A 1,5,6-polysubstituted-2-oxo-3-oxabicyclo[3.1.0]hexane and a preparation method thereof

Abstract

Disclosed are 1,5,6-polysubstituted-2-oxo-3-oxabicyclo[3.1.0]hexane and a preparation method thereof. The reaction process comprises the following steps: using α-substituted allyl acetate as a raw material under the action of an inexpensive metal catalyst, the acetic acid acrylate structure contains a cyclopropane-γ-lactone structure, and the substituent types are diverse, making it easy to perform subsequent derivatization modification. The target product is prepared efficiently and with high non-corresponding selectivity through a one-pot process. The method has the advantages of simple and readily available raw materials, mild reaction conditions, simple operation, wide substrate universality, easy large-scale production, no safety hazards, and low cost, and can provide support for relevant drug activity testing.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical synthesis and mainly relates to 1,5,6-polysubstituted-2-oxo-3-oxabicyclo[3.1.0]hexane and a preparation method thereof. Background Art

[0002] The 1,5,6-polysubstituted-2-oxo-3-oxabicyclo[3.1.0]hexane skeleton, a polysubstituted cyclopropane-γ-lactone structure, is widely present in pharmaceutical and natural product molecules. For example, the natural products Laevinoid A, Sterepolide, and Marasmicacid, as well as the drug molecule Isolactarofulin, all contain this heterocyclic skeleton, a key pharmacophore constituting numerous active pharmaceutical ingredients. Furthermore, as a highly active synthetic intermediate, cyclopropane-γ-lactone structures can be used to achieve a variety of high-value-added transformations through simple chemical methods. Therefore, the construction of polysubstituted-2-oxo-3-oxabicyclo[3.1.0]hexane skeletons has long been a research hotspot in organic synthetic chemistry, attracting widespread attention from researchers.

[0003] To date, the existing methods for preparing related skeletons mainly include the following: 1) through the addition reaction of sulfur ylides with electron-deficient aromatic hydrocarbons (Tetrahedron: Asymmetry, 2014, 15, 2475). This method is limited to the cyclopropanation reaction of electron-deficient alkenes. The structure of the reaction raw materials is relatively limited, and a multi-step synthesis is required, which is cumbersome. 2) transition metal-catalyzed insertion cyclization reaction of diazocarboxylates on alkenes (Acc. Chem. Res. 2016, 49, 2080). This method uses diazoacetic acid ester derivatives as raw materials, needs to introduce diazo functional group in advance on reaction raw materials, and needs the participation of catalysts such as precious metals such as ruthenium, rhodium, palladium, etc., in addition, diazonium activity is extremely high, and there is explosion risk so that the method has certain safety hazards when amplifying preparation; 3) manganese acetate-copper acetate oxidation allyl acetoacetate compounds (J.Org.Chem.1989,54,5684), the structure of this method reaction raw materials has limitations, and the reaction needs to use excessive metal oxidant, is difficult to recycle and reuse, and easily causes environmental problems such as metal pollution. In addition, Japanese patent JP58167581A also reports a method for preparing cyclopropane and γ-lactone structure by inserting carbonyl cyclization reaction of polysubstituted dibromocyclopropane, the method needs to first carry out pre-functionalization to substrate, structural limitation is relatively large, and simultaneously needs to use stoichiometric highly toxic nickel carbonyl species as reaction raw materials, actual operation is more complicated, and may also bring environmental pollution problems. Summary of the Invention

[0004] In view of the shortcomings of the prior art, the present invention aims to provide a 1,5,6-polysubstituted-2-oxo-3-oxabicyclo[3.1.0]hexane and a preparation method thereof. Under the action of an inexpensive metal catalyst, α-substituted allyl acetate is used as a raw material, and the above-mentioned target product is prepared efficiently and with high non-corresponding selectivity through a one-pot process. The present invention has the advantages of simple and readily available raw materials, mild reaction conditions, simple operation, wide substrate universality, easy large-scale production and low cost.

[0005] To achieve the above objectives, the present invention adopts the following technical solutions.

[0006] A 1,5,6-polysubstituted-2-oxo-3-oxabicyclo[3.1.0]hexane, whose structure is shown below:

[0007]

[0008] Among them, EWG represents electron-withdrawing functional groups, including cyano, trifluoromethyl, nitro, ester, and carbonyl groups;

[0009] R 1 Functional groups include methyl, ethyl, propyl, other alkyl substituents, benzene rings, substituted benzene rings or other aromatic heterocycles;

[0010] R 2 Functional groups include methyl, ethyl, propyl, other alkyl substituents, benzene rings, substituted benzene rings or other aromatic heterocycles;

[0011] R 3 Functional groups include methyl, ethyl, propyl, other alkyl substituents, benzene rings, substituted benzene rings or other aromatic heterocycles;

[0012] R 4 Functional groups include methyl, ethyl, propyl, other alkyl substituents, benzene rings, substituted benzene rings or other aromatic heterocycles.

[0013] A method for preparing 1,5,6-polysubstituted-2-oxo-3-oxabicyclo[3.1.0]hexane, wherein the reaction process is as follows:

[0014]

[0015] The specific preparation method comprises the following steps:

[0016] (1) Under a nitrogen atmosphere, substituted acetic acid acrylate, an oxidant, a metal catalyst, and a reaction solvent are added to a reaction tube equipped with a magnet, the reaction system is sealed, and the reaction is heated to proceed;

[0017] (2) The reaction was monitored by TLC plate until the reaction was complete. After cooling to room temperature, the reaction was quenched with saturated sodium chloride aqueous solution and extracted with ethyl acetate. The organic phase was distilled under reduced pressure to remove the solvent. The crude product was separated by column chromatography to obtain 1,5,6-polysubstituted-2-oxo-3-oxabicyclo[3.1.0]hexane.

[0018] The metal catalyst is selected from the following: Cu(OTs)2, Cu(OAc)2, CuBr2, CuI2, CuCl2, CuI, CuBr, CuCl, CuSCN, Fe(OAc)2, FeCl2, FeCl3, Fe(acac)3, NiBr2, NiCl2, Ni(OAc)2, and the amount of the catalyst is 0.1-80 mol% of the substituted acetic acid acrylate.

[0019] The oxidant is selected from the following: di-tert-butyl peroxide DTBP, dicumyl peroxide DCP, benzoyl peroxide BPO, tert-butyl benzoyl peroxide TBPB, lauroyl peroxide LPO, peracetic acid, potassium persulfate; the amount of the oxidant is 0.5-3.5 times the equivalent of substituted acetic acid acrylate.

[0020] The reaction solvent is selected from the following: ethyl acetate, tetrahydrofuran, dichloromethane, dichloroethane, nitromethane, acetonitrile, benzene, toluene, chlorobenzene, trifluorotoluene, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide; the reaction solvent is calculated based on the reaction concentration of acetic acid acrylate, and the reaction concentration is 0.1-0.5M.

[0021] The reaction solvent is 0.1M based on the reaction concentration of acetic acid acrylate.

[0022] The heating temperature is 20-120°C.

[0023] Compared with the prior art, the present invention has the following beneficial effects:

[0024] 1. The structure of acetic acid acrylate contains a cyclopropane γ-lactone structure with a variety of substituent types, which is easy to carry out subsequent derivatization modification and can provide support for related drug activity testing.

[0025] 2. Step (1) is a one-pot method for preparing the target product with high efficiency and high non-corresponding selectivity, and the reaction conditions are mild and the operation is simple.

[0026] 3. Oxidants, metal catalysts and reaction solvents have the characteristics of simple and easy-to-obtain raw materials, wide substrate universality, easy large-scale production, no safety hazards and low cost. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1This is the H NMR spectrum of the intramolecular cyclopropanation product 2aa.

[0028] Figure 2 This is the C NMR spectrum of the intramolecular cyclopropanation product 2aa.

[0029] Figure 3 This is the H NMR spectrum of the intramolecular cyclopropanation product 2ab.

[0030] Figure 4 This is the NMR fluorine spectrum of the intramolecular cyclopropanation product 2ab.

[0031] Figure 5 This is the C NMR spectrum of the intramolecular cyclopropanation product 2ab.

[0032] Figure 6 This is the H NMR spectrum of the intramolecular cyclopropanation product 2ac.

[0033] Figure 7 This is the C NMR spectrum of the intramolecular cyclopropanation product 2ac.

[0034] Figure 8 This is the H NMR spectrum of the intramolecular cyclopropanation product 2ad.

[0035] Figure 9 This is the C NMR spectrum of the intramolecular cyclopropanation product 2ad.

[0036] Figure 10 This is the H NMR spectrum of the intramolecular cyclopropanation product 2ae.

[0037] Figure 11 This is the C NMR spectrum of the intramolecular cyclopropanation product 2ae.

[0038] Figure 12 This is the H NMR spectrum of the intramolecular cyclopropanation product 2af.

[0039] Figure 13 This is the C NMR spectrum of the intramolecular cyclopropanation product 2af.

[0040] Figure 14 This is the H NMR spectrum of the intramolecular cyclopropanation product 2ag.

[0041] Figure 15 This is the C NMR spectrum of the intramolecular cyclopropanation product 2ag.

[0042] Figure 16 This is the H NMR spectrum of the intramolecular cyclopropanation product 2ah.

[0043] Figure 17 This is the C NMR spectrum of the intramolecular cyclopropanation product 2ah.

[0044] Figure 18This is the H NMR spectrum of the intramolecular cyclopropanation product 2ai.

[0045] Figure 19 This is the C NMR spectrum of the intramolecular cyclopropanation product 2ai.

[0046] Figure 20 This is the H NMR spectrum of the intramolecular cyclopropanation product 2aj.

[0047] Figure 21 This is the C NMR spectrum of the intramolecular cyclopropanation product 2aj.

[0048] Figure 22 This is the H NMR spectrum of the intramolecular cyclopropanation product 2ak.

[0049] Figure 23 This is the C NMR spectrum of the intramolecular cyclopropanation product 2ak. Specific implementation plan

[0050] The present invention will be described in detail below with reference to the accompanying drawings.

[0051] Example 1

[0052] The embodiment reaction formula of the present invention is shown in the figure below:

[0053]

[0054] The product prepared in this example has the structure:

[0055] The preparation method of this example is as follows: Under a nitrogen atmosphere, cinnamyl 2-(phenylsulfonyl) acetate (2.7 g, 10 mmol), cuprous iodide (572.7 mg, 30 mol%), and acetonitrile (50 mL) are added to a 100 mL reaction tube equipped with a magnetic rod, followed by the addition of the oxidant di-tert-butyl peroxide (2.9 g, 20 mmol). The reaction tube is sealed and transferred to an oil bath (60-100°C) with stirring. The reaction is allowed to react for 24 hours, and the reaction progress is monitored by TLC. After the reaction is complete, the reaction is quenched with saturated aqueous sodium chloride solution, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. After decompression and evaporation of the solvent, the crude reaction product is obtained, which is separated by column chromatography to obtain the intramolecular cyclopropanation product, 2aa, as a white solid (2.7 g, 87%). Melting point: 174-178°C. Dr>20:1; 1HNMR(400MHz, CDCl3)δ7.56–7.52(m,1H),7.46–7.43(m,2H),7.36–7.29(m,3H),7.26–7.23(m,2H),7.04–7.02 (m,2H),4.61(dd,J=9.5,4.8Hz,1H),4.38(d,J=9.6Hz,1H),3.84(dd,J=6.1,4.5Hz,1H),2.87(d,J=6.2Hz,1H). 13 CNMR(100MHz, CDCl3)δ168.6,138.6,134.0,130.0,128.6,128.6,128.6,128.3,127.9,67.6,52.7,37.3,28.0.HRMS(ESI,m / z):calcd.forC 17 H 14 O4S+Na + [M+Na] + :337.0505; found:337.0508.

[0056] Example 2

[0057] The product prepared in this example has the structure:

[0058] Under a nitrogen atmosphere, cinnamyl 2-((4-fluorophenyl)sulfonyl)acetate (3.3 g, 10 mmol), copper bromide (893.5 mg, 40 mol%), and acetonitrile (50 mL) were added to a 100 mL reaction tube equipped with a magnetic rod, followed by di-tert-butyl peroxide (2.9 g, 20 mmol). The reaction tube was sealed and transferred to an oil bath (60-100°C) with stirring. The reaction was allowed to react for 24 h, and the reaction progress was monitored by TLC. After completion of the reaction, the reaction was quenched with saturated aqueous sodium chloride solution, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. After decompression and evaporation of the solvent, the crude reaction product was obtained, which was separated by column chromatography to obtain the intramolecular cyclopropanation product, 2ab (2.9 g, 88%), as a white solid. Melting point 210-215°C. dr > 20:1; 1HNMR(400MHz, CDCl3)δ7.47–7.40(m,2H),7.38–7.34(m,1H),7.30–7.26(m,2H),7.06–7.03(m,2H),7.02–6.95 (m,2H),4.65(dd,J=9.6,4.7Hz,1H),4.40(d,J=9.6Hz,1H),3.84(dd,J=6.2,4.7Hz,1H),2.87(d,J=6.2Hz,1H). 19 FNMR(376MHz, CDCl3)δ-103.6–-103.7(m,1F). 13 C NMR(100MHz,CDCl3)δ168.5,166.0(d,J C–F =255.1Hz),134.5(d,J C–F =3.0Hz),131.7(d,J C–F =9.6Hz),130.0,128.8,128.3,127.8,115.8(d,J C–F =22.7Hz),67.6,52.7,37.3,27.9.HRMS(ESI,m / z):calcd.for C 17 H 13 FO4S+Na + [M+Na] + :355.0411; found:355.0418.

[0059] Example 3

[0060] The product prepared in this example has the structure: Under a nitrogen atmosphere, cinnamyl2-(pyridin-4-ylsulfonyl)acetate (3.2 g, 10 mmol), cuprous bromide (430.4 mg, 30 mol%), and acetonitrile (50 mL) were added to a 100 mL reaction tube equipped with a magnetic separator. Di-tert-butyl peroxide (4.4 g, 30 mmol) was then added. The reaction tube was sealed and transferred to an oil bath (60-100°C) with stirring. The reaction was allowed to react for 24 h, and the reaction progress was monitored by TLC. After completion of the reaction, the reaction was quenched with saturated aqueous sodium chloride solution, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain the crude reaction product, which was separated by column chromatography to obtain the intramolecular cyclopropanation product, 2ad (1.8 g, 57%), as a white solid. Melting point: 203-206°C. Dr: >20:1. 1HNMR(400MHz,(CD3)2SO)δ8.76(s,2H),7.35–7.23(m,5H),7.16–7.14(m,2H),4.69(dd,J= 9.5, 4.9Hz, 1H), 4.49 (d, J = 9.5Hz, 1H), 4.28 (dd, J = 6.4, 4.6Hz, 1H), 3.47 (d, J = 6.5Hz, 1H). 13 CNMR(100MHz,(CD3)2SO)δ168.7,151.3,146.9,130.6,129.1,128.8,128.3,121.0,68.6,52.5,37.3,29.3.HRMS(ESI,m / z):calcd.forC 16 H 13 NO4S+Na + [M+Na] + :338.0458; found:338.0460.

[0061] Example 4

[0062] The product prepared in this example has the structure:

[0063] Under a nitrogen atmosphere, to a 100 mL reaction tube equipped with a magnetic field, (E)-3-(3,4-dichlorophenyl)allyl2-(phenylsulfonyl)acetate (3.9 g, 10 mmol), cuprous iodide (570.1 mg, 30 mol%), and N,N-dimethylformamide (50 mL) were added, followed by dicumyl peroxide (5.4 g, 20 mmol). The reaction tube was sealed and transferred to an oil bath (60-100°C) with stirring. The reaction was allowed to react for 24 h, and the reaction progress was monitored by TLC. Upon completion, the reaction was quenched with saturated sodium chloride solution, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain the crude product, which was separated by column chromatography to obtain the intramolecular cyclopropanation product, 2ae, as a white solid (3.4 g, 90%). Melting point: 191-200°C. dr = 20:1. 1HNMR (400MHz, CDCl3) δ7.65–7.60(m,1H),7.59–7.57(m,2H),7.44–7.40(m,2H),7.38–7.36(m,1H),7.00(d,J=2.1Hz,1H),6.95 (dd,J=8.4,2.2Hz,1H),4.63(dd,J=9.6,4.7Hz,1H),4.39(d,J=9.6Hz,1H),3.77(dd,J=6.1,4.7Hz,1H),2.81(d,J=6.1Hz,1H). 13 CNMR(100MHz, CDCl3)δ168.0,138.3,134.4,133.0,132.5,132.3,130.2,128.8,128.8,128.5,128.4,67.4,52.6,35.7,28.2.HRMS(ESI,m / z):calcd.forC 17 H 12 35 Cl2O4S+Na + [M+Na] + :404.9726; found:404.9730.

[0064] Example 5

[0065] The product prepared in this example has the structure:

[0066] Under a nitrogen atmosphere, to a 100 mL reaction tube equipped with a magnetic field, 3-methylbut-2-en-1-yl2-(phenylsulfonyl)acetate (2.7 g, 10 mmol), cuprous bromide (286.9 mg, 20 mol%), and dimethyl sulfoxide (50 mL) were added, followed by di-tert-butyl peroxide (5.1 g, 35 mmol). The reaction tube was sealed and transferred to an oil bath (60-100°C) with stirring. The reaction was allowed to react for 24 h, and the progress of the reaction was monitored by TLC. After completion of the reaction, the reaction was quenched with saturated aqueous sodium chloride solution, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain the crude reaction product, which was separated by column chromatography to obtain the intramolecular cyclopropanation product 2af (1.6 g, 61%) as a colorless oil. dr>20:1; 1HNMR (400MHz, CDCl3) δ8.13–8.10(m,2H),7.69–7.65(m,1H),7.60–7.55(m,2H),4.48(dd,J=10.2 ,5.4Hz,1H),4.15(dd,J=10.0,0.9Hz,1H),3.01(dd,J=5.2,1.0Hz,1H),1.52(s,3H),1.16(s,3H). 13 CNMR(100MHz, CDCl3)δ168.4,140.0,134.2,129.2,128.5,64.9,56.8,36.6,33.0,19.9,16.9.HRMS(ESI,m / z):calcd.forC 13 H 14 O4S+Na + [M+Na] + :289.0505;found:289.0508.

[0067] With reference to the above preparation methods, the specific conditions of the oxidant, metal catalyst, temperature, solvent, product and yield of the 21 examples are summarized as follows:

[0068] Table 1. Summary of embodiments of the present invention for oxidants, metal catalysts, temperatures and solvents

[0069]

[0070]

[0071]

[0072]

[0073] Other metal catalysts such as CuSCN, Fe(OAc)2, FeCl2, FeCl3, Fe(acac)3, NiBr2, NiCl2, and Ni(OAc)2 were used to replace the copper bromide in Example 1. The results showed that their catalytic activities were similar to those of copper bromide and they also achieved the same catalytic effect, and the target product could be obtained with a yield of more than 80%.

[0074] Similar experimental results were obtained by replacing the solvent DMF in Example 5 with other solvents such as ethyl acetate, tetrahydrofuran, dichloromethane, dichloroethane, nitromethane, acetonitrile, benzene, toluene, chlorobenzene, trifluorotoluene, N,N-dimethylacetamide, etc., and the target product was obtained with a yield of more than 75%.

[0075] Table 2. Summary of the embodiments of the present invention for the reaction raw materials (when the reaction conditions remain unchanged)

[0076]

[0077]

Claims

1. A method for preparing 1,5,6-polysubstituted-2-oxo-3-oxabicyclo[3.1.0]hexane, characterized in that: The reaction process is: wherein EWG is selected from cyano, trifluoromethyl, nitro, and ester groups; R 1 The functional group is selected from an alkyl group, a benzene ring, a substituted benzene ring or an aromatic heterocycle; R 2 The functional group is selected from an alkyl group, a benzene ring, a substituted benzene ring or an aromatic heterocycle; R 3 The functional group is selected from an alkyl group, a benzene ring, a substituted benzene ring or an aromatic heterocycle; R 4 The functional group is selected from an alkyl group, a benzene ring, a substituted benzene ring or an aromatic heterocycle; The specific steps include: (1) Under a nitrogen atmosphere, substituted acetic acid acrylate, an oxidant, a metal catalyst, and a reaction solvent are added to a reaction tube equipped with a magnet, the reaction system is sealed, and the reaction is heated to proceed; (2) The reaction was monitored by TLC plate until the reaction was complete. After cooling to room temperature, the reaction was quenched with a saturated sodium chloride aqueous solution and extracted with ethyl acetate. The organic phase was distilled under reduced pressure to remove the solvent. The crude product was separated by column chromatography to obtain 1,5,6-polysubstituted-2-oxo-3-oxabicyclo[3.1.0]hexane; The metal catalyst is selected from the following: Cu(OTs)2, Cu(OAc)2, CuBr2, CuI2, CuCl2, CuI, CuBr, CuCl, CuSCN, Fe(OAc)2, FeCl2, FeCl3, Fe(acac)3, NiBr2, NiCl2, Ni(OAc)2, and the amount of the catalyst is 0.1-80 mol% of the substituted acetic acid acrylate; The oxidant is selected from the following: di-tert-butyl peroxide DTBP, diisopropylbenzene peroxide DCP, peracetic acid; the amount of the oxidant is 0.5-3.5 times the equivalent of substituted acetic acid acrylate; The reaction solvent is selected from the following: acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide; the reaction solvent is 0.1-0.5M based on the reaction concentration of substituted acetic acid acrylate; The heating temperature is 60-120°C.

2. The method for preparing 1,5,6-polysubstituted-2-oxo-3-oxabicyclo[3.1.0]hexane according to claim 1, characterized in that: The reaction solvent is 0.1 M based on the reaction concentration of substituted acetic acid acrylate.

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