A method for the synthesis of 1,5-diene compounds by nickel photo synergistic catalysis

Abstract

This invention discloses a method for preparing 1,5-diene compounds. The method involves sequentially adding ethylene glycol dimethyl ether nickel bromide, 4,4′-di-tert-butylbipyridine, sodium carbonate, raw material A, raw material B, and photocatalyst C to a reaction solvent under a nitrogen atmosphere to obtain a mixed solution. Raw material A is silanylmethylarylcyclopropane, raw material B is β-bromostyrene, and photocatalyst C is 3-CzClIPN. The mixed solution is then irradiated with 456 nm blue light and stirred until the reaction is complete at room temperature. The reaction solution is then extracted and separated by silica gel column chromatography to obtain 1,5-diene compounds. This method offers mild preparation conditions, uses a small amount of low-cost metal catalyst, has a wide range of applicable substrates, and the obtained 1,5-diene compounds have broad application prospects in drug development and polymer material preparation.

Description

Technical Field

[0001] This invention belongs to the field of organic chemical synthesis technology, and particularly relates to a 1,5-diene compound, its preparation method and application. Background Technology

[0002] 1,5-Hexadiene, a relatively unique type of diene compound, is widely found in drug molecules such as antibiotics FR-900505, leprosycin B, and nemesistin. Because it can serve as an important structural building block or synthetic intermediate, it has significant value in organic synthetic chemistry research, antiviral drug development, and polymer material preparation. Therefore, the preparation and application of 1,5-diene compounds are still being explored in depth.

[0003] Currently, the preparation of 1,5-diene compounds mainly relies on the cross-coupling reaction between allyl metal reagents and allyl electrophiles. For example, in the method disclosed in Reference 1 (Zhang, P.; Brozek, LA; Morken, JP J Am. Chem. Soc. 2010, 132, 10686), alkyl borate esters and allyl electrophiles can generate 1,5-diene compounds via palladium-catalyzed coupling. The specific reaction process is shown below:

[0004]

[0005] Reference 2 (Hornillos, V.; Pérez, M.; The method disclosed in M.; Feringa, BL J Am. Chem. Soc. 2013, 135, 2140, utilizes copper-catalyzed coupling of allyl bromide with an allyl metal reagent, and through ligand regulation, two diene products with different regioselectivities can be obtained. The specific reaction process is shown below:

[0006]

[0007] Reference 3 (Hamilton, JY; Sarlah, D.; Carreira, EMJAm. Chem. Soc. 2014, 136, 3006) discloses an Ir-catalyzed coupling strategy for allyl alcohols and olefins. This method uses racemic secondary alcohols as starting materials and olefins as nucleophiles to provide chiral 1,5-diene products in high yield and with excellent enantioselectivity. The specific reaction process is shown below:

[0008]

[0009] In the method disclosed in Reference 4 (Rui, U.; Toshifumi, J.; Kazuki, T.; Issey, O.; Yutaka, N. Tetrahedron Lett. 2018, 59, 1121), the coupling reaction of allyl alcohol and allyltrimethylsilane under the catalysis of rhenium complex yields the corresponding 1,5-diene. The specific reaction process is as follows:

[0010]

[0011] Although these published research methods can efficiently synthesize 1,5-diene compounds, these strategies have some drawbacks, such as the use of toxic or reactive allyl metal reagents, insufficiently mild reaction conditions, high cost of using noble metal catalysts such as palladium and iridium, and insufficient reaction selectivity.

[0012] It is worth noting that the strategy proposed in this invention uses cyclopropane and β-bromostyrene as starting materials. The substrate structures are widely found in natural products and drug molecules. The preparation of 1,5-diene compounds through the ring-opening functionalization of cyclopropane is a mild, green and efficient method, opening up a new synthetic route for 1,5-diene compounds. Summary of the Invention

[0013] The purpose of this invention is to provide a method for preparing 1,5-diene compounds, aiming to solve the problems of high and unstable starting materials, noble metal catalysis, harsh reaction conditions, and poor selectivity in existing synthesis methods.

[0014] This invention provides a 1,5-diene compound with the following chemical structural formula (I):

[0015]

[0016] In equation (I), R 1 It can be 4-methoxy, 4-ethoxy, 4-phenoxy, 4-benzyloxy, 4-trifluoromethoxy, 2-methoxy, 4,5-dimethoxy, 2,3-dihydrofuranyl, 2,4,5-trimethoxy, 3,4,5-trimethoxy, etc.

[0017] R 2 It can be hydrogen, 4-acetoxy, 4-methyl, 4-trifluoromethoxy, 4-cyano, 4-methoxy, 4-chloro, 4-bromo, 4-trifluoromethyl, 2-methoxy, 2-fluoro, 2-bromo, 4-phenyl, 3-fluoro-4-methoxy, 3-chloro-4-methoxy, etc.

[0018] R 3 It can be hydrogen, 4,4'-difluoro, 4-phenyl, or other groups.

[0019] This invention further discloses a method for preparing the above-mentioned 1,5-diene compounds, the method comprising the following steps:

[0020] (1) Under a nitrogen atmosphere, ethylene glycol dimethyl ether nickel bromide, 4,4'-di-tert-butylbipyridine, sodium carbonate, photocatalyst C, raw material A, and raw material B are added to the reaction solvent in a molar ratio of (0.05-0.2):(0.08-0.3):(1.0-3.0):(0.01-0.1):1.0:(1.0-3.0) to obtain a mixed solution; wherein, raw material A is silylmethylarylcyclopropane, raw material B is β-bromostyrene, and photocatalyst C is 3-CzClIPN.

[0021] (2) Under 456nm blue light irradiation, the mixed solution described in step (1) is stirred at room temperature until the reaction is completed. The reaction solution can be separated by extraction and silica gel column chromatography to obtain 1,5-diene compounds.

[0022] Preferably, in step (1), the 1,5-diene compound is R 1 and / or R 2 and / or R 3 1,5-dienes substituted with groups; wherein, R 1 It can be 4-methoxy, 4-ethoxy, 4-phenoxy, 4-benzyloxy, 4-trifluoromethoxy, 2-methoxy, 4,5-dimethoxy, 2,3-dihydrofuranyl, 2,4,5-trimethoxy, 3,4,5-trimethoxy, etc.

[0023] R 2 It can be hydrogen, 4-acetoxy, 4-methyl, 4-trifluoromethoxy, 4-cyano, 4-methoxy, 4-chloro, 4-bromo, 4-trifluoromethyl, 2-methoxy, 2-fluoro, 2-bromo, 4-phenyl, 3-fluoro-4-methoxy, 3-chloro-4-methoxy, etc.

[0024] R 3 It contains hydrogen, 4,4′-difluoro, 4-phenyl, and other groups.

[0025] Preferably, in step (1), the reaction solvent is dimethyl sulfoxide; in step (2), the mixture is stirred and reacted under 465 nm blue light at room temperature for 12 to 16 hours.

[0026] This invention further discloses the application of the above-mentioned 1,5-diene compounds in drug molecule synthesis and polymer material research.

[0027] This invention overcomes the shortcomings of existing technologies and provides a 1,5-diene compound and its preparation method. Under a nitrogen atmosphere, ethylene glycol dimethyl ether nickel bromide, 4,4′-di-tert-butylbipyridine, sodium carbonate, photocatalyst C, raw material A, and raw material B are added sequentially to a reaction solvent in a molar ratio of (0.05–0.2):(0.08–0.3):(1.0–3.0):(0.01–0.1):1.0:(1.0–3.0) to obtain a mixed solution. Raw material A is silanylmethylarylcyclopropane, raw material B is β-bromostyrene, and photocatalyst C is 3-CzClIPN. The mixed solution is irradiated with 456 nm blue light at room temperature and stirred until the reaction is complete. The reaction solution is then extracted and separated by silica gel column chromatography to obtain the 1,5-diene compound.

[0028] In the preparation method of this invention, when raw material A is silylmethylcyclopropane and raw material B is β-bromostyrene, the reaction equations for 1,5-diene compounds are as follows:

[0029]

[0030] This 1,5-diene compound is a diene compound containing a quaternary carbon center.

[0031] In the preparation method of this invention, when raw material A is silylmethylcyclopropane and raw material B is alkenyl trifluoromethanesulfonate, the reaction equation of the 1,5-diene compound is as follows:

[0032]

[0033] This 1,5-diene compound is a diene compound containing a quaternary carbon center.

[0034] Therefore, in this invention, silylmethylarylcyclopropane is used as a raw material. Under the activation of a photocatalyst and a base, the carbon-silicon bond breaks, causing the cyclopropane to open the ring and generate a benzylic radical. This radical is then captured by the nickel catalyst and the oxidative addition intermediate of β-bromostyrene. After reduction and elimination, a 1,5-diene compound is obtained, and the catalyst is recycled.

[0035] Compared with the shortcomings and deficiencies of existing technologies, the present invention has the following advantages:

[0036] (1) The preparation method of the present invention can be carried out at room temperature, is simple to operate, uses a wide range of substrates, is low in cost, and has good functional group compatibility;

[0037] (2) The 1,5-diene compounds of this invention, as a class of diene structural unit compounds containing quaternary carbon centers, have important application value in drug molecule synthesis and polymer material preparation, and provide a new technical route for the synthesis of natural products. Attached Figure Description

[0038] Figure 1 This is the proton spectrum of compound 1 in the embodiments of the present invention;

[0039] Figure 2 This is the proton spectrum of compound 25 in the embodiments of the present invention;

[0040] Figure 3 This is the proton spectrum of compound 28 in the embodiments of the present invention; Detailed Implementation

[0041] 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 and not intended to limit the invention.

[0042] Example 1

[0043] (1) Under a nitrogen atmosphere, ethylene glycol dimethyl ether nickel bromide (0.02 mmol), 4,4′-di-tert-butylbipyridine (0.03 mmol), sodium carbonate (0.2 mmol), photocatalyst 3-CzClIPN (0.01 mmol), 4-methoxysilylmethylcyclopropane (0.2 mmol), and β-bromostyrene (0.24 mmol) were sequentially added to dimethyl sulfoxide (4.0 ml) to obtain a mixed solution;

[0044] (2) The mixed solution was irradiated with 456nm blue light at room temperature and stirred until the reaction was complete. The reaction solution was extracted and separated by silica gel column chromatography to obtain 1,5-diene compound 1.

[0045] Its structural formula is shown below:

[0046]

[0047] The proton spectrum of compound 1 is as follows: Figure 1 As shown, the proton NMR spectrum data are as follows: 1 H NMR (400MHz, Chloroform-d) δ7.36 (dd, J=8.3, 1.4Hz, 2H), 7.30 (t, J=7.5Hz, 2H), 7.23-7.18 (m, 3H), 6.91-6.87 (m, 2H), 6.38 (d, J =5.3Hz, 2H), 5.79 (ddt, J=17.1, 10.1, 6.9Hz, 1H), 5.10-4.99 (m, 2H), 3.81 (s, 3H), 3.51 (td, J=7.3, 4.9Hz, 1H), 2.63-2.54 (m, 2H).

[0048] Examples 2-24

[0049] Examples 2-24 are the same as Example 1, except that the substituent R in cyclopropane is different. 1 R in β-bromostyrene 2 They are as follows:

[0050] Table 1 Examples 2-24

[0051]

[0052]

[0053] Example 25

[0054] (1) Under a nitrogen atmosphere, ethylene glycol dimethyl ether nickel bromide (0.02 mmol), 4,4′-di-tert-butylbipyridine (0.03 mmol), sodium carbonate (0.2 mmol), photocatalyst 3-CzClIPN (0.01 mmol), 4-methoxysilylmethylcyclopropane (0.2 mmol), and cyclohexene trifluoromethanesulfonate (0.24 mmol) were sequentially added to dimethyl sulfoxide (4.0 ml) to obtain a mixed solution;

[0055] (2) The mixed solution was irradiated with 456nm blue light at room temperature and stirred until the reaction was complete. The reaction solution was extracted and separated by silica gel column chromatography to obtain 1,5-diene compound 25.

[0056] Its structural formula is shown below:

[0057]

[0058] The proton spectrum of compound 25 is as follows: Figure 2 As shown, the proton NMR spectrum data are as follows: 1 H NMR (400MHz, Chloroform-d) δ7.13-7.07 (m, 2H), 6.85-6.80 (m, 2), 5.70 (ddt, J=17.0, 1 0.1, 6.9Hz, 1H), 5.59 (td, J=3.8, 2.0Hz, 1), 4.98 (dq, J=17.1, 1.6Hz, 1H), 4.92 (ddt, J= 10.1, 2.3, 1.2Hz, 1H), 3.79 (s, 3H), 3.13 (t, J=7.8Hz, 1H), 2.55 (dtt, J=14.2, 7.2, 1.3H z, 1H), 2.47-2.38 (m, 1H), 2.08-2.00 (m, 2H), 1.83-1.73 (m, 2H), 1.51 (p, J=2.9Hz, 4H).

[0059] Examples 26-27

[0060] Examples 26 and 27 are basically the same as Example 25, except for the substituent R in cyclopropane. 1 R in alkenyl trifluoromethanesulfonate 3 They are as follows:

[0061]

[0062]

[0063] Example 28

[0064] (1) Under a nitrogen atmosphere, ethylene glycol dimethyl ether nickel bromide (0.02 mmol), 4,4′-di-tert-butylbipyridine (0.03 mmol), sodium carbonate (0.2 mmol), photocatalyst 3-CzClIPN (0.01 mmol), 4-methoxysilylmethylcyclopropane (0.2 mmol), and cyclooctene trifluoromethanesulfonate (0.24 mmol) were added sequentially to dimethyl sulfoxide (4.0 ml) to obtain a mixed solution;

[0065] (2) The mixed solution was irradiated with 456nm blue light at room temperature and stirred until the reaction was complete. The reaction solution was extracted and separated by silica gel column chromatography to obtain 1,5-diene compound 28.

[0066] Its structural formula is shown below:

[0067]

[0068] The proton spectrum of compound 28 is as follows: Figure 3 As shown, the proton NMR spectrum data are as follows: 1 H NMR (400MHz, Chloroform-d) δ7.14-7.08 (m, 2H), 6.84-6.78 (m, 2H), 5.70 (ddt, J=14.2, 10.8, 4.9Hz, 1), 5.53 (t, J=8.2Hz, 1H), 4.95 (dd, J=26.4, 13.8Hz, 2H ), 3.79 (s, 3H), 3.22 (t, J = 7.7Hz, 1H), 2.57 (dt, J = 14.4, 7.1Hz, 1H), 2.45 (dt, J=14.9, 7.6Hz, 1H), 2.22-1.86 (m, 5H), 1.50-1.36 (m, 6H), 0.93-0.80 (m, 1H).

[0069] The reaction equations involved in the embodiments of the present invention are as follows:

[0070]

[0071] Among them, the proton spectrum of compound 1 is as follows Figure 1 As shown.

[0072] 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 method for preparing a 1,5-diene compound, characterized in that, The method includes the following steps: (1) Under a nitrogen atmosphere, ethylene glycol dimethyl ether nickel bromide, 4,4′-di-tert-butylbipyridine, sodium carbonate, photocatalyst C, raw material A, and raw material B are added to the reaction solvent in a molar ratio of (0.05~0.2):(0.08~0.3):(1.0~3.0):(0.01~0.1):1.0:(1.0~3.0) to obtain a mixed solution; Wherein, raw material A is a silylmethylarylcyclopropane compound; Raw material B is a β-bromostyrene compound or an alkenyl trifluoromethanesulfonate compound; The photocatalyst C is 3-CzClIPN; (2) Under 456nm blue light irradiation, the mixed solution described in step (1) is stirred at room temperature until the reaction is completed. The reaction solution can be separated by extraction and silica gel column chromatography to obtain 1,5-diene compounds. When raw material B is a β-bromostyrene compound, the reaction equation for the 1,5-diene compound is shown in equation (I) below: When raw material B is an alkenyl trifluoromethanesulfonate compound, the reaction equation for the 1,5-diene compound is shown in equation (II) below: Among them, R 1 It is a 4-methoxy, 4-ethoxy, 4-phenoxy, 4-benzyloxy, 4-trifluoromethoxy, 2-methoxy, 4,5-dimethoxy, 2,3-dihydrofuranyl, 2,4,5-trimethoxy, or 3,4,5-trimethoxy group. R 2 The groups are hydrogen, 4-acetoxy, 4-methyl, 4-trifluoromethoxy, 4-cyano, 4-methoxy, 4-chloro, 4-bromo, 4-trifluoromethyl, 2-methoxy, 2-fluoro, 2-bromo, 4-phenyl, 3-fluoro-4-methoxy, and 3-chloro-4-methoxy groups. R 3 It consists of hydrogen, 4,4′-difluoro, and 4-phenyl groups.

2. The method for preparing 1,5-diene compounds as described in claim 1, characterized in that, In step (1), the reaction solvent is dimethyl sulfoxide; in step (2), the mixed solution is stirred and reacted at room temperature and under 456 nm blue light irradiation for 12 to 16 hours.

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