is the carbon spectrum nuclear magnetic resonance spectrum of the product obtained in Example 1; Figure 2A Figure A is the hydrogen spectrum nuclear magnetic resonance spectrum of the product obtained in Example 2, Figure 2BThe carbon spectrum nuclear magnetic resonance spectrum of the product obtained in Example 2; 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; 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; 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; 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; 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; 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: 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; Figure 10A The hydrogen spectrum nuclear magnetic resonance spectrum of the product obtained in Example 10, Figure 10B The carbon spectrum nuclear magnetic resonance spectrum of the product obtained in Example 10. Specific embodiments

[0024] 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 An'aiji, Bide, Sigma-Aldrich, Acros, Alfa Aesar, Adamas-beta or J&K. The nuclear magnetic resonance spectrometer is Bruker 400M and JEOL 400M made in Japan.

[0025] Example 1

[0026] In a glove box filled with nitrogen, a dry microwave tube with a magnet was charged with LiN(SiMe3)2(33.5 mg, 0.2 mmol), CsF (15.2 mg, 0.1 mmol), 2-methylpyridine (30 μL, 0.3 mmol), isopropyl ether (1.6 mL) sequentially, and reacted at 110 °C for 3 h. Then cooled to 50 °C, added N,N-dimethylformamide (8.0 μL, 0.1 mmol, 1 equiv) and stirred for 3 h, cooled to 0 °C, added Nf-F (1.6 equiv) and LiO t Bu (3 equiv), 0 °C for 30 min, then warmed to 50 °C for 6 h, 90 °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 (81% yield). 1 H NMR (400 MHz, CDC13) δ 8.58 (ddd, J = 4.9, 1.7, 1.0 Hz, 1H), 7.66 (td, J = 7.7, 1.8 Hz, 1H), 7.48 (dt, J = 7.8, 1.1 Hz, 1H), 7.30-7.25 (m, 1H), 3.14 (s, 1H); 13 C{ 1 H} NMR (101 MHz, CDC13) δ 150.0, 142.3, 136.1, 127.4, 123.4, 82.7, 77.0 ppm.

[0027] 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 serial numbers of the nuclear magnetic resonance spectra of the products of the remaining 2-10 groups correspond to the serial numbers of the corresponding examples.

[0028] The structural formulas of the products in Examples 1-10 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.

[0029]

[0030] Example 2

[0031] In a glove box under nitrogen, a dry microwave tube with a magnet was charged with LiN(SiMe3)2(33.5 mg, 0.2 mmol), CsF (15.2 mg, 0.1 mmol), 2,4-dimethylpyridine (35 μL, 0.3 mmol), isopropyl ether (1.6 mL), and heated at 110 °C for 3 h. Then cooled to 50 °C, N,N-dimethylformamide (8.0 μL, 0.1 mmol, 1 equiv) was added and stirred for 3 h, cooled to 0 °C, Nf-F (1.6 equiv) and LiO t Bu (3 equiv) at 0 °C for 30 min, then warmed to 50 °C for 6 h, 90 °C for 6 h, cooled to room temperature, and the reaction was complete. The crude product was purified by flash chromatography on silica gel to give the product (88% yield). 1 H NMR (400 MHz, CDC13) δ 8.39 (d, J = 5.1 Hz, 1H), 7.31 (s, 1H), 7.10 (d, J = 5.1 Hz, 1H), 3.11 (s, 1H), 2.33 (s, 3H); 13 C{ 1 H} NMR (101 MHz, CDC13) δ 149.3, 148.2, 141.5, 128.6, 124.8, 82.3, 77A, 20.9 ppm.

[0032] Example 3

[0033] In a glove box under nitrogen, a dry microwave tube with a magnet was charged with LiN(SiMe3)2(33.5 mg, 0.2 mmol), CsF (15.2 mg, 0.1 mmol), 2,5-dimethylpyridine (35 μL, 0.3 mmol), isopropyl ether (1.6 mL), and heated at 110 °C for 3 h. Then cooled to 50 °C, N,N-dimethylformamide (8.0 μL, 0.1 mmol, 1 equiv) was added and stirred for 3 h, cooled to 0 °C, Nf-F (1.6 equiv) and LiO t Bu (3 equiv) at 0 °C for 30 min, then warmed to 50 °C for 6 h, 90 °C for 6 h, cooled to room temperature, and the reaction was complete. The crude product was purified by flash chromatography on silica gel to give the product (50% yield). 1 H NMR (400 MHz, CDC13) δ 8.39 (d, J = 5.1 Hz, 1H), 7.31 (s, 1H), 7.10 (d, J = 5.1 Hz, 1H), 3.11 (s, 1H), 2.33 (s, 3H); 13 C{ 1H NMR (400 MHz, CDC13) δ 8.21 (s, 1H), 7.33 (s, 1H), 3.28 (s, 1H), 2.39 (s, 3H), 2.30 (s, 3H);

[0034] Example 4

[0035] In a glove box under nitrogen, a dry microwave tube with a magnet was charged with LiN(SiMe3)2(33.5 mg, 0.2 mmol), CsF (15.2 mg, 0.1 mmol), 2,3,5-trimethylpyridine (39 μL, 0.3 mmol), isopropyl ether (1.6 mL), and heated at 110 °C for 3 h. Then cooled to 50 °C, N,N-dimethylformamide (8.0 μL, 0.1 mmol, 1 equiv) was added and stirred for 3 h, cooled to 0 °C, Nf-F (1.6 equiv) and LiO t Bu (3 equiv), 0 °C for 30 min, then warmed to 50 °C for 6 h, 90 °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 (55% yield). 1 H NMR (400 MHz, CDC13) δ 8.21 (s, 1H), 7.33 (s, 1H), 3.28 (s, 1H), 2.39 (s, 3H), 2.30 (s, 3H); 13 C{ 1 H NMR (400 MHz, CDC13) δ 8.21 (s, 1H), 7.33 (s, 1H), 3.28 (s, 1H), 2.39 (s, 3H), 2.30 (s, 3H);

[0036] Example 5

[0037] In a glove box under nitrogen, a dry microwave tube with a magnet was charged with LiN(SiMe3)2(33.5 mg, 0.2 mmol), CsF (15.2 mg, 0.1 mmol), 2,3,5-trimethylpyridine (39 μL, 0.3 mmol), isopropyl ether (1.6 mL), and heated at 110 °C for 3 h. Then cooled to 50 °C, N,N-dimethylformamide (8.0 μL, 0.1 mmol, 1 equiv) was added and stirred for 3 h, cooled to 0 °C, Nf-F (1.6 equiv) and LiO t Bu (3 equiv), 0 °C for 30 min, then warmed to 50 °C for 6 h, 90 °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 (55% yield). 1H NMR (400 MHz, CDC13) δ 8.42 (d, J = 1.6 Hz, 1H), 7.47 (dd, J = 8.0, 2.2 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 3.09 (s, 1H), 2.65 (q, J = 7.6 Hz, 2H), 1.24 (t, J = 7.6 Hz, 3H); 13 C{ 1 H} NMR (101 MHz, CDC13) δ 150.0, 139.7, 139.6, 135.5, 127.2, 82.9, 76.5, 26.1, 15.2 ppm.

[0038] Example 6

[0039] In a glove box under nitrogen, a dry microwave tube with a magnet was charged with LiN(SiMe3)2(33.5 mg, 0.2 mmol), CsF (15.2 mg, 0.1 mmol), 2-methoxy-6-methylpyridine (12 μL, 0.1 mmol), isopropyl ether (0.8 mL) and heated at 110 °C for 3 h. Then cooled to 50 °C, N,N-dimethylformamide (8.0 μL, 0.1 mmol, 1 equiv) was added and stirred for 3 h, cooled to 0 °C, Nf-F (1.6 equiv) and LiO t Bu (3 equiv) was added and kept at 0 °C for 30 min, then warmed to 50 °C for 6 h, 90 °C for 6 h, cooled to room temperature, and the reaction was complete. The crude product was purified by flash chromatography on silica gel to give the product (61% yield). 1 H NMR (400 MHz, CDC13) δ 8.42 (d, J = 1.6 Hz, 1H), 7.47 (dd, J = 8.0, 2.2 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 3.09 (s, 1H), 2.65 (q, J = 7.6 Hz, 2H), 1.24 (t, J = 7.6 Hz, 3H); 13 C{ 1 H} NMR (101 MHz, CDC13) δ 150.0, 139.7, 139.6, 135.5, 127.2, 82.9, 76.5, 26.1, 15.2 ppm.

[0040] Example 7

[0041] In a glove box under nitrogen, a dry microwave tube with a magnet was charged with LiN(SiMe3)2(33.5 mg, 0.2 mmol), CsF (15.2 mg, 0.1 mmol), 2-methylquinoline (41 μL, 0.3 mmol), isopropyl ether (0.8 mL), and heated at 110 °C for 3 h. Then cooled to 50 °C, N,N-dimethylformamide (8.0 μL, 0.1 mmol, 1 equiv) was added and stirred for 3 h, cooled to 0 °C, Nf-F (1.6 equiv) and LiO t Bu (3 equiv) was added at 0 °C for 30 min, then warmed to 50 °C for 6 h, 90 °C for 6 h, cooled to room temperature, and the reaction was complete. The crude product was purified by flash chromatography on silica gel to give the product (78% yield). 1 H NMR (401 MHz, CDC13) δ 7.99 (dd, J = 15.3, 8.9 Hz, 2H), 7.58 - 7.45 (m, 3H), 3.21 (s, 1H), 2.51 (s, 3H); 13 C{ 1 H} NMR (101 MHz, CDC13) δ 148.1, 142.4, 136.4, 130.3, 129.5, 127.6, 127.5, 127.4, 124.2, 83.4, 77.7 ppm.

[0042] Example 8

[0043] In a glove box under nitrogen, a dry microwave tube with a magnet was charged with LiN(SiMe3)2(33.5 mg, 0.2 mmol), CsF (15.2 mg, 0.1 mmol), 2-methylquinoline (41 μL, 0.3 mmol), isopropyl ether (0.8 mL), and heated at 110 °C for 3 h. Then cooled to 50 °C, N,N-dimethylformamide (8.0 μL, 0.1 mmol, 1 equiv) was added and stirred for 3 h, cooled to 0 °C, Nf-F (1.6 equiv) and LiO t Bu (3 equiv) was added at 0 °C for 30 min, then warmed to 50 °C for 6 h, 90 °C for 6 h, cooled to room temperature, and the reaction was complete. The crude product was purified by flash chromatography on silica gel to give the product (78% yield). 1 H NMR (401 MHz, CDC13) δ 7.99 (dd, J = 15.3, 8.9 Hz, 2H), 7.58 - 7.45 (m, 3H), 3.21 (s, 1H), 2.51 (s, 3H); 13 C{ 1H} NMR (101 MHz, CDC13) δ 158.5, 144.3, 139.7, 135.0, 130.9, 128.6, 124.59, 123.2, 104.8, 83.5, 77.0, 55.7 ppm.

[0044] Example 9

[0045] In a glove box under nitrogen, a dry microwave tube with a magnet was charged with LiN(SiMe3)2(33.5 mg, 0.2 mmol), CsF (15.2 mg, 0.1 mmol), 6-methoxy-2-methylquinoline (52 mg, 0.3 mmol), methyl-tert-butyl ether (1.6 mL), and heated at 110 °C for 3 h. Then cooled to 50 °C, N,N-dimethylformamide (8.0 μL, 0.1 mmol, 1 equiv) was added and stirred for 3 h, cooled to 0 °C, Nf-F (1.6 equiv) and LiO t Bu (3 equiv), 0 °C for 30 min, then warmed to 50 °C for 6 h, 90 °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 (98% yield). 1 H NMR (400 MHz, CDC13) δ 7.98 (dd, J = 8.6, 6.3 Hz, 2H), 7.48 (d, J = 8.5 Hz, 1H) 7.36 (dd, J = 9.3, 2.8 Hz, 1H), 7.02 (d, J = 2.8 Hz, 1H), 3.91 (s, 3H), 3.19 (s, 1H); 13 C{ 1 H} NMR (101 MHz, CDC13) δ 158.5, 144.3, 139.7, 135.0, 130.9, 128.6, 124.59, 123.2, 104.8, 83.5, 77.0, 55.7 ppm.

[0046] Example 10

[0047] In a glove box under nitrogen, a dry microwave tube with a magnet was charged with LiN(SiMe3)2(33.5 mg, 0.2 mmol), CsF (15.2 mg, 0.1 mmol), 6-methoxy-2-methylquinoline (52 mg, 0.3 mmol), methyl-tert-butyl ether (1.6 mL), and heated at 110 °C for 3 h. Then cooled to 50 °C, N,N-dimethylformamide (8.0 μL, 0.1 mmol, 1 equiv) was added and stirred for 3 h, cooled to 0 °C, Nf-F (1.6 equiv) and LiO tBu (3 equiv), 0 °C for 30 min, then warmed to 50 °C for 6 h, 90 °C for 6 h, cooled to room temperature, reaction was completed. The crude product was purified by silica gel column flash chromatography to obtain the product (95% yield). 1 H NMR (400 MHz, CDC13) δ 7.96 (d, J = 8.7 Hz, 2H), 7.47 (d, J = 8.2 Hz, 1H), 7.35 (dd, J = 9.2, 2.8 Hz, 1H), 7.00 (d, J = 2.8 Hz, 1H), 4.12 (q, J = 7.0 Hz, 2H), 3.19 (s, 1H), 1.47 (t, J = 7.0 Hz, 3H); 13 C{ 1 H} NMR (101 MHz, CDC13) δ 157.9, 144.2, 139.7, 134.9, 130.9, 128.7, 124.5, 123.4, 105.5, 83.5, 76.9, 63.9, 14.8 ppm.

Claims

1. A method for synthesizing terminal alkynes, characterized in that: The terminal alkyne shown in Formula 3 was synthesized by reacting a 2-methylpyridine derivative of Formula 1 and an N,N-dimethylformamide of Formula 2 with an organic solvent in the presence of a strong base, cesium fluoride, and perfluorobutylsulfonyl fluoride; wherein the strong base was lithium di(trimethylsilyl)amino and lithium tert-butoxide. Wherein R is selected from any one of hydrogen, 4-methyl, 5-methyl, 3,5-dimethyl, 5-ethyl, and 6-methoxy, or compound 1 is 2-methylquinoline, 6-methyl-2-methylquinoline, 6-methoxy-2-methylquinoline, and 6-ethoxy-2-methylquinoline.

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

3. The synthesis method according to claim 1, characterized in that, The organic solvent is isopropyl ether or methyl tert-butyl ether.

4. The synthesis method according to claim 1, characterized in that, In the reaction, the molar ratio of the 2-methylpyridine derivative shown in Formula 1, N,N-dimethylformamide shown in Formula 2, lithium di(trimethylsilyl)amino, cesium fluoride, perfluorobutylsulfonyl fluoride, and potassium tert-butoxide is 2–3:1–2:1.6–3.2:3–6; the reaction temperature of the synthesis method is 50–110 °C.

5. The synthesis method according to claim 1, characterized in that, The 2-methylpyridine derivative and the terminal alkyne of the product are one of the following: 。

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