Method for preparing beta-trichloromethyl butyl ester or amide

Abstract

The invention relates to a method for preparing beta-trichloromethyl butyl ester and amide. Specifically, the beta-trichloromethyl butyl ester and amide derivatives are prepared from carbon tetrachloride and nucleophilic reagents (including phenol, alcohol and amine) by a one-pot method in the atmosphere of carbon monoxide and ethylene under the catalytic condition of light-induced copper and bipyridine ligands. According to the preparation method, commercially available raw materials with wide substrates and low price are adopted, C-Cl bonds of carbon tetrachloride are uniformly cracked under the photocatalytic condition to generate trichloromethyl free radicals, then carbonylation relay reaction is performed, and the multifunctional beta-trichloromethyl butyl ester and amide derivatives are efficiently obtained.

Description

Technical Field

[0001] The invention relates to a method for synthesizing beta-trichloromethylbutyl ester and / or amide. Background Art

[0002] Ester and amide compounds are commonly found in fine chemicals, natural products, bioactive molecules and polymers. Polychloroalkyl groups can be used as key components to change the drug activity of compounds, and can be used as synthetic precursors to convert into functional groups with different functionalities such as aldehydes, ketones and carboxylic acids, providing strong support for the later synthesis and modification of natural products. Chemists have discovered and isolated more than thousands of natural products containing one or more C-Cl bonds. In particular, esters and amides containing trichloromethyl are important core structures of many bioactive compounds and drug molecules, which have a wide range of biological activities such as antibiotics, anti-tumor, anti-HIV and analgesic activities. The traditional method for synthesizing such compounds requires the use of stoichiometric oxidants and corresponding multi-step reactions, while there are few reports on the one-pot multi-component reaction to synthesize β-trichloromethylbutyl esters and amides in one step.

[0003] Here, we developed a photocatalytic synthesis of β-trichloromethylbutyl ester and amide. Using ethylene, which is easy to obtain, as the parent molecule, carbon tetrachloride, and nucleophilic reagents (phenols, alcohols, amines, etc.) as reaction substrates, we can convert these raw materials into a series of β-trichloromethylbutyl esters and amides with high yields and high selectivity under mild conditions.

[0004] In summary, this paper describes a method for the direct preparation of β-trichloromethylbutyl ester and amide compounds in a one-step free radical relay with high efficiency, high atom economy, and low-cost raw materials. Summary of the invention

[0005] The object of the present invention is to provide a method for synthesizing β-trichloromethylbutyl ester and amide derivatives.

[0006]

[0007] Reaction equation 1: Synthesis of β-trichloromethylbutyl ester and amide derivative 3

[0008] The specific operation steps are as follows (reaction equation 1):

[0009] The reaction is carried out in a high-pressure reactor, and the catalyst, ligand, base, carbon tetrachloride, and nucleophilic agent are weighed and placed in a carbon monoxide and ethylene gas atmosphere at 20-40° C., preferably 25° C. The reaction time is 10-36 hours, preferably 24 hours; after the reaction is completed, β-trichloromethylbutyl ester and amide derivative 3 are separated.

[0010] The amount ratio of the nucleophile is 0.1-10 mmol, preferably 0.4 mmol.

[0011] The amount of carbon tetrachloride used is 0.5-15 mmol, preferably 2.0 mmol.

[0012] The catalyst is copper acetylacetonate (Cu(acac) 2 ), copper acetate (Cu(OAc) 2 ), cuprous iodide (CuI), cuprous bromide (CuBr), copper trifluoromethanesulfonate (Cu(OTf) 2 ) is preferably copper trifluoromethanesulfonate; the ligand is triphenylphosphine (PPh 3 ), bipyridine (bpy), 1,10-phenanthroline (1,10-Phen), 1,10-phenanthroline-5,6-dione, 4,4'-dimethoxy-2,2'-bipyridine, 6,6'-dimethyl-2,2'-bipyridine, preferably bipyridine; the base is potassium carbonate, potassium phosphate, sodium carbonate, cesium carbonate, preferably potassium carbonate.

[0013] The molar ratio of the nucleophilic agent is 0.2-10 equivalents, preferably 1.0 equivalents (0.4 mmol). The molar ratio of the nucleophilic agent to carbon tetrachloride and the base is 1:1:1.2-1:10:6, preferably 1:5:2; the molar ratio of the nucleophilic agent to the catalyst and the ligand is 1000:2:3-100:20:40, preferably 100:1:2.

[0014] The gas pressure of ethylene is 1 to 20 atmospheres, preferably 1 atmosphere.

[0015] The gas pressure of carbon monoxide is 10-70 atmospheres, preferably 50 atmospheres.

[0016] The light source (50w) can be white light (incandescent lamp), green light, or blue light, preferably blue light.

[0017] The amount of acetonitrile used is 0.2-3.0 mL, preferably 0.5 mL, per 0.1 mmol of nucleophile.

[0018] The present invention has the following advantages:

[0019] Cheap and commercially available carbon tetrachloride, nucleophilic reagents (phenols, alcohols, amines, etc.), and carbon monoxide were selected as starting materials, and ethylene was used as the parent molecule. Under the catalysis of 50W blue light as the light source, these raw materials were converted into β-trichloromethylbutyl ester and amide 3 in high yield. The reaction has good atom economy, high chemical selectivity, and good compatibility of functional groups in the reaction system.

[0020] The invention uses a widely available, cheap and commercially available raw material, and efficiently obtains multifunctionalized products, beta-trichloromethylbutyl ester and amide derivatives, through a free radical relay carbonylation reaction under photocatalytic conditions.

[0021] Under photocatalytic conditions, the C-Cl bond of carbon tetrachloride is homolytically cleaved to generate trichloromethyl radicals, which then undergo a carbonylation relay reaction to efficiently obtain multifunctional β-trichloromethylbutyl esters and amide derivatives. DETAILED DESCRIPTION

[0022] In order to better understand the present invention, the following examples are provided for illustration. The reaction materials and results of Examples 1-10 are shown in Table 1.

[0023] Table 1 Reaction results of nucleophilic reagents

[0024]

[0025]

[0026]

[0027] The product structure is as follows:

[0028]

[0029] Example 1

[0030] The reaction was carried out in a high-pressure reactor. First, copper trifluoromethanesulfonate (0.004 mmol), bipyridine (0.008 mmol), a nucleophile (0.4 mmol), carbon tetrachloride (2.0 mmol), and potassium carbonate (0.8 mmol) were added to a 4 ml glass vial. 2 ml of acetonitrile was added under a nitrogen atmosphere. A sealing rubber stopper was plugged into the mouth of the glass vial. A syringe needle was inserted into the rubber stopper so that the tip of the needle was inserted into the vial and the other end was outside the vial, so that the inner cavity of the vial was connected to the outside through the needle. The glass vial was placed in a high-pressure reactor, carbon monoxide was replaced in the high-pressure reactor, ethylene at 1 atmosphere and carbon monoxide at 50 atmospheres were flushed in, and the reaction time was 24 hours under blue light (440-460 nm) at 25° C.; after the reaction was completed, β-trichloromethylbutyramide 3a was obtained by column chromatography with a yield of 75%, and the compound was identified by nuclear magnetic resonance (hydrogen spectrum, carbon spectrum and fluorine spectrum) and high-resolution mass spectrometry.

[0031] The test data are as follows:

[0032] 3a: 1 H NMR (400 MHz, CDCl 3)δ7.49(d,J=7.7Hz,2H),7.45(s,1H),7.32(t,J=7.9Hz,2H),7.13(t,J=7.4Hz,1H),3.31–3.03(m,2H),2.95–2.70(m,2H).

[0033] 13 C NMR (101 MHz, CDCl 3 )δ168.1,137.4,129.1,124.7,120.0,98.9,50.1,34.3.

[0034] HR-MS(ESI-TOF)m / z:[M+H] + calcd.for C 10 H 11 Cl 3 NO 265.9901, found 265.9902.

[0035] Embodiment 2:

[0036] The operation process and conditions were the same as those in Example 1, except that the structure of the raw material 1 in Table 1, the yield of 3b was 47%, and the structure of the compound was identified by NMR (hydrogen spectrum, carbon spectrum and fluorine spectrum) and high-resolution mass spectrometry.

[0037] 3b: 1 H NMR (400 MHz, CDCl 3 )δ7.68(s,1H),7.39(d,J=8.4Hz,1H),7.26(d,J=8.1Hz,1H),7.17(t,J=6.8Hz,1H),7.11(t,J= 7.6Hz,1H),3.14–3.07(m,2H),3.02(p,J=6.8Hz,1H),2.87–2.76(m,2H),1.18(d,J=6.9Hz,6H).

[0038] 13 C NMR (101 MHz, CDCl 3 )δ169.0,141.8,133.4,126.7,126.2,125.73,125.67,99.0,50.2,33.6,27.8,23.1.

[0039] HR-MS(ESI-TOF)m / z:[M+H] + calcd.for C 13 H 17 Cl 3 NO 308.0370, found 308.0375.

[0040] Embodiment 3:

[0041] The operation process and conditions were the same as those in Example 1, except that the structure of the raw material 1 in Table 1, the yield of 3c was 83%, and the compound was identified by NMR (hydrogen spectrum, carbon spectrum and fluorine spectrum) and high-resolution mass spectrometry.

[0042] 3c: 1 H NMR (400 MHz, DMSO-d 6 )δ10.49(s,1H),7.80(d,J=8.5Hz,2H),7.64(d,J=8.6Hz,2H),3.20–3.07(m,2H),2.93–2.77(m,2H).

[0043] 13 C NMR (101 MHz, DMSO-d 6 )δ168.9,142.5,126.0(q,J=3.8Hz),124.3(q,J=271.2Hz),123.3(q,J=32.0Hz),118.9,99.7,49.4,33.5.

[0044] 19 F NMR (376 MHz, DMSO-d 6 )δ-60.5.

[0045] HR-MS(ESI-TOF)m / z:[M+H] + calcd.for C 11 H 10 Cl 3 F 3 NO 333.9775, found 333.9776.

[0046] Embodiment 4:

[0047] The operation process and conditions are the same as those in Example 1, except that the structure of raw material 1 in Table 1, the yield of 3d is 82%, and the structure of the compound is identified by nuclear magnetic resonance (hydrogen spectrum, carbon spectrum and fluorine spectrum) and high-resolution mass spectrometry.

[0048] 3d: 1 H NMR (400 MHz, DMSO-d 6 )δ10.23(s,1H),7.62(d,J=8.7Hz,2H),7.43(d,J=8.8Hz,2H),3.18–3.02(m,2H),2.88–2.72(m,2H).

[0049] 13C NMR (101 MHz, DMSO-d 6 )δ168.3,138.8,137.3,121.2,99.7,86.6,49.5,33.4.HR-MS(ESI-TOF)m / z:[M+H] + calcd.for C 10 H 10 ICl 3 NO 391.8867, found 391.8871.

[0050] Embodiment 5:

[0051] The operation process and conditions were the same as those in Example 1, except that the yield of raw materials 1, 3e in Table 1 was 70%, and the structure of the compound was identified by nuclear magnetic resonance (hydrogen spectrum, carbon spectrum and fluorine spectrum) and high-resolution mass spectrometry.

[0052] 3e: 1 H NMR (400 MHz, DMSO-d 6 )δ10.55(s,1H),7.85–7.66(m,4H),3.19–3.05(m,2H),2.91–2.75(m,2H).

[0053] 13 C NMR (101 MHz, DMSO-d 6 )δ169.1,143.1,133.2,119.0,119.0,105.0,99.6,49.3,33.5.HR-MS(ESI-TOF)m / z:[M+H] + calcd.for C 11 H 10 Cl 3 N 2 O 290.9853, found 290.9853.

[0054] Embodiment 6:

[0055] The operation process and conditions are the same as those in Example 1, except that the structure of raw material 1 in Table 1, the yield of 3f is 87%, and the structure of the compound is identified by nuclear magnetic resonance (hydrogen spectrum, carbon spectrum and fluorine spectrum) and high-resolution mass spectrometry.

[0056] 3f: 1 H NMR (400 MHz, DMSO-d 6 )δ8.02(s,1H),7.95(d,J=8.7Hz,2H),7.41(s,1H),7.25(d,J=8.6Hz,2H),3.25–3.16(m,2H),3.11–3.00(m,2H).

[0057] 13 C NMR (101 MHz, DMSO-d 6 )δ169.3,167.2,152.5,132.1,129.0,121.5,99.0,49.1,31.2.HR-MS(ESI-TOF)m / z:[M+H] + calcd.for C 11 H 11 Cl 3 NO 3 309.9799, found 309.9805.

[0058] Embodiment 7:

[0059] The operation process and conditions are the same as those in Example 1, except that the structure of raw material 1 in Table 1, 3 g yield is 76%, and the compound is identified by nuclear magnetic resonance (hydrogen spectrum, carbon spectrum and fluorine spectrum) and high-resolution mass spectrometry.

[0060] 3g: 1 H NMR (400 MHz, CDCl 3 )δ9.99(s,1H),8.01–7.83(m,2H),7.35–7.24(m,2H),3.22–3.15(m,2H),3.14–3.08(m,2H).

[0061] 13 C NMR (101 MHz, CDCl 3 )δ190.7,168.9,154.9,134.1,131.2,122.1,98.1,49.4,31.5.HR-MS(ESI-TOF)m / z:[M+H] + calcd.for C 11 H 10 Cl 3 O 3 294.9690, found 294.9695.

[0062] Embodiment 8:

[0063] The operation process and conditions are the same as those in Example 1, except that the structure of the raw material 1 in Table 1 is used, the yield in 3h is 67%, and the structure of the compound is identified by NMR (hydrogen spectrum, carbon spectrum and fluorine spectrum) and high-resolution mass spectrometry.

[0064] 3h: 1 H NMR (400 MHz, CDCl 3)δ7.45–7.30(m,5H),5.18(s,2H),3.18–3.05(m,2H),2.95–2.79(m,2H).

[0065] 13 C NMR (101 MHz, CDCl 3 )δ170.8,135.4,128.6,128.4,128.3,98.5,66.8,49.8,31.4.HR-MS(ESI-TOF)m / z:[M+H] + calcd.for C 11 H 12 Cl 3 O 2 280.9897, found 280.9896.

[0066] Embodiment 9:

[0067] The operation process and conditions were the same as those in Example 1, except that the structure of the raw material 1 in Table 1, the yield of 3i was 66%, and the compound was identified by NMR (hydrogen spectrum, carbon spectrum and fluorine spectrum) and high-resolution mass spectrometry.

[0068] 3i: 1 H NMR (400 MHz, CDCl 3 )δ4.68(q,J=2.4Hz,2H),3.10–3.01(m,2H),2.87–2.79(m,2H),1.85(t,J=2.4Hz,3H).

[0069] 13 C NMR (101 MHz, CDCl 3 )δ170.4,98.4,83.6,72.7,53.3,49.7,31.3,3.6.

[0070] HR-MS(ESI-TOF)m / z:[M+H] + calcd.for C 8 H 10 Cl 3 O 2 242.9741, found 242.9749.

[0071] Embodiment 10:

[0072] The operation process and conditions are the same as those in Example 1, except that the structure of raw material 1 in Table 1, the yield of 3j is 69%, and the structure of the compound is identified by nuclear magnetic resonance (hydrogen spectrum, carbon spectrum and fluorine spectrum) and high-resolution mass spectrometry.

[0073] 3j:1 H NMR (400 MHz, CDCl 3 )δ4.34(s,4H),3.13–2.99(m,4H),2.89–2.74(m,4H). 13 CNMR (101MHz, CDCl 3 )δ170.8,98.4,62.5,49.7,31.3.

[0074] HR-MS (ESI-TOF) m / z: [M+NH 4 ] + calcd.for C 10 H 16 Cl 6 NO 4 423.9205,found423.9213,[M+Na] + calcd.for C 10 H 12 Cl 6 NaO 4 428.8759, found 428.8763.

[0075] The products in Table 1 are unknown compounds.

[0076] The actual application process is as follows: β-trichloromethylbutyl ester is used as a synthetic intermediate in the synthesis of bioactive molecules 1-2

[0077]

[0078] Reaction Scheme 1: Synthesis of synthetic analogs of the marine natural product cintocarbamide

[0079] For example, β-trichloromethylbutyl ester is used as a synthetic intermediate in the synthesis of synthetic analogs of the marine natural product cintocarbamide, which is an androgen receptor N-terminal antagonist used to treat metastatic castration-resistant prostate cancer. 1

[0080] References: [1] L. Yan, C. A. Banuelos, N. R. Mawji, B. O. Patrick, M. D. Sadar, and R. J. Andersen, Structure-Activity Relationships for the Marine Natural Product Sintokamides: Androgen Receptor N-Terminus Antagonists of Interest for Treatment of Metastatic Castration-Resistant Prostate Cancer. J. Nat. Prod. 2021, 84, 797–813.

[0081] [2] S. E. De Laszlo and P. G. Williard, Total synthesis of (+)-demethyldysidenin and (-)-demethylisodysidenin, hexachlorinated amino acids from the marine sponge Dysidea herbacea. Assignment of absolute stereochemistry. J. Am. Chem. Soc. 1985, 107, 199–203.

Claims

1. A method for preparing β-trichloromethylbutyl ester or amide, characterized in that: CCl4 (carbon tetrachloride), ethylene, CO (carbon monoxide), and nucleophilic reagents shown in the following formula are used as raw materials to generate β-trichloromethylbutyl ester or amide 3. The reaction formula is as follows: NuH is a nucleophilic reagent, including one or more of amines (such as aniline, 2-isopropylaniline, trifluoromethylaniline, 4-iodoaniline, 4-cyanoaniline, benzylamine), phenols (such as phenol, 4-aminoacylphenol, 4-formylphenol, 4-methoxyphenol), alcohols (such as benzyl alcohol, octanol, 2-hexyl alcohol, ethylene glycol), preferably one or more of two.

2. The method for preparing β-trichloromethylbutyl ester and amide according to claim 1, characterized in that: The specific steps are as follows: The reaction is carried out in a high-pressure reactor. The catalyst, ligand, base, carbon tetrachloride and nucleophilic reagent are weighed and placed in a carbon monoxide and ethylene gas atmosphere. The reaction is carried out at 20-40° C. (preferably 25-30° C.) under irradiation with a light source (400-500 nm) (preferably 440-460 nm) for 10-36 hours (preferably 24-30 hours). After the reaction is completed, β-trichloromethylbutyl ester and amide 3 are separated.

3. The method according to claim 2, characterized in that: The catalyst is one or more of copper acetylacetonate (Cu(acac)2), copper acetate (Cu(OAc)2), cuprous iodide (CuI), cuprous bromide (CuBr), and copper trifluoromethanesulfonate (Cu(OTf)2), preferably copper trifluoromethanesulfonate; the amount of the catalyst used is 0.25%-20mol%, preferably 0.5%-10mol% of the amount of the nucleophile used.

4. The method according to claim 2, characterized in that: The ligand is one or more of triphenylphosphine (PPh3), bipyridine (bpy), 1,10-phenanthroline (1,10-Phen), 1,10-phenanthroline-5,6-dione, 4,4'-dimethoxy-2,2'-bipyridine, and 6,6'-dimethyl-2,2'-bipyridine, preferably bipyridine. The amount of the ligand used is 0.5%-20mol% of the amount of the nucleophile used, preferably 1%-10mol%.

5. The method according to claim 2, characterized in that: The base is one or more of potassium carbonate, potassium phosphate, sodium carbonate and cesium carbonate, preferably potassium carbonate. The amount of the base is 1.2-6 times the molar amount of the nucleophile, preferably 1.5-4 times, more preferably 2-4 times.

6. The method according to claim 2, characterized in that: The amount of carbon tetrachloride used is 1-20 times, preferably 2-10 times, the molar amount of the nucleophile used.

7. The method according to claim 2, characterized in that: The gas pressure of ethylene is 1 to 20 atmospheres, preferably 1 to 10 atmospheres.

8. The method according to claim 2, characterized in that: The gas pressure of carbon monoxide is 10 to 70 atmospheres, preferably 40 to 60 atmospheres.

9. The method according to claim 2, characterized in that: The solvent is one or more of acetonitrile, tetrahydrofuran, trifluorotoluene, dimethyl sulfoxide, and 1,4-dioxane, preferably acetonitrile, and the amount used is 0.3-2.0 mL, preferably 0.5-1.0 mL, of acetonitrile per 0.2 mmol of nucleophile.

10. The method according to claim 2, characterized in that: Before the carbon monoxide and ethylene gas replacement is performed in the reactor, the total loading amount of the catalyst, ligand, base, nucleophilic reagent and solvent in the reactor is 70% or less of the volume of the reactor.

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