Method for synthesizing 1, 5-diene compound through nickel light concerted catalysis

Abstract

The invention discloses a preparation method of a 1, 5-diene compound. The preparation method comprises the following steps: in a nitrogen atmosphere, sequentially adding ethylene glycol dimethyl ether nickel bromide, 4, 4 '-di-tert-butyl dipyridine, sodium carbonate, a raw material A, a raw material B and a photocatalyst C into a reaction solvent to obtain a mixed solution; wherein the raw material A is silicon methyl aryl cyclopropane, the raw material B is beta-bromostyrene, and the photocatalyst C is 3-CzClIPN. The mixed solution is irradiated by 456nm blue light at room temperature and stirred until the reaction is finished, and the reaction liquid is subjected to extraction and silica gel column chromatography separation to obtain the 1, 5-diene compound. The preparation method disclosed by the invention is mild in condition, the used metal catalyst is small in dosage and low in cost, the substrate application range is wide, and the obtained 1, 5-diene compound has a wide application prospect in drug research and development and polymer material preparation.

Description

Technical Field

[0001] The invention belongs to the technical field of organic chemical synthesis, and in particular relates to a 1,5-diene compound and a preparation method and application thereof. Background Art

[0002] 1,5-hexadiene is a special diene compound, which is widely found in drug molecules such as antibiotic FR-900505, leptomycin B, and nemadectin. As it can be used as an important structural building block or synthetic intermediate, it has important value in the fields of 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] At present, the preparation of 1,5-diene compounds mainly relies on the cross-coupling reaction of allyl metal reagents and allyl electrophiles. For example, in the method disclosed in document 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 through palladium-catalyzed coupling reaction. The specific reaction process is as follows:

[0004]

[0005] Reference 2 (Hornillos, V.; Pérez, M.; In the method disclosed by M.; Feringa, BLJ Am. Chem. Soc. 2013, 135, 2140), copper is used to catalyze the coupling of allyl bromide and allyl metal reagent, and two diene products with different regioselectivity can be obtained by ligand regulation. The specific reaction process is as follows:

[0006]

[0007] The method disclosed in document 3 (Hamilton, JY; Sarlah, D.; Carreira, EMJAm.Chem.Soc.2014, 136, 3006) discloses an Ir-catalyzed coupling strategy for allyl alcohol and olefin. The method uses racemic secondary alcohol as a raw material and olefin as a nucleophilic reagent to provide chiral 1,5-diene products with high yield and excellent enantioselectivity. The specific reaction process is as follows:

[0008]

[0009] In the method disclosed in document 4 (Rui, U.; Toshifumi, J.; Kazuki, T.; Issey, O.; Yutaka, N. Tetrahedron Lett. 2018, 59, 1121), under the catalysis of a rhenium complex, the coupling reaction of allyl alcohol and allyltrimethylsilane 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 shortcomings, such as the use of toxic or active allyl metal reagents, the reaction conditions are not mild enough, the use of precious metal catalysts such as palladium and iridium, the high cost, and the lack of specificity of the 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 present 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 model, which opens up a new synthetic route for 1,5-diene compounds. Summary of the invention

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

[0014] The present invention is achieved by a 1,5-diene compound, the chemical structure of which is shown in the following formula (I):

[0015]

[0016] In formula (I), R 1 is 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 and the like;

[0017] R 2 is 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 and the like;

[0018] R 3 It is a group such as hydrogen, 4,4'-difluoro, 4-phenyl, etc.

[0019] The present invention further discloses a method for preparing the above 1,5-diene compounds, which comprises the following steps:

[0020] (1) Under a nitrogen atmosphere, ethylene glycol dimethyl ether nickel bromide, 4,4'-di-tert-butyl bipyridyl, sodium carbonate, photocatalyst C, raw material A, and raw material B are added 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; wherein the raw material A is silylmethylarylcyclopropane, the raw material B is β-bromostyrene, and the photocatalyst C is 3-CzClIPN.

[0021] (2) Under 456 nm blue light irradiation, the mixed solution of step (1) is stirred at room temperature until the reaction is completed, and the reaction solution is extracted and separated by 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-diene substituted with a group; wherein R 1 is 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 and the like;

[0023] R 2 is 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 and the like;

[0024] R 3 It is a group such as hydrogen, 4,4'-difluoro, 4-phenyl, etc.

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

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

[0027] The present invention overcomes the deficiencies of the prior art and provides a 1,5-diene compound and a preparation method thereof. Under a nitrogen atmosphere, ethylene glycol dimethyl ether nickel bromide, 4,4′-di-tert-butyl bipyridyl, sodium carbonate, photocatalyst C, raw material A, and raw material B are sequentially added 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; wherein the raw material A is silylmethyl aryl cyclopropane, the raw material B is β-bromostyrene, and the photocatalyst C is 3-CzClIPN. The mixed solution is irradiated with 456nm blue light at room temperature and stirred until the reaction is completed, and the reaction solution is extracted and separated by silica gel column chromatography to obtain a 1,5-diene compound.

[0028] In the preparation method of the present invention, when the raw material A is silylmethylcyclopropane and the raw material B is β-bromostyrene, the reaction equation of 1,5-diene 1,5-diene compound is as follows:

[0029]

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

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

[0032]

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

[0034] Therefore, in the present invention, silylmethylarylcyclopropane is used as a raw material, and under the activation of a photocatalyst and a base, the carbon-silicon bond is broken to promote the ring opening of the cyclopropane to produce a benzylic free radical, which is then captured by the oxidative addition intermediate of a nickel catalyst and β-bromostyrene, and after reduction and elimination, a 1,5-diene compound is obtained and the catalyst cycle is realized.

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

[0036] (1) The preparation method of the present invention can be carried out at room temperature, is easy 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 the present invention, as a class of diene structural unit compounds containing a quaternary carbon center, have important application value in the synthesis of drug molecules and the preparation of polymer materials, and provide a new technical route for the synthesis of natural products. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 is the hydrogen spectrum of compound 1 in the embodiment of the present invention;

[0039] Figure 2 is the hydrogen spectrum of compound 25 in the example of the present invention;

[0040] Figure 3 is the hydrogen spectrum of compound 28 in the example of the present invention; DETAILED DESCRIPTION

[0041] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0042] Example 1

[0043] (1) Under a nitrogen atmosphere, ethylene glycol dimethyl ether nickel bromide (0.02 mmol), 4,4′-di-tert-butyl bipyridyl (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) irradiating the mixed solution with 456 nm blue light at room temperature and stirring until the reaction is completed, and extracting and separating the reaction solution by silica gel column chromatography to obtain 1,5-diene compound 1;

[0045] Its structural formula is as follows:

[0046]

[0047] The hydrogen spectrum of compound 1 is as follows Figure 1 As shown, the H 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] Embodiments 2 to 24

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

[0050] Table 1 Examples 2 to 24

[0051]

[0052]

[0053] Embodiment 25

[0054] (1) Under a nitrogen atmosphere, ethylene glycol dimethyl ether nickel bromide (0.02 mmol), 4,4′-di-tert-butyl bipyridyl (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 added to dimethyl sulfoxide (4.0 ml) in sequence to obtain a mixed solution;

[0055] (2) irradiating the mixed solution with 456 nm blue light at room temperature and stirring until the reaction is completed, and extracting and separating the reaction solution by silica gel column chromatography to obtain 1,5-diene compound 25;

[0056] Its structural formula is as follows:

[0057]

[0058] The hydrogen spectrum of compound 25 is as follows Figure 2 As shown, the H 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] Embodiments 26 to 27

[0060] Examples 26 to 27 are substantially the same as Example 25, except that the substituent R in the cyclopropane 1 and R in alkenyl triflate 3 They are as follows:

[0061]

[0062]

[0063] Embodiment 28

[0064] (1) Under a nitrogen atmosphere, ethylene glycol dimethyl ether nickel bromide (0.02 mmol), 4,4′-di-tert-butyl bipyridyl (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 to dimethyl sulfoxide (4.0 ml) in sequence to obtain a mixed solution;

[0065] (2) irradiating the mixed solution with 456 nm blue light at room temperature and stirring until the reaction is completed, and extracting and separating the reaction solution by silica gel column chromatography to obtain 1,5-diene compound 28;

[0066] Its structural formula is as follows:

[0067]

[0068] The hydrogen spectrum of compound 28 is as follows Figure 3 As shown, the H 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 equation involved in the embodiment of the present invention is as follows:

[0070]

[0071] Among them, the hydrogen spectrum of compound 1 is as follows Figure 1 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 in the protection scope of the present invention.

Claims

1. A 1,5-diene compound, characterized in that: The chemical structure of the compound is shown in the following formula (I): In formula (I), R 1 is 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 and the like; R 2 is 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 and the like; R 3 It is a group such as hydrogen, 4,4'-difluoro, 4-phenyl, etc.

2. The method for preparing 1,5-diene compounds according to claim 1, characterized in that: The method comprises the following steps: (1) Under a nitrogen atmosphere, ethylene glycol dimethyl ether nickel bromide, 4,4′-di-tert-butyl bipyridine, sodium carbonate, photocatalyst C, raw material A, and raw material B are added 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; wherein the raw material A is silylmethylarylcyclopropane, the raw material B is β-bromostyrene, and the photocatalyst C is 3-CzClIPN. (2) Under 456 nm blue light irradiation, the mixed solution of step (1) is stirred at room temperature until the reaction is completed, and the reaction solution is extracted and separated by silica gel column chromatography to obtain 1,5-diene compounds.

3. The method for preparing 1,5-diene compounds according to claim 2, characterized in that: In step (1), the 1,5-hexadiene is R 1 and / or R 2 and / or R 3 1,5-hexadiene substituted with a group; wherein R 1 is 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 and the like; R 2 is 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 and the like; R 3 It is a group such as hydrogen, 4,4'-difluoro, 4-phenyl, etc.

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

5. Use of the 1,5-diene compound according to claim 1 in drug molecule synthesis and polymer material research.

6. The use according to claim 5, characterized in that The drug molecules and polymer materials include 1,5-diene compounds and derivatives thereof.

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