Synthesis method of TMS protected alkyne

Abstract

The invention belongs to the field of organic synthesis, and particularly relates to a synthesis method of TMS protected alkyne. The preparation method comprises the following steps: mixing an alkylamide derivative shown in a formula 1 and N, N-dimethylformamide shown in a formula 2 with an organic solvent (tetrahydrofuran) in the presence of a strong base (lithium bis (trimethylsilyl) amide) and an activating agent (diethyl chlorophosphate), and reacting to synthesize the TMS protected alkyne 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 TMS protected alkyne compounds can be synthesized, reaction substrates can be adjusted according to needs, and a series of TMS protected 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 TMS-protected alkynes. Background Art

[0002] TMS alkynes have a variety of applications. They can be used as cross-coupling partners, chemical anchors between electrodes, and organometallic polymer backbones. The synthesis of functionalized TMS acetylenes can start from terminal alkynes and requires additional synthetic operations. They can also be prepared by Sonogashira coupling with trimethylsilylacetylene if Pd and Cu are used without problems. However, the expensive transition metals involved make large-scale production difficult. The development of new synthetic strategies to prepare TMS alkynes is of great research significance. Summary of the invention

[0003] The present invention provides a one-pot synthesis of TMS-protected alkynes from alkylamide derivatives and N,N-dimethylformamide, which is expected to complement the state-of-the-art technology by simplifying the synthesis of TMS-protected alkynes, reducing the production cost of these valuable building blocks, and increasing the sustainability of TMS-protected alkyne synthesis. The specific scheme is as follows:

[0004]

[0005] A method for synthesizing a TMS-protected alkyne compound comprises: using an alkylamide derivative shown in formula 1 and N,N-dimethylformamide shown in formula 2, in the presence of a strong base and an activator, and mixing with an organic solvent to react and synthesize a TMS-protected alkyne shown in formula 3, wherein the strong base is lithium bis(trimethylsilyl)amide;

[0006] Wherein R is selected from methyl, ethyl, isopropyl, morpholine ring, and isoquinoline ring.

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

[0008] Preferably, R is selected from methyl, ethyl, isopropyl, morpholine ring, isoquinoline 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 reaction is carried out in the presence of an activator, and preferably, the activator is diethyl chlorophosphate.

[0011] Preferably, the organic solvent is tetrahydrofuran.

[0012] Preferably, the molar ratio of the alkylamide derivative shown in Formula 1, N,N-dimethylformamide shown in Formula 2, lithium bis(trimethylsilyl)amide, and diethyl chlorophosphate in the reaction is 1:1:5:1.6; and the reaction temperature is 0-50°C.

[0013] Preferably, the method of the present invention can be used to synthesize TMS-protected alkynes of the following structure:

[0014]

[0015] Alkylamide derivatives and N, N-dimethylformamide are reacted in the presence of a strong base (lithium bis(trimethylsilyl)amide) and an activator (diethyl chlorophosphate) in a mixture with an organic solvent (tetrahydrofuran) to finally synthesize TMS-protected alkynes.

[0016] The technical solution of the present invention can achieve at least one of the following beneficial effects:

[0017] The raw materials used in the synthesis method of the present invention are cheap and readily available;

[0018] The synthesis method of the present invention does not use transition metal catalysts and is green and environmentally friendly;

[0019] 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;

[0020] 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.

[0021] 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

[0022] 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 2B The carbon nuclear magnetic resonance spectrum of the product obtained in Example 2 is as follows: Figure 3A is the hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 3, Figure 3B 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 5Ais 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 The carbon nuclear magnetic resonance spectrum of the product obtained in Example 6 is shown in FIG. Specific embodiments

[0023] 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 a limitation of the present invention, 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 after simple synthesis, other drugs are purchased from Anaiji, Bi De, Sigma-Aldrich, Acros, AlfaAesar, Adamas-beta or J&K., and the nuclear magnetic resonance spectrometer models are Bruker 400M and JEOL 400M.

[0024] Example 1

[0025] In a glove box filled with nitrogen, LiN(SiMe3)2 (50.2 mg, 0.3 mmol), N,N-diethylacetamide (0.1 mmol, 12 μL), N,N-dimethylformamide (8.0 μL, 0.1 mmol, 1 equiv), and tetrahydrofuran (0.6 mL) were added to a dry microwave tube with a magnet in sequence, and reacted at 50°C for 3 h. Then cooled to 0°C, diethyl chlorophosphate (1.6 equiv) and LiN(SiMe3)2 (33.6 mg, 0.2 mmol) in 0.3 mL of tetrahydrofuran were added, kept at 0°C for 30 min, then heated to room temperature for 1 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 (83% yield). 1 HNMR (400MHz, CDCl3) δ3.58 (q, J=7.2Hz, 2H), 3.41 (q, J=7.2Hz, 2H), 1.22 (t, J=7.1Hz, 3H), 1.13 (t, J=7.1Hz, 3H), 0.23 (s, 9H); 13 C{ 1 H}NMR (126MHz, CDCl3) δ153.3, 96.5, 95.8, 43.5, 39.1, 14.2, 12.7, 0.6ppm.

[0026] The raw materials in Example 1 were changed to design the following 6 groups of experimental examples, wherein the first group of experiments is Example 1, and the corresponding nuclear magnetic resonance spectrum of the product is shown in Figure 1. The serial numbers of the nuclear magnetic resonance spectra of the remaining 2-6 groups of products correspond to the serial numbers of the corresponding examples.

[0027] The table lists the structural formulas of the products in Examples 1-6, 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.

[0028]

[0029]

[0030] Example 2

[0031] In a glove box filled with nitrogen, LiN(SiMe3)2 (50.2 mg, 0.3 mmol), N,N-dimethylacetamide (0.1 mmol, 9.3 μL), N,N-dimethylformamide (8.0 μL, 0.1 mmol, 1 equiv), and tetrahydrofuran (0.6 mL) were added to a dry microwave tube with a magnet in sequence, and reacted at 50°C for 3 h. Then cooled to 0°C, diethyl chlorophosphate (1.6 equiv) and LiN(SiMe3)2 (33.6 mg, 0.2 mmol) were added in 0.3 mL of tetrahydrofuran, and kept at 0°C for 30 min, then heated to room temperature for 1 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 (68% yield). 1 HNMR (400MHz, CDCl3) δ3.21 (s, 3H), 2.96 (s, 3H), 0.23 (s, 9H); 13 C{ 1 H}NMR (126MHz, CDCl3) δ154.0, 97.1, 96.0, 38A, 34.0, 0.6ppm.

[0032] Example 3

[0033] In a glove box filled with nitrogen, LiN(SiMe3)2 (50.2 mg, 0.3 mmol), N,N-diisopropylacetamide (0.1 mmol, 7.8 μL), N,N-dimethylformamide (8.0 μL, 0.1 mmol, 1 equiv), and tetrahydrofuran (0.6 mL) were added to a dry microwave tube with a magnet in sequence, and reacted at 50°C for 3 h. Then cooled to 0°C, diethyl chlorophosphate (1.6 equiv) and LiN(SiMe3)2 (33.6 mg, 0.2 mmol) in 0.3 mL of tetrahydrofuran were added, kept at 0°C for 30 min, then heated to room temperature for 1 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 (73% yield). 1HNMR (400MHz, CDCl3) δ4.61-4.45 (m, 1H), 3.75-3.53 (m, 1H), 1.35 (d, J=6.8Hz, 6H), 1.25 (d, J=6.8Hz, 6H), 0.22 (s, 9H); 13 C{ 1 H}NMR (126MHz, CDCl3) δ153.0, 97.7, 95.0, 45.6, 20.9, 20.0ppm.

[0034] Example 4

[0035] In a glove box filled with nitrogen, LiN(SiMe3)2 (50.2 mg, 0.3 mmol), 4-acetylmorpholine (0.1 mmol, 7.8 μL), N,N-dimethylformamide (8.0 μL, 0.1 mmol, 1 equiv), and tetrahydrofuran (0.6 mL) were added to a dry microwave tube with a magnet in sequence, and the mixture was reacted at 50°C for 3 h. The mixture was then cooled to 0°C, and diethyl chlorophosphate (1.6 equiv) and LiN(SiMe3)2 (33.6 mg, 0.2 mmol) were added in 0.3 mL of tetrahydrofuran, and the mixture was kept at 0°C for 30 min, then heated to room temperature for 1 h, cooled to room temperature, and the reaction was completed. The crude product was purified by flash chromatography on a silica gel column to obtain the product (78% yield). 1 H NMR (401MHz, CDCl3) δ3.79-3.68(m, 4H), 3.68-3.59(m, 4H), 0.23(s, 9H); 13 C{ 1 H} NMR (101MHz, CDCl3) δ152.5, 98.3, 95.1, 66.8, 66.4, 47.2, 41.8, 0.6ppm.

[0036] Example 5

[0037] In a glove box filled with nitrogen, LiN(SiMe3)2 (50.2 mg, 0.3 mmol), NN-dimethylthioacetamide (0.1 mmol, 10.3 mg), N,N-dimethylformamide (8.0 μL, 0.1 mmol, 1 equiv), and tetrahydrofuran (0.6 mL) were added to a dry microwave tube with a magnet in sequence, and reacted at 50°C for 3 h. Then cooled to 0°C, diethyl chlorophosphate (1.6 equiv) and LiN(SiMe3)2 (33.6 mg, 0.2 mmol) in 0.3 mL of tetrahydrofuran were added, kept at 0°C for 30 min, then heated to room temperature for 1 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). 1HNMR (400MHz,CDCl3) 1 H NMR (400MHz, CDCl3) δ3.52 (s, 3H), 3.42 (s, 3H), 0.23 (s, 9H); 13 C{ 1 H}NMR (101MHz, CDCl3) δ177.5, 103.4, 100.0, 43.8, 41.0, 0.5ppm.

[0038] Example 6

[0039] In a glove box filled with nitrogen, LiN(SiMe3)2 (50.2 mg, 0.3 mmol), 1-(1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one (0.1 mmol, 38.5 mg), N,N-dimethylformamide (8.0 μL, 0.1 mmol, 1 equiv), and tetrahydrofuran (0.6 mL) were added to a dry microwave tube equipped with a magnetic pole in sequence, and the mixture was reacted at 50°C for 3 h. The mixture was then cooled to 0°C, and diethyl chlorophosphate (1.6 equiv) and LiN(SiMe3)2 (33.6 mg, 0.2 mmol) in 0.3 mL of tetrahydrofuran were added, and the mixture was kept at 0°C for 30 min, then heated to room temperature for 1 h, cooled to room temperature, and the reaction was terminated. The crude product was purified by flash chromatography on a silica gel column to obtain the product (52% yield). 1 H NMR (400MHz, CDCl3) δ6.80-6.69 (m, 1H), 6.69-6.46 (m, 3H), 6.27 (s, 1H, rotamer), 5.65-5.30 (t, J=5.2Hz, 1H, rotamer), 4.50-4 .12 (ddd, J=13.2, 6.1, 3.3Hz, 1H, rotamer), 3.89-3.74 (m, 9H), 3.68 (s, 3H, rotamer), 3.53-2.26 (m, 5H), 0.23 (s, 9H, rotamer); 13 C{ 1H}NMR(101MHz,CDCl3)δ152.0,148.8(148.7),148.1(148.0),147.8(147.7),147.2(147.1),130.1(129.9),127.3(127.2),126.2(125.7),121.9,113.3(112.8),111.4(111.3),111.0(110.8),110.4,97.6(97.2),96.1(95.9),59.5,55.9(53.7),55.9(55.8),55.8(55.7),43.1,42.3(41.5),36.1,28.5(27.7),0.6ppm.

Claims

1. A method for synthesizing TMS-protected alkynes, characterized in that: The TMS protected alkyne shown in Formula 3 is synthesized by using an alkylamide derivative shown in Formula 1 and N,N-dimethylformamide shown in Formula 2 to react with an organic solvent in the presence of a strong base and an activator; the strong base is lithium bis(trimethylsilyl)amide; Wherein R is selected from methyl, ethyl, isopropyl, morpholine ring, and isoquinoline ring.

2. 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.

3. The synthesis method according to claim 1, characterized in that The activator is diethyl chlorophosphate.

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

5. The synthesis method according to claim 1, characterized in that In the reaction, the molar ratio of the alkylamide derivative shown in formula 1, N,N-dimethylformamide shown in formula 2, lithium bis(trimethylsilyl)amide and diethyl chlorophosphate is 1:1:5:1.6; and the reaction temperature is 0-50°C.

6. The synthesis method according to claim 1, characterized in that The alkylamide derivatives and the product TMS protected alkyne are as shown in the following table:

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