5-aryl-3-trimethylsiloxy-1-valeronitrile compound and preparation method thereof

Abstract

The invention discloses a method for preparing a 5-aryl-3-trimethylsiloxy-1-valeronitrile compound through photocatalysis, and belongs to the technical field of organic synthesis. The method comprises the following steps: under the protection of inert gas, by taking 3-bromo-5-trimethylsilyl-4, 5-dihydroisoxazole and aryl olefin as raw materials, adding 1, 3, 5-trimethylhexahydro-1, 3, 5-triazine, 4CzIPN, t-BuSH and a solvent, carrying out a photocatalytic reaction under the conditions that the wavelength is 450-460 nm, the wavelength is 10 W LED light source is irradiated and the temperature is 25-30 DEG C, and carrying out column chromatography purification to obtain a target product. According to the method, a visible light catalysis strategy is adopted, and the compound containing the beta-hydroxynitrile fragment is efficiently constructed. Compared with a traditional method, the method has the advantages of mild reaction conditions, no need of a transition metal catalyst, good functional group compatibility and the like. The synthesized 5-aryl-3-trimethylsiloxy-1-valeronitrile compound has important application value in the fields of drug molecule design, functional material development, pesticide synthesis and the like.

Description

Technical Field

[0001] This invention belongs to the field of organic chemical synthesis technology, specifically relating to a method for preparing 5-aryl-3-trimethylsiloxy-1-pentanilide compounds. Background Technology

[0002] β-Hydroxynitriles and their derivatives have broad research and application value in organic synthetic chemistry and medicinal chemistry, serving as important precursors for the synthesis of numerous bioactive compounds and drug fragments, such as β-hydroxy acids, β-lactones, and γ-amino alcohols. Among these, the synthesis of 5-aryl-3-trimethylsiloxy-1-pentanilide, an important class of β-hydroxynitrile compounds, has attracted considerable attention from chemical researchers. Currently, the main synthetic strategies reported for this class of compounds are as follows.

[0003] Firstly, as disclosed in Reference 1 (Tetrahedron Letters, 1990, 31, 2205), the Reformatsky reaction between α-bromoacetonitrile and phenylpropionaldehyde is catalyzed by zinc induction to generate 5-phenyl-3-trimethylsiloxy-1-pentanilonitrile. The specific reaction pathway is as follows. Trimethylchlorosilane has a significant impact on whether the reaction can occur, and this method does not investigate the effect of substituents on the benzene ring of phenylpropionaldehyde on the reaction efficiency.

[0004]

[0005] Secondly, as disclosed in reference 2 (Bioorganic & Medicinal Chemistry Letters, 2009, 19, 3125), aldehyde compound A is used as the starting material, and the chiral 5-phenyl-3-tert-butyldiphenylsiloxy-1-pentanenitrile F is obtained through a 6-step reaction. This method has a relatively cumbersome synthetic procedure and requires the introduction of the cyano group using highly toxic potassium cyanide. The specific reaction process is shown below:

[0006]

[0007] Thirdly, in the method disclosed in reference 3 (Synlett, 2017, 28, 1816), phenylacetonitrile and phenylpropionaldehyde undergo a direct addition reaction under mild conditions via TIPSOTf (triisopropylsilyltrifluoromethanesulfonate) and TMP (2,2,6,6-tetramethylpiperidine) to generate 2,5-diphenyl-3-triisopropylsiloxy-1-pentanilonitrile. However, the yield of the reaction is relatively low and the diastereoselectivity is poor. The specific reaction process is shown below:

[0008]

[0009] However, current synthetic methods for 5-aryl-3-trimethylsiloxy-1-pentanilide require highly toxic reagents, have low reaction efficiency, poor functional group compatibility, or are quite cumbersome. Therefore, developing new preparation methods with milder reaction conditions remains of great importance. Summary of the Invention

[0010] This invention provides a novel method for preparing 5-aryl-3-trimethylsiloxy-1-pentanilide compounds by visible light photocatalysis. This method can rapidly introduce silicon-protected β-hydroxynitrile fragments and has the advantages of simple operation, economic and environmental protection, mild conditions, and good functional group compatibility.

[0011] The technical solution proposed in this invention is: a novel method for preparing 5-aryl-3-trimethylsiloxy-1-pentanilide compounds by photocatalysis, comprising the following steps:

[0012] Step 1: Under an inert gas atmosphere, 3-bromo-5-trimethylsilyl-4,5-dihydroisoxazole (1), arylethylene (2), 1,3,5-trimethylhexahydro-1,3,5-triazine (N1), 4CzIPN (photocatalyst), t-BuSH, and solvent (dry DCM) are added sequentially to a Shrek tube and magnetically stirred until homogeneous to obtain a mixture;

[0013] Step 2: Under an inert gas atmosphere, the above mixture was irradiated with an LED lamp (wavelength 427nm, power 10W) ​​and magnetically stirred at room temperature until the reaction was complete. The 5-aryl-3-trimethylsiloxy-1-pentanilide compound (3) was separated from the reaction mixture by rapid column chromatography.

[0014] The specific reaction route is as follows:

[0015]

[0016] Wherein, Ar is 4-methylsulfonylphenyl, 4-methoxycarbonylphenyl, 4-(tetrahydropyran-4-methoxycarbonyl)phenyl, 4-cyclohexyloxycarbonylphenyl, 4-(thiophene-2-methoxycarbonyl)phenyl, 4-benzyloxycarbonylphenyl, 4-indoxocarbonylphenyl, 4-phenoxycarbonylphenyl, 4-(4-methylphenoxycarbonyl)phenyl, 4-(4-chlorophenoxycarbonyl)phenyl, 2-pyridyl.

[0017] Preferably, in steps one and two, the inert gas is either nitrogen or argon.

[0018] Preferably, in step one, the solvent is dichloromethane.

[0019] Preferably, in step one, the photocatalyst is 4CzIPN.

[0020] Preferably, in step one, the molar ratio of 3-bromo-5-trimethylsilyl-4,5-dihydroisoxazole, aryl olefin, 1,3,5-trimethylhexahydro-1,3,5-triazine, 4CzIPN, and t-BuSH is 1:2:2:0.01:0.1.

[0021] Preferably, in step two, the LED light source has a wavelength of 450–460 nm, a power of 10 W, and a reaction temperature of 25–30 °C.

[0022] Preferably, in step two, the separation conditions of the rapid column chromatography method are as follows: the reaction product is passed through a chromatography column packed with 200-300 mesh silica gel, and a mixed solvent of ethyl acetate and petroleum ether is used as the eluent for column chromatography separation, thereby obtaining pure 5-aryl-3-trimethylsiloxy-1-pentanilide compounds.

[0023] This invention utilizes 3-bromo-5-trimethylsilyl-4,5-dihydroisoxazole as a substrate under photocatalytic conditions. It employs an excited-state photocatalyst to generate α-aminoalkyl radicals through single-electron oxidation and deprotonation of 1,3,5-trimethyl-1,3,5-triazine. These radicals then abstract bromine atoms from the substrate to produce sp. 2 The carbon radical initiates isoxazole ring-opening to obtain alkoxy radicals, which are then subjected to radical 1,2-Brook rearrangement, radical addition and hydrogen transfer reactions to obtain 5-aryl-3-trimethylsiloxy-1-pentanilide compounds.

[0024] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0025] 1. This invention provides a 5-aryl-3-trimethylsiloxy-1-pentanilide compound and its synthesis method, which has mild reaction conditions, high reaction efficiency, and easy product separation.

[0026] 2. By optimizing the reaction conditions, this invention can obtain the target compound in high yield, has good reaction versatility, and high atom economy. Attached Figure Description

[0027] Figure 1 It is compound 3a 1 H NMR spectrum;

[0028] Figure 2 It is compound 3a 13 C NMR spectrum;

[0029] Figure 3 It is compound 3b. 1 H NMR spectrum;

[0030] Figure 4 It is compound 3b. 13C NMR spectrum;

[0031] Figure 5 It is compound 3c. 1 H NMR spectrum;

[0032] Figure 6 It is compound 3c. 13 C NMR spectrum; Detailed Implementation

[0033] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.

[0034] The method of this invention uses compounds with different structures as reaction substrates and, through the same reaction process, can synthesize various types of 5-aryl-3-trimethylsiloxy-1-pentanilide compounds.

[0035] Example 1

[0036]

[0037] (1) Under a nitrogen atmosphere, 3-bromo-5-trimethylsilyl-4,5-dihydroisoxazole (0.2 mmol), 4-vinylbenzylsulfone (0.4 mmol), 1,3,5-trimethylhexahydro-1,3,5-triazine (0.4 mmol), 4CzIPN (0.002 mmol), t-BuSH (0.02 mmol) and solvent (dry DCM) were added sequentially to a Shrek tube equipped with a magnetic stir bar and stirred until homogeneous to obtain a mixture;

[0038] (2) Under a nitrogen atmosphere, the above mixture was irradiated with an LED lamp (wavelength 450-460nm, power 10W) ​​and magnetically stirred at 25-30℃ for 12h. The 5-aryl-3-trimethylsiloxy-1-pentanilide compound 3a was obtained from the reaction mixture by rapid column chromatography.

[0039] The characterization data of compound 3a are as follows: 1H NMR (400MHz, Chloroform-d): δ7.85 (dq, J=8.5, 2.0Hz, 2H), 7.43-7.32 (m, 2H), 4.04-3.94 (m, 1H), 3.03 (s, 3H), 2.83 (dt, J=14. 5, 8.2Hz, 1H), 2.68 (dt, J=13.9, 8.2Hz, 1H), 2.50 (dd, J=5.7, 0.9Hz, 2H), 1.90 (dddd, J=9.1, 7.6, 6.0, 1.5Hz, 2H), 0.17 (s, 9H). 13 C NMR (101MHz, Chloroform-d): δ149.76, 140.30, 131.22, 129.59, 119.37, 69.61, 46.49, 40.10, 33.45, 28.29, 2.13.

[0040] Example 2

[0041]

[0042] (1) Under a nitrogen atmosphere, 3-bromo-5-trimethylsilyl-4,5-dihydroisoxazole (0.2 mmol), methyl 4-vinylbenzoate (0.4 mmol), 1,3,5-trimethylhexahydro-1,3,5-triazine (0.4 mmol), 4CzIPN (0.002 mmol), t-BuSH (0.02 mmol) and solvent (dry DCM) were added sequentially to a Shrek tube equipped with a magnetic stir bar and stirred until homogeneous to obtain a mixture;

[0043] (2) Under a nitrogen atmosphere, the above mixture was irradiated with an LED lamp (wavelength 450-460nm, power 10W) ​​and magnetically stirred at 25-30℃ for 12h. The 5-aryl-3-trimethylsiloxy-1-pentanilide compound 3b was obtained from the reaction mixture by rapid column chromatography.

[0044] The characterization data of compound 3b are as follows: 1 H NMR (400MHz, Chloroform-d): δ7.94-7.89 (m, 2H), 7.23-7.17 (m, 2H), 3.92 (p, J=5.9Hz, 1H), 3.85 (s, 3H), 2. 74 (dt, J=13.9, 8.1Hz, 1H), 2.61 (dt, J=13.9, 8.1Hz, 1H), 2.48-2.40 (m, 2H), 1.89-1.81 (m, 2H), 0.12 (s, 9H). 13C NMR (101MHz, Chloroform-d): δ167.96, 147.52, 130.82, 129.28, 129.09, 118.48, 68.72, 52.98, 39.16, 32.50, 27.30, 1.15.

[0045] Example 3

[0046]

[0047] (1) Under a nitrogen atmosphere, 3-bromo-5-trimethylsilyl-4,5-dihydroisoxazole (0.2 mmol), tetrahydro-2H-pyran-4-ylmethyl 4-vinylbenzoate (0.4 mmol), 1,3,5-trimethylhexahydro-1,3,5-triazine (0.4 mmol), 4CzIPN (0.002 mmol), and t-BuSH (0.02 mmol) solvent (dry DCM) were sequentially added to a Shrek tube equipped with a magnetic stir bar and stirred until homogeneous to obtain a mixture;

[0048] (2) Under a nitrogen atmosphere, the above mixture was irradiated with an LED lamp (wavelength 450-460nm, power 10W) ​​and magnetically stirred at 25-30℃ for 12h. The 5-aryl-3-trimethylsiloxy-1-pentanilide compound 3c was obtained from the reaction mixture by rapid column chromatography.

[0049] The characterization data of compound 3c are as follows: 1 H NMR (400MHz, Chloroform-d): δ7.98-7.91 (m, 2H), 7.28-7.20 (m, 2H), 4.16 (d, J=6.4Hz, 2H), 4.03-3.90(m, 3H), 3.41(td, J=11.8, 2.1Hz, 2H), 2.83-2.71(m, 1H), 2.70-2.58(m, 1H), 2.50-2.44 (m, 2H), 2.03 (ttd, J=10.4, 6.6, 3.4Hz, 1H), 1.88 (td, J=8.0, 5.9Hz, 2H) , 1.69 (ddd, J=13.0, 4.1, 2.0Hz, 2H), 1.46 (dtd, J=13.4, 11.9, 4.5Hz, 2H), 0.15 (s, 9H). 13 C NMR (101MHz, Chloroform-d): δ166.53, 146.79, 129.96, 128.47, 128.30, 117.64, 69.08, 67.87, 67.62, 38.35, 34.77, 31.67, 29.66, 26.46, 0.31.

[0050] Examples 4-11

[0051] Examples 4-11 are basically the same as Example 1, except that the substituents in the aryl olefin compounds are different. The specific structures of the obtained 5-aryl-3-trimethylsiloxy-1-pentanilide compounds are shown in the table below:

[0052] Table 1 Examples 4-11

[0053]

[0054]

[0055] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A 5-aryl-3-trimethylsiloxy-1-pentanilide compound and its preparation method, characterized in that, The chemical structural formula of the compound is as follows: Wherein, Ar is 4-methylsulfonylphenyl, 4-methoxycarbonylphenyl, 4-(tetrahydropyran-4-methoxycarbonyl)phenyl, 4-cyclohexyloxycarbonylphenyl, 4-(thiophene-2-methoxycarbonyl)phenyl, 4-benzyloxycarbonylphenyl, 4-indoxocarbonylphenyl, 4-phenoxycarbonylphenyl, 4-(4-methylphenoxycarbonyl)phenyl, 4-(4-chlorophenoxycarbonyl)phenyl, 2-pyridyl.

2. The method for photocatalytic preparation of 5-aryl-3-trimethylsiloxy-1-pentanilide compounds according to claim 1, characterized in that, Includes the following steps: Step 1: Under an inert gas atmosphere, 3-bromo-5-trimethylsilyl-4,5-dihydroisoxazole, aryl olefin, 1,3,5-trimethylhexahydro-1,3,5-triazine, 4CzIPN (photocatalyst), t-BuSH, and solvent are sequentially added to a Shrek tube and magnetically stirred until homogeneous to obtain a mixture. Step 2: Under an inert gas atmosphere, the above mixture was irradiated with an LED lamp (wavelength 450-460nm, power 10W) ​​and magnetically stirred at room temperature for 12 hours. After the reaction was complete, 5-aryl-3-trimethylsiloxy-1-pentanilides were separated from the reaction mixture by rapid column chromatography.

3. The method for preparing 5-aryl-3-trimethylsiloxy-1-pentanilide compounds according to claim 1, characterized in that, In steps one and two, the inert gas is either nitrogen or argon.

4. The method for preparing the 5-aryl-3-trimethylsiloxy-1-pentanilide compound according to claim 1, characterized in that: The photocatalyst is 4CzIPN.

5. The method for preparing the 5-aryl-3-trimethylsiloxy-1-pentanilide compound according to claim 1, characterized in that, The solvent is one of dichloromethane, acetonitrile, and 1,2-dichloroethane.

6. The method for preparing the 5-aryl-3-trimethylsiloxy-1-pentanilide compound according to claim 1, characterized in that, The reaction temperature is 25–30°C; the reaction time is 10–15 h.

7. The method for preparing the 5-aryl-3-trimethylsiloxy-1-pentanilide compound according to claim 1, characterized in that... The molar ratio of 3-bromo-5-silyl-4,5-dihydroisoxazole, olefin, 1,3,5-trimethylhexahydro-1,3,5-triazine, 4CzIPN, and t-BuSH is 1:2:2:0.01:0.1.

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