Palladium-catalyzed cyclization extension reaction method of butadienes

Abstract

The invention relates to a method for a palladium-catalyzed cyclization extension reaction of butadienes. Specifically, under the condition that tert-butyl nitrite is oxidized under the catalysis of palladium, the cyclopentanone compound is obtained through a ring extension reaction of butyl fulvene and water. According to the invention, green and rich water is used as a raw material, and a series of cyclopentanone compounds are obtained under mild conditions.

Description

TECHNICAL FIELD

[0001] The present application relates to a method of palladium-catalyzed hydration ring expansion reaction of butafulvene. BACKGROUND

[0002] The direct reaction of olefins with water, named hydration reaction, is a fundamental reaction in the field of chemical industry and drug synthesis. In the past few decades, the hydration reaction of simple olefins has made substantial development. Through the hydration reaction of olefins, a variety of alcohols or carbonyl compounds can be synthesized under oxidative or neutral redox conditions. Alcohols and carbonyl compounds are rich in natural products and artificial products, and have rich biological activity. Compared with the hydration reaction of olefins, the catalytic hydration reaction of benzene compounds has developed relatively slowly due to its 6e electron π conjugated system and aromaticity. Non-substituted butafulvene, as a four-membered cyclic isomer of benzene, has a three-conjugated unsaturated system and a high ring strain. Therefore, it is urgent to develop a new and efficient hydration ring expansion reaction of butafulvene. The synthesized cyclopentanone target product has a very wide application in the synthesis of natural products and drug molecules.

[0003] In summary, the present application describes a method for directly synthesizing a high-value-added cyclopentanone compound by innovatively utilizing the hydration ring expansion reaction of butafulvene under palladium catalysis. SUMMARY

[0004] The present application aims to provide a palladium-catalyzed hydration ring expansion reaction of butafulvene.

[0005]

[0006] Reaction equation 1: palladium-catalyzed hydration ring expansion reaction of butafulvene

[0007] The specific operation steps are as follows (reaction equation 1):

[0008] In an air atmosphere, butafulvene derivative 1, water, palladium catalyst preferably Pd(OAc)2, and an amount of 0.05-0.15 molar equivalent, preferably 0.10 molar equivalent, are added to a reaction bottle, and an oxidizing agent, an additive, and a solvent are added. The reaction is carried out at room temperature (20-30℃) for 12 hours. After the reaction is completed, the cyclopentanone compound 2 is separated.

[0009] The molar amount ratio of butafulvene derivative 1 to water is 1:10-30, preferably 1:25-30.

[0010] The oxidizing agent is t one or two or more of BuONO, CuCl2, TBHP, and K2S2O8, preferably tBuONO; the amount of the oxidant is 1.0-4.0 molar equivalents, preferably 3.0-4.0 molar equivalents of the amount of butafulvene derivative 1.

[0011] The additive is one or two or more of AgNO2, AgNO3, AgClO4 and AgNTf2, preferably AgNO2; the amount of the additive is 0.05-0.15 molar equivalents, preferably 0.08-0.12 molar equivalents of the amount of butafulvene derivative 1.

[0012] The solvent is one or two or more of methanol, ethanol, dichloromethane, toluene, tetrahydrofuran, preferably a mixture of methanol and dichloromethane; the amount of the solvent is 1.0-10 mL, preferably 6-10 mL of solvent per mmol of butafulvene derivative 1; the ratio of dichloromethane and methanol is 1:1-10, preferably 1:3-5.

[0013] The present application is a ring expansion reaction of butafulvene and water under the condition of palladium-catalyzed oxidation of tert-butyl nitrite to obtain a cyclopentanone compound.

[0014] The present application obtains a series of cyclopentanone derivatives under relatively mild conditions from simple and easily stored raw materials.

[0015] The present application has the following advantages:

[0016] Firstly, the most abundant water on earth is used as a raw material, making the reaction more green and sustainable. Secondly, it is carried out at room temperature, and the reaction conditions are simple and mild. Finally, the obtained product cyclopentanone derivative has high added value and has great application prospect in the field of natural product and drug molecule synthesis. DETAILED DESCRIPTION

[0017] In order to better understand the present application, the following examples are used for illustration. The reaction raw materials and results of examples 1-16 are shown in table 1.

[0018] Table 1 Reaction results of different substituted substrates

[0019]

[0020]

[0021]

[0022]

[0023] Example 1

[0024] In an open-tube reaction tube, butafulvene 1a (0.20 mmol, 1.0 equiv.), water (6.0 mmol, 30.0 equiv.), Pd(OAc)2(0.02 mmol, 10 mol%), BuONO (0.60 mmol, 3.0 equiv.), AgNO2(0.02 mmol, 10 mol%) were added in sequence under air atmosphere at room temperature (25 °C) and reacted for 12 hours. After the reaction was completed, the cyclopentanone compound 2a was separated by column chromatography with a yield of 84% and its structure was identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum). t BuONO (0.60 mmol, 3.0 equiv.), AgNO2(0.02 mmol, 10 mol%), methanol / dichloromethane (1.6 mL / 0.4 mL) at room temperature (25 °C) and reacted for 12 hours. After the reaction was completed, the cyclopentanone compound 2a was separated by column chromatography with a yield of 84% and its structure was identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum).

[0025] Compound 2a has good activity in inhibiting SARS-CoV-2 novel coronavirus that causes COVID-19. The specific test steps of the corresponding 3CL protease inhibition activity are as follows: first, prepare the bio-oil of the test compound 2a. The compound 2a is pulverized using a pulverizer, and then mixed with water at a final mass concentration of 0.01%, 1%, and 100% to obtain a biomass slurry or powder. The biomass slurry is liquefied in a high-pressure reaction kettle under the conditions of heating from room temperature to 150 °C (the heating rate is 1 °C / min), 7-15 MPa (here, 12 MPa), the stirring speed is 150-300 rpm (here, 280 rpm), and the reaction time is 10-30 minutes (here, 20 minutes). The obtained reaction liquid is separated into solid and liquid, the solid is extracted with acetone, filtered, and the filtrate is evaporated to recover the acetone to obtain the bio-oil of the test compound 2a.

[0026] Using polyprotein PP1A (Hefei Bomei Biotechnology Co., Ltd.) as the substrate, 20 mg of the substrate, 2 mg / mL of SARS-CoV-2 3CL protease solution (Jier Biochemical Co., Ltd., Shanghai) 2 mL, and 2 mL of the bio-oil of the test compound 2a are mixed well by vortexing, and then placed in a 37 °C shaking bed with a shaking speed of 400 r / min for 20 minutes. Then, 5 mL of 0.5 mol / L phosphate buffer with a pH of 6.0 is immediately added, mixed well by vortexing, and then an appropriate amount of the mixed solution is taken into a 2 mL centrifuge tube, centrifuged for 10 minutes, and 200 μL of the supernatant is accurately taken into a 96-well plate, and the absorbance is measured at a wavelength of 495 nm, and a spectrum scan is performed at a wavelength of 400-800 nm. By changing the addition components in the above preparation process, a plurality of experimental groups (enzyme inhibition groups) are set.

[0027] The blank control group is the substrate plus enzyme solution (without the test compound 2a, and the other processes and conditions are the same as those of the enzyme inhibition group), the enzyme inhibition group is the substrate plus enzyme and the test compound 2a, and the background group is the substrate plus the test compound 2a without the enzyme solution (the other processes and conditions are the same as those of the enzyme inhibition group). Each group has 2 duplicate holes. Inhibition rate (%) = [1–(A n –An ′) / (A n –A0)]×100%, where A0 is the absorbance of the background group, A n A represents the absorbance of the blank control group. n ′ represents the absorbance of the enzyme inhibition group. The test results are shown in Table 1:

[0028]

[0029] Table 1

[0030] The detection data for compound 2a are as follows:

[0031] 2a Yellow solid,mp 146–147℃,46.3mg,84%yield.R f =0.5 (PE / EA = 10 / 1). 1 HNMR (400MHz, CDCl3) δ7.35–7.29(m,3H),7.19–7.11(m,5H),7.09–7.04(m,2H),3.27(s,2H),1.90(s,3H),1.36(s,3H). 13 C NMR (100MHz, CDCl3) δ202.8,165.9,137.3,135.6,131.3,129.7,129.5,128.5,128.04,128.01,127.7,127.3,41.7,25.2,21.7.

[0032] Example 2:

[0033] The operation process and conditions were the same as in Example 1, except that the raw material 1 (see Table 1) was used instead of MeOH, and the product 2b was produced with a yield of 35%. The structure of the compound was identified by nuclear magnetic resonance (H1N and C1N spectra).

[0034] The detection data for compound 2b are as follows:

[0035] 2b:Yellow solid,mp 71–72℃,28.6mg,35%yield.R f =0.4 (PE / EA = 10 / 1). 1 HNMR (400MHz, CDCl3) δ7.35–7.29(m,3H),7.17–7.13(m,2H),6.99–6.96(m,4H),3.26(s,2H),2.24(s,3H),1.89(s,3H),1.34(s,3H). 13C NMR (100MHz, CDCl3) δ203.1,165.4,141.8,137.5,137.1,135.1,129.8,129.3,128.6,128.5,128.3,128.0,127.9,41.7,25.1,21.6,21.2.

[0036] Example 3:

[0037] The operation process and conditions were the same as in Example 1, except that the raw material 1 (see Table 1) and product 2c were used, with a yield of 69%. The structure of the compound was identified by NMR (H1N and C1N spectra).

[0038] The detection data for compound 2c are as follows:

[0039] 2c: Yellow oil, 41.8mg, 69% yield.R f =0.3 (PE / EA = 10 / 1). 1 H NMR (400MHz, CDCl3) δ7.29–7.23(m,3H),7.11–7.07(m,2H),6.95–6.92(m,4H),3. 19(s,2H),2.47(q,J=7.6Hz,2H),1.82(s,3H),1.27(s,3H),1.08(t,J=7.6Hz,3H). 13 C NMR (100MHz, CDCl3) δ203.1,165.4,143.3,141.8,137.5,135.1,129.7,129.4,128. 8,128.7,128.51,128.49,128.2,128.0,127.9,127.3,41.7,28.6,25.2,21.6,15.2.

[0040] Example 4:

[0041] The operation process and conditions were the same as in Example 1, except that the raw material was 1 (see Table 1 for details), the product was 2 days old, the yield was 75%, and the structure of the compound was identified by NMR (H1N and C1N spectra).

[0042] The 2d detection data of the compound are as follows:

[0043] 2d: Yellow solid, mp 139–140℃, 49.4mg, 75% yield.R f =0.3 (PE / EA = 10 / 1). 1HNMR (400MHz, CDCl3) δ7.36–7.31(m,3H),7.19–7.15(m,4H),7.04–7.00(m,2H),3.26(s,2H),1.89(s,3H),1.33(s,3H),1.23(s,9H). 13 CNMR(100MHz, CDCl3)δ203.2,165.4,150.1,141.5,137.6,135.1,129.8,129.1,128.5,128.2,128.1,128.0,124.7,41.7,34.5,31.2,25.2,21.6.

[0044] Example 5:

[0045] The operation process and conditions were the same as in Example 1, except that the raw material 1 (see Table 1) and product 2e were produced with a yield of 75%. The structure of the compound was identified by nuclear magnetic resonance (H1N and C1N spectra).

[0046] Example 6:

[0047] The operation process and conditions were the same as in Example 1, except that the raw material 1 (see Table 1) and product 2f were used, with a yield of 75%. The structure of the compound was identified by NMR (H1N and C1N spectra).

[0048] Example 7:

[0049] The operation process and conditions were the same as in Example 1, except that the raw material was 1 (see Table 1 for details), the product was 2g, the yield was 52%, and the structure of the compound was identified by nuclear magnetic resonance (H1N and C1N spectra).

[0050] Example 8:

[0051] The operation process and conditions were the same as in Example 1, except that the raw material 1 (see Table 1 for details) was used, the product was processed in 2 hours, the yield was 46%, and the structure of the compound was identified by nuclear magnetic resonance (H1N and C1N spectra).

[0052] Example 9:

[0053] The operation process and conditions were the same as in Example 1, except that the raw material 1 (see Table 1) and product 2i were used, with a yield of 58%. The structure of the compound was identified by NMR (H1N and C1N spectra).

[0054] The detection data for compound 2i are as follows:

[0055] 2i: Yellow solid, mp 134–135℃, 33.7mg, 58% yield.R f =0.4 (PE / EA = 10 / 1). 1HNMR (400MHz, CDCl3) δ7.19–7.09(m,5H),7.08–7.06(m,2H),7.03–7.01(m,2H),3.26(s,2H),2.34(s,3H),1.89(s,3H),1.38(s,3H). 13 C NMR (100MHz, CDCl3) δ202.9,166.2,141.8,137.9,135.5,134.2,131.5,129.9,129.5,129.2,127.9,127.7,127.2,41.8,25.2,21.8,21.4.

[0056] Example 10:

[0057] The operation process and conditions were the same as in Example 1, except that the raw material 1 (see Table 1) and product 2j were used, with a yield of 52%. The structure of the compound was identified by NMR (H1N and C1N spectra).

[0058] The detection data for compound 2j are as follows:

[0059] 2j:Yellow oil,31.7mg,52%yield.R f =0.3 (PE / EA = 10 / 1). 1 H NMR (400MHz, CDCl3) δ7.19–7.11(m,5H),7.10–7.02(m,4H),3.26(s,2H),2.64(q,J=7.6Hz,2H),1.89(s,3H),1.37(s,3H),1.23(t,J=7.6Hz,3H). 13 C NMR (100MHz, CDCl3) δ202.9,166.3,144.3,141.8,135.5,134.4,131.5,129.9,129.5,127.95,127.91,127.8,127.2,41.8,28.6,25.2,21.7,15.4.

[0060] Example 11:

[0061] The operation process and conditions were the same as in Example 1, except that the raw material 1 (see Table 1) and product 2k were used, with a yield of 58%. The structure of the compound was identified by NMR (H1N and C1N spectra).

[0062] The detection data for compound 2k are as follows:

[0063] 2k: Yellow solid, mp 93–94℃, 38.5mg, 58% yield.R f=0.5 (PE / EA = 10 / 1). 1 HNMR (400MHz, CDCl3) δ7.26–7.23(m,2H),7.09–7.04(m,3H),7.01–6.96(m,4H),3.19(s,2H),1.82(s,3H),1.29(s,3H),1.23(s,9H). 13 C NMR (100MHz, CDCl3) δ202.9,166.3,151.3,141.8,135.5,134.1,131.5,129.9,129.5,127.7,127.6,127.2,125.3,41.8,34.7,31.3,25.2,21.7.

[0064] Example 12:

[0065] The operation process and conditions were the same as in Example 1, except that the raw material 1 (see Table 1 for details) and product 21 were used, with a yield of 67%. The structure of the compound was identified by nuclear magnetic resonance (H1N, C1N, and fluorine spectra).

[0066] The detection data for compound 2l are as follows:

[0067] 2l:Yellow soild,mp 138–139℃,39.3mg,67%yield.R f =0.3 (PE / EA = 10 / 1). 1 HNMR (400MHz, CDCl3) δ7.21–7.09(m,5H),7.07–6.98(m,4H),3.27(s,2H),1.90(s,3H),1.38(s,3H). 13 C NMRδ202.6,164.7,162.5(d,J=248.4Hz),142.3,135.6,133.1(d,J=3.5Hz),131.1,12 9.9(d,J=8.3Hz),129.7,129.4,127.8,127.4,115.7(d,J=21.7Hz),41.7,25.2,21.8. 19 F NMR (376MHz, CDCl3) δ-113.1.

[0068] Example 13:

[0069] The operation process and conditions were the same as in Example 1, except that the raw material 1 (see Table 1 for details) and product 2m were used, with a yield of 58%. The structure of the compound was identified by NMR (H1N and C1N spectra).

[0070] Example 14:

[0071] The operation process and conditions were the same as in Example 1, except that the raw material 1 (see Table 1) and product 2n were used, with a yield of 87%. The structure of the compound was identified by nuclear magnetic resonance (H1N and C1N spectra).

[0072] Example 15:

[0073] The operation process and conditions were the same as in Example 1, except that the raw material 1 (see Table 1) and product 2o were used, with a yield of 68%. The structure of the compound was identified by NMR (H1N and C1N spectra).

[0074] Example 16:

[0075] The operation process and conditions were the same as in Example 1, except that the raw material 1 (see Table 1) was used, the product 2p was used, the yield was 70%, and the structure of the compound was identified by NMR (H1N and C1N spectra).

[0076] Example 17:

[0077] The operation process and conditions were the same as in Example 1, except that the palladium catalyst used in the reaction was Pd(TFA)2, the product was 2a, the yield was 42%, and the structure of the compound was identified by nuclear magnetic resonance (H1N and C1N spectra).

[0078] Example 18:

[0079] The operation process and conditions were the same as in Example 1, except that the oxidant used in the reaction was K2S2O8, the product was 2a, the yield was 10%, and the structure of the compound was identified by nuclear magnetic resonance (H1N and C1N spectra).

[0080] Example 19:

[0081] The operation process and conditions were the same as in Example 1, except that AgNO3 was used as the additive in the reaction, the product was 2a, the yield was 72%, and the structure of the compound was identified by nuclear magnetic resonance (H1N and C1N spectra).

[0082] Example 20:

[0083] The operation and conditions were the same as in Example 1, except that 1 equivalent of tert-butyl nitrite was used instead of 4 equivalents of tert-butyl nitrite in the reaction. The product was 2a, with a yield of 33%. The structure of the compound was identified by nuclear magnetic resonance (H1N and C1N spectra).

[0084] Comparative Example 1:

[0085] The operation process and conditions were the same as in Example 1, except that no catalyst was used in the reaction, and the target product 2a was not obtained.

[0086] Comparative Example 2:

[0087] The operation process and conditions were the same as in Example 1, except that no oxidant was used in the reaction, and the target product 2a was not obtained.

[0088] Comparative Example 3:

[0089] The operation process and conditions were the same as in Example 1, except that the catalyst used in the reaction was Co(OAc)2, and the target product 2a was not obtained.

[0090] Comparative Example 4:

[0091] The operation process and conditions were the same as in Example 1, except that the reaction used triethylamine as an additive, and the target product 2a was not obtained.

[0092] Comparative Example 5:

[0093] The operation process and conditions were the same as in Example 1, except that 1 equivalent of AgNO2 was used instead of 0.10 equivalent of AgNO2 in the reaction. The product was 2a, with a yield of 75%. The structure of the compound was identified by NMR (H1N and C1N NMR).

Claims

1. A method for a palladium-catalyzed hydration ring extension reaction of butene, characterized in that: Where R 1 It can be one or more of the following groups: hydrogen, methyl, ethyl, tert-butyl, fluorine, chlorine, acetyl, trifluoromethyl, phenyl, or naphthalene; R 2 It is one or more of the following groups: hydrogen, methyl, ethyl, tert-butyl, fluorine, chlorine, acetyl, trifluoromethyl, phenyl, or naphthalene; Two Rs 3 Each of the following groups can be individually one or more of the following groups: methyl, ethyl, n-propyl, cyclohexyl, tetrahydropyranyl, etc.

2. The method according to claim 1, characterized in that: The specific steps are as follows: In an air atmosphere, butene derivative 1, water, palladium catalyst, oxidant, additive and solvent were added to a reaction flask and reacted at room temperature (20-30℃) for 12 hours; after the reaction was completed, cyclopentanone compound 2 was separated.

3. The method according to claim 2, characterized in that: The molar ratio of butene derivative 1 to water is 1:10-30, with a preferred ratio of 1:25-30.

4. The method according to claim 1 or 2, characterized in that: The palladium catalyst used can be one or more of Pd(OAc)2, Pd(TFA)2, PdCl2(MeCN)2 and Pd(BF)2(MeCN)4, with Pd(OAc)2 being preferred as the catalyst. The amount used is 0.05-0.15 molar equivalents (relative to the raw material butene derivative 1), preferably 0.08-0.12 molar equivalents.

5. The method according to claim 2, characterized in that: Oxidizing agent is t One or more of BuONO (tert-butyl nitrite), CuCl2, TBHP (tert-butanol peroxide), and K2S2O8 are preferred. t BuONO; the amount of oxidant used is 1.0-4.0 molar equivalents of the amount of butene derivative 1 used, preferably 3.0-4.0 molar equivalents.

6. The method according to claim 2, characterized in that: The additive is one or more of AgNO2, AgNO3, AgClO4 and AgNTf2 (silver bis(trifluoromethanesulfonyl)imide), with AgNO2 being preferred; the amount of additive used is 0.05-0.15 molar equivalents of the amount of butaluminum derivative 1, with 0.08-0.12 molar equivalents being preferred.

7. The method according to claim 2, characterized in that: The solvent is one or more of methanol, ethanol, dichloromethane, toluene, and tetrahydrofuran, preferably a mixture of methanol and dichloromethane, with a volume ratio of dichloromethane to methanol of 1:1-10, preferably 1:3-5; the amount of solvent used is 1.0-10 mL per millimole of butyrate derivative 1, preferably 6-10 mL.

Images