Synthetic method of terminal alkyne

Abstract

The invention belongs to the field of organic synthesis, and particularly relates to a synthesis method of terminal alkyne. # imgabs0 is prepared by mixing a 2-methylpyridine compound as shown in a formula 1 and N, N-dimethylformamide as shown in a formula 2 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 reacting to synthesize terminal alkyne as shown in a formula 3. The raw materials adopted by the invention are common chemicals in the market. The method is wide in application range, common terminal alkyne compounds can be synthesized, reaction substrates can be adjusted according to needs, and a series of terminal alkyne derivatives can be synthesized. Certain support is provided for research in the fields of medicine, material science and the like.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and particularly relates to a method for synthesizing terminal alkynes. Background Art

[0002] As a precursor in many organic reactions, alkynes are key motifs in chemistry, which are mainly used to synthesize biologically active compounds, polymers and new materials. The methods for synthesizing terminal alkynes with extended carbon skeletons are relatively harsh. There are two traditional methods for preparing terminal alkynes: the Corey-Fuchs reaction, which requires the use of dangerous reagents such as n-BuLi at low temperatures. The Seyferth-Gilbert reaction or the modified Bestmann-Ohira reaction is the formation of terminal alkynes from aldehydes with phosphonates. These hazardous diazo compounds are difficult to handle, especially for large-scale production. The development of new synthetic strategies to prepare aromatic terminal alkynes is of great research significance. Summary of the invention

[0003] The present invention provides a one-pot synthesis of terminal alkynes from 2-methylpyridine compounds and N,N-dimethylformamide, which is expected to complement the most advanced technology by simplifying the synthesis of alkynes, reducing the production cost of these valuable building blocks, and increasing the sustainability of alkyne synthesis. The specific scheme is as follows:

[0004]

[0005] A method for synthesizing a terminal alkyne compound comprises: using a 2-methylpyridine compound shown in Formula 1 and N,N-dimethylformamide shown in Formula 2 to mix with an organic solvent in the presence of a strong base, a cesium salt additive, and an activator, and reacting to synthesize a terminal alkyne shown in Formula 3, wherein the strong base is lithium bis(trimethylsilyl)amide and lithium tert-butoxide:

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

[0007] The method of the invention can realize the one-pot preparation of terminal alkyne compounds, reduce the reaction steps, and thus improve the product yield; the raw materials used in the synthesis method are simple and economical; and R in the invention can be selected from a variety of options, and has wider applicability.

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

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

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

[0011] Preferably, the reaction is carried out in the presence of an activator, and preferably, the activator 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 shown in Formula 1, N,N-dimethylformamide shown in 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; and the reaction temperature is 50-130°C.

[0014] Preferably, the method of the present invention can be used to synthesize terminal alkynes of the following structure:

[0015]

[0016] 2-methylpyridine compounds 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), a cesium salt additive (cesium fluoride), and an activator Nf-F (perfluorobutylsulfonyl fluoride) to react, and finally a terminal alkyne is synthesized.

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

[0018] The raw materials used in the synthesis method of the present invention are cheap and readily available;

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

[0020] The present invention adopts a one-pot synthesis method, which reduces the loss of raw materials and improves the yield of the product due to fewer reaction steps;

[0021] The operation steps required by the present invention are relatively simple, and no extreme heating or cooling is required. The reaction can be performed at normal pressure, which is safe and convenient.

[0022] R in the present invention can be selected from a variety of options, so the method of the present invention has wider applicability and can synthesize a variety of terminal alkyne compounds. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] The accompanying drawings are hydrogen and carbon nuclear magnetic resonance spectra of the products of each embodiment. The serial numbers of the accompanying drawings correspond to the serial numbers of the embodiments. Figure A is a hydrogen nuclear magnetic resonance spectrum, and Figure B is a carbon nuclear magnetic resonance spectrum. Figure 1A is the hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 1, Figure 1B The carbon nuclear magnetic resonance spectrum of the product obtained in Example 1; Figure 2A is the hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 2, Figure 2Bis the carbon nuclear magnetic resonance spectrum of the product obtained in Example 2; Figure 3A is the hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 3, Figure 3B is the carbon nuclear magnetic resonance spectrum of the product obtained in Example 3; Figure 4A is the hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 4, Figure 4B The carbon nuclear magnetic resonance spectrum of the product obtained in Example 4; Figure 5A is the hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 5, Figure 5B is the carbon nuclear magnetic resonance spectrum of the product obtained in Example 5; Fig. 6A is the hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 6, Figure 6B is the carbon nuclear magnetic resonance spectrum of the product obtained in Example 6; Fig. 7A is the hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 7, Figure 7B is the carbon nuclear magnetic resonance spectrum of the product obtained in Example 7; Fig. 8A is the hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 8, Figure 8B The carbon nuclear magnetic resonance spectrum of the product obtained in Example 8 is as follows: Fig.9A is the hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 9, Fig. 9B is the carbon nuclear magnetic resonance spectrum of the product obtained in Example 9; Fig. 10A is the hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 10, Fig. 10B The carbon nuclear magnetic resonance spectrum of the product obtained in Example 10 is shown in FIG. Specific embodiments

[0024] In order to facilitate the understanding of those skilled in the art, the concept of the present invention is further described below in conjunction with the embodiments. The specific description of the following embodiments is not intended to limit the present invention, but is only intended to facilitate the understanding of the present technical solution by those skilled in the art. The various raw materials involved in the specification are purchased from the market or are simply synthesized. Other drugs are purchased from Anaiji, Bi De, Sigma-Aldrich, Acros, Alfa Aesar, Adamas-beta or J&K. The nuclear magnetic resonance spectrometer models are Bruker 400M and JEOL 400M.

[0025] Example 1

[0026] In a glove box filled with nitrogen, LiN(SiMe3)2 (33.5 mg, 0.2 mmol), CsF (15.2 mg, 0.1 mmol), 2-methylpyridine (30 μL, 0.3 mmol), and isopropyl ether (1.6 mL) were added to a dry microwave tube with a magnet in sequence and reacted at 110°C for 3 h. Then, the mixture was cooled to 50°C, N,N-dimethylformamide (8.0 μL, 0.1 mmol, 1 equiv) was added, and stirred for 3 h. The mixture was cooled to 0°C, and Nf-F (1.6 equiv) and LiO were added. t Bu (3 equiv), 0°C for 30 min, then heated 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 flash chromatography to obtain the product (81% yield). 1 H NMR (400MHz, CDCl3) δ8.58 (ddd, J=4.9, 1.7, 1.0Hz, 1H), 7.66 (td, J=7.7, 1.8Hz, 1H), 7.48 (dt, J=7.8, 1.1Hz, 1H), 7.30-7.25 (m, 1H), 3.14 (s, 1H); 13 C{ 1 H}NMR (101MHz, CDCl3) δ150.0, 142.3, 136.1, 127.4, 123.4, 82.7, 77.0ppm.

[0027] The raw materials in Example 1 were changed, and the following 10 groups of experimental examples were designed, wherein the first group of experiments was Example 1, and the corresponding nuclear magnetic resonance spectrum of the product was shown in Figure 1. The serial numbers of the nuclear magnetic resonance spectra of the remaining groups 2-10 of products correspond to the serial numbers of the corresponding examples.

[0028] The table lists the structural formulas of the products in Examples 1-10, the last column lists the yields of the products in each Example, and indicates the specific implementation conditions of each Example. The specific meanings of the implementation conditions of each Example are shown below the table.

[0029]

[0030] Example 2

[0031] In a glove box filled with nitrogen, LiN(SiMe3)2 (33.5 mg, 0.2 mmol), CsF (15.2 mg, 0.1 mmol), 2,4-dimethylpyridine (35 μL, 0.3 mmol), and isopropyl ether (1.6 mL) were added to a dry microwave tube with a magnet in sequence and reacted at 110°C for 3 h. Then, the mixture was cooled to 50°C, N,N-dimethylformamide (8.0 μL, 0.1 mmol, 1 equiv) was added, and stirred for 3 h. The mixture was cooled to 0°C, and Nf-F (1.6 equiv) and LiO were added. t Bu (3 equiv), 0°C for 30 min, then heated 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 flash chromatography to obtain the product (88% yield). 1 H NMR (400MHz, CDCl3) δ8.39 (d, J=5.1Hz, 1H), 7.31 (s, 1H), 7.10 (d, J=5.1Hz, 1H), 3.11 (s, 1H), 2.33 (s, 3H); 13 C{ 1 H}NMR (101MHz, CDCl3) δ149.3, 148.2, 141.5, 128.6, 124.8, 82.3, 77A, 20.9ppm.

[0032] Example 3

[0033] In a glove box filled with nitrogen, LiN(SiMe3)2 (33.5 mg, 0.2 mmol), CsF (15.2 mg, 0.1 mmol), 2,5-dimethylpyridine (35 μL, 0.3 mmol), and isopropyl ether (1.6 mL) were added to a dry microwave tube with a magnet in sequence and reacted at 110°C for 3 h. Then, the mixture was cooled to 50°C, N,N-dimethylformamide (8.0 μL, 0.1 mmol, 1 equiv) was added, and stirred for 3 h. The mixture was cooled to 0°C, and Nf-F (1.6 equiv) and LiO were added. t Bu (3 equiv), 0°C for 30 min, then heated to 50°C for 6 h, 90°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 (50% yield). 1 H NMR (400MHz, CDCl3) δ8.34 (s, 1H), 7.42-7.36 (m, 1H), 7.30 (d, J = 7.9Hz, 1H), 3.05 (s, 1H), 2.27 (s, 3H); 13 C{ 1H}NMR (101MHz, CDCl3) δ150.6, 139.5, 136.6, 133.4, 126.9, 82.8, 76.5, 18.5ppm.

[0034] Example 4

[0035] In a glove box filled with nitrogen, 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), and isopropyl ether (1.6 mL) were added to a dry microwave tube with a magnetron in sequence and reacted at 110°C for 3 h. Then, the mixture was cooled to 50°C, N,N-dimethylformamide (8.0 μL, 0.1 mmol, 1 equiv) was added, and stirred for 3 h. The mixture was cooled to 0°C, and Nf-F (1.6 equiv) and LiO were added. t Bu (3 equiv), 0°C for 30 min, then heated to 50°C for 6 h, 90°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 (55% yield). 1 H NMR (400MHz, CDCl3) δ8.21 (s, 1H), 7.33 (s, 1H), 3.28 (s, 1H), 2.39 (s, 3H), 2.30 (s, 3H); 13 C{ 1 H} NMR (101MHz, CDCl3) δ148.0, 139.2, 137.7, 135.9, 133.3, 81.7, 80.1, 19.2, 18.4ppm.

[0036] Example 5

[0037] In a glove box filled with nitrogen, LiN(SiMe3)2 (33.5 mg, 0.2 mmol), CsF (15.2 mg, 0.1 mmol), 5-ethyl-2-methylpyridine (39 μL, 0.3 mmol), and isopropyl ether (0.8 mL) were added to a dry microwave tube with a magnet in sequence and reacted at 110°C for 3 h. Then, the mixture was cooled to 50°C, N,N-dimethylformamide (8.0 μL, 0.1 mmol, 1 equiv) was added, and stirred for 3 h. The mixture was cooled to 0°C, and Nf-F (1.6 equiv) and LiO t Bu (3 equiv), 0°C for 30 min, then heated to 50°C for 6 h, 90°C for 6 h, cooled to room temperature, the reaction was complete. The crude product was purified by silica gel column flash chromatography to obtain the product (70% yield). 1H NMR (400MHz, CDCl3) δ8.42 (d, J=1.6Hz, 1H), 7.47 (dd, J=8.0, 2.2Hz, 1H), 7.39 (d, J=8.0Hz, 1H), 3.09 (s, 1H), 2.65 (q, J=7.6Hz, 2H), 1.24 (t, J=7.6Hz, 3H); 13 C{ 1 H} NMR (101MHz, CDCl3) δ150.0, 139.7, 139.6, 135.5, 127.2, 82.9, 76.5, 26.1, 15.2ppm.

[0038] Example 6

[0039] In a glove box filled with nitrogen, 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), and isopropyl ether (0.8 mL) were added to a dry microwave tube with a magnet in sequence and reacted at 110°C for 3 h. Then, the mixture was cooled to 50°C, N,N-dimethylformamide (8.0 μL, 0.1 mmol, 1 equiv) was added, and stirred for 3 h. The mixture was cooled to 0°C, and Nf-F (1.6 equiv) and LiO were added. t Bu (3 equiv), 0°C for 30 min, then heated 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 flash chromatography to obtain the product (61% yield). 1 H NMR (400MHz, CDCl3) δ7.50 (dd, J=8.4, 7.3Hz, 1H), 7.07 (dd, J=7.2, 0.7Hz, 1H), 6.74-6.65 (m, 1H), 3.93 (s, 3H), 3.11 (s, 1H); 13 C{ 1 H}NMR (101MHz, CDCl3) δ163.9, 139.1, 138.5, 121.0, 112.0, 83.0, 76.5, 53.7ppm.

[0040] Example 7

[0041] In a glove box filled with nitrogen, LiN(SiMe3)2 (33.5 mg, 0.2 mmol), CsF (15.2 mg, 0.1 mmol), 2-methylquinoline (41 μL, 0.3 mmol), and isopropyl ether (0.8 mL) were added to a dry microwave tube with a magnet in sequence and reacted at 110°C for 3 h. Then, the mixture was cooled to 50°C, N,N-dimethylformamide (8.0 μL, 0.1 mmol, 1 equiv) was added, and stirred for 3 h. The mixture was cooled to 0°C, and Nf-F (1.6 equiv) and LiO t Bu (3 equiv), 0°C for 30 min, then heated 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 flash chromatography to obtain the product (78% yield). 1 H NMR (400MHz, CDCl3) δ8.11 (dd, J=14.6, 8.3Hz, 2H), 7.80 (d, J=8.1Hz, 1H), 7.73 (ddd, J=8.4, 6.9, 1.4Hz, 1H), 7.58-7.52 (m, 2H), 3.25 (s, 1H); 13 C{ 1 H} NMR (101MHz, CDCl3) δ148.1, 142.4, 136.4, 130.3, 129.5, 127.6, 127.5, 127.4, 124.2, 83.4, 77.7ppm.

[0042] Example 8

[0043] In a glove box filled with nitrogen, LiN(SiMe3)2 (33.5 mg, 0.2 mmol), CsF (15.2 mg, 0.1 mmol), 2,6-dimethylquinoline (47 mg, 0.3 mmol), and isopropyl ether (0.8 mL) were added to a dry microwave tube with a magnetron in sequence and reacted at 110°C for 3 h. Then, the mixture was cooled to 50°C, N,N-dimethylformamide (8.0 μL, 0.1 mmol, 1 equiv) was added, and stirred for 3 h. The mixture was cooled to 0°C, and Nf-F (1.6 equiv) and LiO t Bu (3 equiv), 0°C for 30 min, then heated 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 flash chromatography to obtain the product (98% yield). 1 H NMR (401MHz, CDCl3) δ7.99 (dd, J = 15.3, 8.9Hz, 2H), 7.58-7.45 (m, 3H), 3.21 (s, 1H), 2.51 (s, 3H); 13 C{ 1H}NMR (101MHz, CDCl3) δ146.7, 141.5, 137.6, 135.6, 132.5, 129.1, 127.5, 126.4, 124.2, 83.5, 77.3, 21.7ppm.

[0044] Example 9

[0045] In a glove box filled with nitrogen, 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), and methyl tert-butyl ether (1.6 mL) were added to a dry microwave tube with a magnet in sequence and reacted at 110°C for 3 h. Then, the mixture was cooled to 50°C, N,N-dimethylformamide (8.0 μL, 0.1 mmol, 1 equiv) was added, stirred for 3 h, cooled to 0°C, and Nf-F (1.6 equiv) and LiO t Bu (3 equiv), 0°C for 30 min, then heated 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 flash chromatography to obtain the product (98% yield). 1 H NMR (400MHz, CDCl3) δ7.98 (dd, J = 8.6, 6.3Hz, 2H), 7.48 (d, J = 8.5Hz, 1H) 7.36 (dd, J = 9.3, 2.8Hz, 1H), 7.02 (d, J = 2.8Hz, 1H), 3.91 (s, 3H), 3.19 (s, 1H); 13 C{ 1 H} NMR (101MHz, CDCl3) δ158.5, 144.3, 139.7, 135.0, 130.9, 128.6, 124.59, 123.2, 104.8, 83.5, 77.0, 55.7ppm.

[0046] Example 10

[0047] In a glove box filled with nitrogen, LiN(SiMe3)2 (33.5 mg, 0.2 mmol), CsF (15.2 mg, 0.1 mmol), 6-ethoxy-2-methylquinoline (56 mg, 0.3 mmol), and methyl tert-butyl ether (1.6 mL) were added to a dry microwave tube with a magnetron in sequence and reacted at 110°C for 3 h. Then, the mixture was cooled to 50°C, N,N-dimethylformamide (8.0 μL, 0.1 mmol, 1 equiv) was added, stirred for 3 h, cooled to 0°C, and Nf-F (1.6 equiv) and LiO tBu (3 equiv), 0°C for 30 min, then heated 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 flash chromatography to obtain the product (95% yield). 1 H NMR (400MHz, CDCl3) δ7.96 (d, J = 8.7 Hz, 2H), 7.47 (d, J = 8.2 Hz, 1H), 7.35 (dd, J = 9.2, 2.8H z, 1H), 7.00 (d, J = 2.8Hz, 1H), 4.12 (q, J = 7.0Hz, 2H), 3.19 (s, 1H), 1.47 (t, J = 7.0Hz, 3H); 13 C{ 1 H} NMR (101MHz, CDCl3) δ157.9, 144.2, 139.7, 134.9, 130.9, 128.7, 124.5, 123.4, 105.5, 83.5, 76.9, 63.9, 14.8ppm.

Claims

1. A method for synthesizing terminal alkynes, characterized in that: The terminal alkyne shown in Formula 3 is synthesized by mixing a 2-methylpyridine derivative shown in Formula 1 and N,N-dimethylformamide shown in Formula 2 with an organic solvent in the presence of a strong base, a cesium salt additive, and an activator; the strong base is lithium bis(trimethylsilyl)amide and lithium tert-butoxide; Wherein R is selected from methyl, methoxy, and quinoline ring.

2. The synthesis method according to claim 1, characterized in that The cesium salt additive 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, wherein the inert gas is nitrogen.

4. The synthesis method according to claim 1, characterized in that The activator is Nf-F (perfluorobutylsulfonyl fluoride).

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

6. 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 bis(trimethylsilyl)amide, cesium fluoride, Nf-F and potassium tert-butoxide is: 2-3: 1-2: 1.6-3.2: 3-6; the reaction temperature is 50-110°C.

7. The synthesis method according to claim 1, characterized in that The 2-methylpyridine derivative and the product terminal alkyne are as follows:

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