A synthetic method for the tms protection of alkyne

Abstract

The application belongs to the field of organic synthesis, and particularly relates to a synthesis method of TMS protected alkyne. An alkyl amide derivative shown in formula 1 and N,N-dimethylformamide shown in formula 2 are mixed with an organic solvent (tetrahydrofuran) in the presence of a strong base (lithium bis(trimethylsilyl)amide) and an activating agent (diethyl chlorophosphate), and a reaction is performed to synthesize TMS protected alkyne shown in formula 3. The raw materials used in the application are common chemicals on the market. The application has a wide range of applications, and not only can common TMS protected alkyne compounds be synthesized, but also a series of TMS protected 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] This invention belongs to the field of organic synthesis, and specifically relates to a method for synthesizing TMS-protected alkynes. Background Technology

[0002] TMS alkynes have a variety of applications. They can be used as cross-coupling partners, chemical anchors between electrodes, and organometallic polymer frameworks. Synthetic methods for functionalized TMS acetylenes can start with terminal alkynes, requiring additional synthetic steps. They can also be prepared by coupling Sonogashira with trimethylsilylacetylene without problems using Pd and Cu. However, the involvement of expensive transition metals makes large-scale production difficult. Developing new synthetic strategies for the preparation of TMS alkynes is of significant research importance. Summary of the Invention

[0003] This invention provides a one-pot synthesis reaction of TMS-protected alkynes from alkylamide derivatives and N,N-dimethylformamide. This method is expected to simplify the synthesis of TMS-protected alkynes, reduce the production cost of these valuable building blocks, and increase the sustainability of TMS-protected alkyne synthesis, thus complementing state-of-the-art technologies. The specific scheme is as follows:

[0004]

[0005] A method for synthesizing TMS-protected alkyne compounds involves mixing an alkylamide derivative of Formula 1 and N,N-dimethylformamide of Formula 2 with an organic solvent in the presence of a strong base and an activator to synthesize the TMS-protected alkyne of Formula 3. The strong base is lithium di(trimethylsilyl)amino.

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

[0007] The method of this invention can achieve one-pot TMS protection of alkyne compounds, reducing reaction steps and thus improving product yield; the raw materials used in the synthesis method are simple and economical; and R in this invention can be selected from multiple options, making it more widely applicable.

[0008] Preferably, R is selected from methyl, ethyl, isopropyl, morpholine ring, and 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 under an activating agent, and preferably, the activating agent 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 di(trimethylsilyl)aminophosphate, 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 synthesize TMS-protected alkynes with the following structures:

[0014]

[0015] TMS-protected alkynes were synthesized by reacting alkylamide derivatives and N,N-dimethylformamide in a mixture of a strong base (lithium di(trimethylsilyl)amino) and an activator (diethyl chlorophosphate) with an organic solvent (tetrahydrofuran).

[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 this invention are all inexpensive and readily available;

[0018] The synthesis method of this invention does not use transition metal catalysts, making it green and environmentally friendly;

[0019] This invention employs a one-pot synthesis method, which reduces the loss of raw materials and increases the yield of the product due to fewer reaction steps.

[0020] The operation steps required by this invention are relatively simple, requiring no extreme heating or cooling, and the reaction can be carried out under normal pressure, making it safe and convenient.

[0021] In this invention, R can be selected from a variety of options, thus making the method of this invention more widely applicable and capable of synthesizing a variety of terminal alkyne compounds. Attached Figure Description

[0022] The attached figures show the proton and carbon NMR spectra of the products from each embodiment. The figure numbers correspond to the embodiment numbers. Figure A is the proton NMR spectrum, and Figure B is the carbon NMR spectrum. Figure 1A The above is the proton NMR spectrum of the product obtained in Example 1. Figure 1B The carbon NMR spectrum of the product obtained in Example 1; Figure 2A The above is the proton NMR spectrum of the product obtained in Example 2. Figure 2B The carbon NMR spectrum of the product obtained in Example 2 is as follows: Figure 3A The image shows the proton NMR spectrum of the product obtained in Example 3. Figure 3B The carbon NMR spectrum of the product obtained in Example 3; Figure 4A The above is the proton NMR spectrum of the product obtained in Example 4. Figure 4B The carbon NMR spectrum of the product obtained in Example 4; Figure 5AThe above is the proton NMR spectrum of the product obtained in Example 5. Figure 5B The carbon NMR spectrum of the product obtained in Example 5; Figure 6A The above is the proton NMR spectrum of the product obtained in Example 6. Figure 6B The image shows the carbon NMR spectrum of the product obtained in Example 6. Specific Implementation

[0023] To facilitate understanding by those skilled in the art, the concept of the present invention will be further explained below with reference to embodiments. The specific descriptions of the following embodiments are not intended to limit the present invention, but are merely for the convenience of those skilled in the art to understand the technical solution. All raw materials mentioned in the specification were purchased from the market or synthesized through simple methods. Other pharmaceuticals were purchased from Amex, Bide, Sigma-Aldrich, Acros, Alfa Aesar, Adamas-beta, or J&K. The nuclear magnetic resonance spectrometer was a Bruker 400M and a JEOL 400M.

[0024] Example 1

[0025] In a nitrogen-filled glove box, 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 sequentially to a dry microwave tube equipped with a magnetic inlet. The reaction was carried out 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 to 0.3 mL of tetrahydrofuran. The mixture was kept at 0 °C for 30 min, then heated to room temperature for 1 h, and finally cooled to room temperature to complete the reaction. The crude product was purified by rapid silica gel column chromatography to obtain the final 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] By changing the raw materials in Example 1, the following six sets of experimental examples were designed, where the first set of experiments is Example 1, and the corresponding NMR spectrum of the product is shown in Figure 1. The NMR spectra of the products in the remaining sets 2-6 correspond to the sequence numbers of the respective examples.

[0027] The table lists the structural formulas of the products in each of the 1-6 embodiments. The last column lists the yield of the products in each embodiment and indicates the specific implementation conditions of each embodiment. The specific meaning of the implementation conditions of each embodiment is shown below the table.

[0028]

[0029]

[0030] Example 2

[0031] In a nitrogen-filled glove box, 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 sequentially to a dry microwave tube equipped with a magnetic dome, and the reaction was carried out 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 to 0.3 mL of tetrahydrofuran. The mixture was kept at 0 °C for 30 min, then heated to room temperature for 1 h, and finally cooled to room temperature to complete the reaction. The crude product was purified by rapid silica gel column chromatography to obtain the final 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 nitrogen-filled glove box, 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 sequentially to a dry microwave tube equipped with a magnetic inlet. The reaction was carried out 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 to 0.3 mL of tetrahydrofuran. The mixture was kept at 0 °C for 30 min, then heated to room temperature for 1 h, and finally cooled to room temperature to complete the reaction. The crude product was purified by rapid silica gel column chromatography to obtain the final 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 nitrogen-filled glove box, 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 sequentially to a dry microwave tube equipped with a magnetic dome, and the reaction was carried out 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 to 0.3 mL of tetrahydrofuran. The mixture was kept at 0 °C for 30 min, then heated to room temperature for 1 h, and finally cooled to room temperature to complete the reaction. The crude product was purified by rapid silica gel column chromatography to obtain the final 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 nitrogen-filled glove box, LiN(SiMe3)2 (50.2 mg, 0.3 mmol), N,N-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 sequentially to a dry microwave tube equipped with a magnetic dome, and the reaction was carried out 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 to 0.3 mL of tetrahydrofuran. The mixture was kept at 0 °C for 30 min, then heated to room temperature for 1 h, and finally cooled to room temperature to complete the reaction. The crude product was purified by rapid silica gel column chromatography to obtain the final 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 nitrogen-filled glove box, LiN(SiMe3)2 (50.2 mg, 0.3 mmol), 1-(1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-yl)ethyl-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 sequentially to a dry microwave tube equipped with a magnetic dome. The reaction was carried out 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 to 0.3 mL of tetrahydrofuran. The mixture was kept at 0 °C for 30 min, then heated to room temperature for 1 h, and finally cooled to room temperature to complete the reaction. The crude product was purified by rapid silica gel column chromatography to obtain the final 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 was synthesized by reacting an alkylamide derivative of Formula 1 and an N,N-dimethylformamide of Formula 2 with an organic solvent in the presence of a strong base and an activator; the strong base was lithium di(trimethylsilyl)amino. The activator is selected from diethyl chlorophosphate; The alkylamide derivative shown in Formula 1 is selected from... The TMS-protected alkynes shown in Formula 3 are selected from 2. A method for synthesizing TMS-protected alkynes, characterized in that: Synthesized by reacting alkylamide derivatives and N,N-dimethylformamide with an organic solvent in the presence of a strong base and an activator. TMS protects alkynes; the strong base is lithium di(trimethylsilyl)amino; The activator is selected from diethyl chlorophosphate; The alkylamide derivative is selected from TMS-protected alkynes are selected from 3. The synthesis method according to any one of claims 1 or 2, characterized in that, The reaction was carried out under nitrogen gas protection.

4. The synthesis method according to any one of claims 1 or 2, characterized in that, The organic solvent is tetrahydrofuran.

5. The synthesis method according to any one of claims 1 or 2, characterized in that, The molar ratio of alkylamide derivative, N,N-dimethylformamide, lithium di(trimethylsilyl)aminophosphate, and diethyl chlorophosphate in the reaction was 1:1:5:1.6; the reaction temperature was 0–50 °C.

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