A method for preparing asymmetric ketone compounds

Abstract

The present invention belongs to the technical field of organic chemical synthesis and discloses a method for preparing asymmetric ketone compounds. This invention, for the first time, achieves the denitrogenation and decarboxylation coupling of vinyl azide with alkyl carboxylates / Katritz salts in the absence of a photocatalyst, filling a gap in the prior art. The method of the present invention features mild process conditions, a short flow, simple steps, and a wide range of substrate applicability, meeting industrial production requirements. Research has found that the product yield can reach as high as 88%, and the resulting ketone compounds have broad application prospects in organic synthesis and drug development. Therefore, the present invention has significant application value.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic chemical synthesis, and relates to the preparation of a series of ketone compounds by reacting cheap and readily available alkyl carboxylic acids / amines with vinyl azide under visible light induction. Background Art

[0002] Ketone compounds are widely present in natural products, bioactive molecules, and pharmaceuticals. For example, nitrazofenone, aryl hydrocarbon receptor (AhR) agonists (ITEs), and topsentin have demonstrated promising efficacy in lipid-lowering, neuroprotective, anti-tumor, and anti-cancer activities. Furthermore, the ketone carbonyl group is a common functional group in organic chemistry and plays a crucial role in synthetic chemistry. Therefore, developing new, efficient methods for the synthesis of ketone compounds is of great significance.

[0003] In the past few decades, many synthetic methods for ketone compounds have been reported [see: (a) Synthetic methods.16. Umpolung of alkyl anions by reactions with vinylazides. In situ generation of primary enamines, J.Am.Chem.Soc.1980,102,6185-618. (b) Amide Synthesis by Nucleophilic Attack of Vinyl Azides, Angew.Chem.,Int.Ed.2014,53,4390-4394. (c) Palladium-Catalyzed Suzuki–Miyaura Coupling of Aryl Esters, J.Am.Chem.Soc.2017,139,1311. (d) Nickel-Catalyzed Directed Cross-Electrophile Coupling of Phenolic Esters with Alkyl Bromides, Org. Lett. 2020, 22, 9203. (e) Vinyl Azides as Radical Acceptors in the Vitamin B12-Catalyzed Synthesis of Unsymmetrical Ketones, Org. Lett. 2021, 23, 9068-9072], which can be summarized as nucleophilic / electrophilic addition, transition metal catalysis and photocatalysis. However, the above reaction still has some defects, such as harsh reaction conditions, complicated operation, limited substrate range and expensive catalysts. Therefore, the development of a simple reaction system, starting from cheap and readily available raw materials, and using only visible light to drive the synthesis of ketones without adding any catalyst has important research significance and application potential.

[0004] Alkyl carboxylates / amines are a rich class of raw material chemicals, commonly found in simple building blocks, natural products, and pharmaceutical molecules. They are inexpensive and stable. Alkyl carboxylates / amines can be converted into the corresponding N-hydroxyphthalimide (NHPI) esters / Katritzky salts via a one-step reaction, which can generate alkyl radicals under visible light induction. Furthermore, NHPI esters are recognized as redox-active esters, capable of undergoing N-O bond homolysis under mild reaction conditions to generate alkyl radicals, which subsequently participate in a variety of alkylation chemical transformations. Compared with other alkyl radical precursors, NHPI esters have the advantages of a wide range of sources, simple preparation conditions (prepared from alkyl carboxylic acids in one step), and good stability. Therefore, they have become a highly sought-after alkylating agent in recent years. Katritzky salts can be easily prepared by the one-step condensation of primary alkylamines and pyrylium salts, providing alkyl radicals with good efficiency.

[0005] This method uses inexpensive and readily available alkyl carboxylic acids / amines as raw materials, converting them into stable NHPI esters / Katritzky salts in a single step. Under catalyst-free visible light excitation, these amines undergo a denitrogenation coupling reaction with vinyl azide to produce a series of asymmetric ketone derivatives. Compared to traditional synthesis methods, visible light, as a green energy source, allows for milder reaction conditions and improved functional group compatibility, providing a new approach for the green and efficient synthesis of ketone compounds. Summary of the Invention

[0006] This invention provides a novel synthetic method for preparing ketones by using readily available 2,6-dimethyl-3,5-dicarboxylic acid dimethyl ester-1,4-dihydropyridine as an electron donor to promote the denitrogenation coupling reaction of NHPI ester / Katritzky salt with vinyl azide under light excitation. This method has the advantages of mild reaction conditions, convenient experimental operation, good substrate compatibility, and easy scale-up. Therefore, the invention has great application value and socioeconomic benefits.

[0007] The technical solution of the present invention:

[0008] A method for preparing asymmetric ketone compounds uses vinyl azide, NHPI ester or Katritzky salt as raw materials to prepare a series of ketone compounds under light irradiation; the synthetic route is as follows:

[0009]

[0010] Here are the steps:

[0011] The reducing agent, vinyl azide, NHPI ester or Katritzky salt, solvent, and H2O were added to the reaction flask in sequence, and the reaction was placed under blue light;

[0012] R1 of the vinyl azide is a naphthalene ring or a benzene ring, wherein the benzene ring is further substituted by a halogen;

[0013] R2 of the NHPI ester is phenylpropyl, 10-undecenyl, furanyl, isopropyl, tert-butyl or adamantyl;

[0014] R3 of the Katritzk salt is 1-tert-butoxycarbonyl--4-piperidinyl;

[0015] The solvent is selected from one or a mixture of two or more of toluene, n-hexane, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, dichloromethane, acetone, and acetonitrile, preferably N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, and tetrahydrofuran.

[0016] The reducing agent is selected from 3-ethyl 5-methyl 2,6-dimethyl-3,5-dicarboxylate-1,4-dihydropyridine, 2,6-dimethyl-3,5-diacetyl-1,4-dihydropyridine, 2,6-diphenyl-3,5-dibenzoyl-1,4-dihydropyridine, 2,6-dimethyl-3,5-dicarboxylic acid di-tert-butyl ester-1,4-dihydropyridine, 2,6-dimethyl-3,5-dicyano-1,4-dihydropyridine and 2,4,6-trimethyl-3,5-diacetyl-1,4-dihydropyridine.

[0017] The concentration of vinyl azide in the system is 0.1M-0.3M.

[0018] The molar ratio of vinyl azide to NHPI ester is 1:1.0 to 1:2.0.

[0019] The molar ratio of vinyl azide to the reducing agent is 1:1.0 to 1:2.0.

[0020] The molar ratio of vinyl azide to H2O is 1:1.0 to 1:2.0.

[0021] The reaction time ranges from 8 to 24 hours, preferably from 12 to 18 hours.

[0022] The light intensity range is 10W-40W.

[0023] The wavelength range is 390nm-456nm.

[0024] Beneficial effects of the present invention: The present method for preparing asymmetric ketone compounds achieves, for the first time, the denitrogenation and decarboxylation coupling of vinyl azide with alkyl carboxylates / Katritz salts in the absence of a photocatalyst, filling a gap in the prior art. The method features mild process conditions, a short flow, simple steps, and a wide range of substrate applicability, meeting industrial production requirements. Research has shown that product yields can reach as high as 88%, and the resulting ketone compounds have broad application prospects in organic synthesis and drug development. This demonstrates the significant application value of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 For compound 3a 1 H-NMR spectrum.

[0026] Figure 2 For compound 3a 13 C-NMR spectrum.

[0027] Figure 3 For compound 3b 1 H-NMR spectrum.

[0028] Figure 4 For compound 3b 13 C-NMR spectrum.

[0029] Figure 5 For compound 3c 1 H-NMR spectrum.

[0030] Figure 6 For compound 3c 13 C-NMR spectrum.

[0031] Figure 7 For compound 3d 1 H-NMR spectrum.

[0032] Figure 8 For compound 3d 13 C-NMR spectrum.

[0033] Figure 9 For compound 3e 1 H-NMR spectrum.

[0034] Figure 10 For compound 3e 13 C-NMR spectrum.

[0035] Figure 11 For compound 3f 1 H-NMR spectrum.

[0036] Figure 12 For compound 3f 13 C-NMR spectrum.

[0037] Figure 13 For compound 3g 1 H-NMR spectrum.

[0038] Figure 14 For compound 3g 13 C-NMR spectrum.

[0039] Figure 15 For compound 3h 1 H-NMR spectrum.

[0040] Figure 16 For compound 3h 13 C-NMR spectrum.

[0041] Figure 17 For compound 3i 1 H-NMR spectrum.

[0042] Figure 18 For compound 3i 13 C-NMR spectrum.

[0043] Figure 19 For compound 3j 1 H-NMR spectrum.

[0044] Figure 20 For compound 3j 13 C-NMR spectrum.

[0045] Figure 21 For compound 3k 1 H-NMR spectrum.

[0046] Figure 22 For compound 3k 13 C-NMR spectrum. DETAILED DESCRIPTION

[0047] The specific implementation of the present invention is further described below in conjunction with the accompanying drawings and technical solutions.

[0048] Example 1: Synthesis of 2-cyclohexyl-1-(2-naphthyl)-1-ethanone [2-cyclohexyl-1-(naphthalen-2-yl)ethan-1-one] (3a)

[0049]

[0050] In a glove box, 2-(1-azidovinyl)naphthalene (58.5 mg, 0.3 mmol), cyclohexyl NHPI ester (164 mg, 0.60 mmol), and dimethyl 2,6-dimethyl-3,5-dicarboxylate-1,4-dihydropyridine (67.5 mg, 0.3 mmol) were accurately weighed and added to an 8 mL reaction vial. DMA (3.0 mL) and H₂O (8.1 μL, 0.45 mmol) were then added. The resulting mixture was stirred at room temperature under irradiation with a blue LED (456 nm, 10 W) for 12 hours. After completion of the reaction, the reaction mixture was diluted with EA and washed 3-4 times with saturated brine. The organic layer was separated, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography. The yield of 2-cyclohexyl-1-(2-naphthyl)-1-ethanone was 80%. 1 H NMR(600MHz,Chloroform-d)δ8.46(d,J=1.8Hz,1H),8.03(dd,J=8.6,1.7Hz,1H),7.97(d,J=8.1Hz,1H),7.88(dd,J=10.0,8.2Hz,2H),7.62–7.52(m,2H ),2.96(d,J=6.8Hz,2H),2.12–1.99(m,1H),1.87–1.76(m,2H),1.76–1.65( m,3H),1.38–1.25(m,2H),1.25–1.12(m,1H),1.07(qd,J=12.3,3.5Hz,2H); 13 C NMR (151MHz, CDCl3) δ200.26,135.48,134.84,132.54,129.69,129.54,12 8.35,128.30,127.73,126.67,124.03,46.27,34.75,33.48,26.26,26.16.

[0051] Example 2: Synthesis of 1-(4-chlorophenyl)-2-cyclohexyl-1-one [1-(4-chlorophenyl)-2-cyclohexylethan-1-one] (3b)

[0052]

[0053] In a glove box, 1-(1-azidovinyl)-4-chlorobenzene (54 mg, 0.3 mmol), cyclohexyl NHPI ester (164 mg, 0.6 mmol), and 2,6-dimethyl-3,5-diacetyl-1,4-dihydropyridine (115.7 mg, 0.6 mmol) were accurately weighed and added to an 8 mL reaction vial. DMF (1.5 mL) and H₂O (8.1 μL, 0.45 mmol) were then added. The resulting mixture was stirred at room temperature under irradiation with a blue LED (456 nm, 40 W) for 12 hours. After completion of the reaction, the reaction mixture was diluted with EA and washed 3-4 times with saturated brine. The organic layer was separated, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography. The yield of 1-(4-chlorophenyl)-2-cyclohexyl-1-ethanone was 78%. 1 H NMR (400MHz, CDCl3) δ7.88(d,J=8.6Hz,2H),7.42(d,J=8.6Hz,2H),2.78(d,J=6.8Hz,2H),2. 05–1.84(m,1H),1.78–1.62(m,5H),1.33-1.25(m,2H),1.23–1.15(m,1H),1.05-0.96(m,2H). 13 C NMR (101MHz, CDCl3) δ199.00,139.26,135.76,129.55,128.83,46.16,34.54,33.40,26.20,26.11.

[0054] Example 3: Synthesis of 1-(2-naphthyl)-5-phenylpentan-1-one [1-(naphthalen-2-yl)-5-phenylpentan-1-one] (3c)

[0055]

[0056] In a glove box, 2-(1-azidovinyl)naphthalene (58.5 mg, 0.3 mmol), phenylpropyl NHPI ester (139 mg, 0.45 mmol), and 2,6-dimethyl-3,5-diacetyl-1,4-dihydropyridine (69.4 mg, 0.36 mmol) were accurately weighed and added to an 8 mL reaction vial. DMSO (3.0 mL) and H₂O (8.1 μL, 0.45 mmol) were then added. The resulting mixture was stirred at room temperature under irradiation with a blue LED (399 nm, 10 W) for 8 hours. After completion of the reaction, the reaction mixture was diluted with EA and washed 3-4 times with saturated brine. The organic layer was separated, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography. The yield of 1-(naphthalen-2-yl)-5-phenylpentan-1-one was 60%.1 H NMR(400MHz, CDCl3)δ8.41(s,1H),7.98(dd,J=8.7,1.8Hz,1H),7.94–7.87(m,1H),7.87–7.78(m,2H),7.60–7.47(m,2H), 7.28–7.19(m,2H),7.20–7.10(m,3H),3.07(t,J=7.2Hz,2H),2.66(t,J=7.5Hz,2H),1.86–1.77(m,2H),1.77–1.67(m,2H). 13 C NMR (101MHz, CDCl3) δ200.21,142.23,135.50,134.34,132.52,129.58,129.51,128 .39,128.33,128.29,127.74,126.69,125.73,123.90,38.46,35.79,31.10,24.12.

[0057] Example 4: Synthesis of 1-(naphthalen-2-yl)dodec-11-en-1-one (3d)

[0058]

[0059] In a glove box, 2-(1-azidovinyl)naphthalene (58.5 mg, 0.3 mmol), 10-undecene NHPI ester (148 mg, 0.45 mmol), and 2,6-diphenyl-3,5-dibenzoyl-1,4-dihydropyridine (132.4 mg, 0.3 mmol) were accurately weighed and added to an 8 mL reaction vial. DMSO (2.0 mL) and H₂O (5.4 μL, 0.30 mmol) were then added. The resulting mixture was stirred at room temperature under irradiation with a blue LED (456 nm, 30 W) for 12 hours. After completion of the reaction, the reaction mixture was diluted with EA and washed 3-4 times with saturated brine. The organic layer was separated, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography. The yield of 1-(2-naphthyl)-11-ene-1-dodecanone was 54%. 1H NMR (400MHz, CDCl3) δ8.47(s,1H),8.04(dd,J=8.7,1.7Hz,1H),7.97(d,J=8.0Hz,1H),7.94–7.83(m,2H),7.69–7.51(m,2H),5 .93–5.73(m,1H),5.04–4.87(m,2H),3.10(t,J=7.4Hz,2H),2.04(q,J=7.1Hz,2H),1.80(p,J=7.4Hz,2H),1.44–1.28(m,12H). 13 C NMR (101MHz, CDCl3) δ200.55,139.20,135.48,134.41,132.54,129.57,129.50,128.35,128.28, 127.73,126.67,123.95,114.09,38.68,33.77,29.46,29.42,29.42,29.39,29.09,28.90,24.52.

[0060] Example 5: Synthesis of 1-(2-naphthyl)-2-(tetrahydro-2H-4-pyranyl)ethan-1-one [1-(naphthalen-2-yl)-2-(tetrahydro-2H-pyran-4-yl)ethan-1-one] (3e)

[0061]

[0062] In a glove box, 2-(1-azidovinyl)naphthalene (58.5 mg, 0.3 mmol), tetrahydropyranyl NHPI ester (247 mg, 0.6 mmol), and 2,6-dimethyl-3,5-diacetyl-1,4-dihydropyridine (86.8 mg, 0.45 mmol) were accurately weighed and added to an 8 mL reaction vial. DMSO (1.0 mL) and H₂O (6.5 μL, 0.36 mmol) were then added. The resulting mixture was stirred at room temperature under irradiation with a blue LED (427 nm, 10 W) for 16 hours. After completion of the reaction, the reaction mixture was diluted with EA and washed 3-4 times with saturated brine. The organic layer was separated, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography. The yield of 1-(naphthalen-2-yl)-2-(3,4,5,6-tetrahydro-2H-pyranyl)-1-ethanone was 72%. 1H NMR (400MHz, CDCl3) δ8.46(s,1H),8.05–7.94(m,2H),7.89(t,J=7.9Hz,2H),7.70–7.50(m,2H),3.97(dd,J=10.7,3.6 Hz,2H),3.46(td,J=11.8,2.1Hz,2H),3.03(d,J=6.7Hz,2H),2.45–2.23(m,1H),1.76–1.70(m,2H),1.53–1.35(m,2H). 13 C NMR (101MHz, CDCl3) δ199.14,135.56,134.57,132.50,129.67,129.53,128.47,128.45,127.75,126.78,123.80,67.87,45.40,33.10,31.54.

[0063] Example 6: Synthesis of 3-methyl-1-(2-naphthyl)butan-1-one [3-methyl-1-(naphthalen-2-yl)butan-1-one] (3f)

[0064]

[0065] In a glove box, 2-(1-azidovinyl)naphthalene (58.5 mg, 0.3 mmol), isopropyl NHPI ester (105 mg, 0.45 mmol), and 2,6-dimethyl-3,5-diacetyl-1,4-dihydropyridine (86.8 mg, 0.45 mmol) were accurately weighed and added to an 8 mL reaction vial. DMA (3.0 mL) and H₂O (10.8 μL, 0.60 mmol) were then added. The resulting mixture was stirred at room temperature under irradiation with a blue LED (456 nm, 10 W) for 8 hours. After completion of the reaction, the reaction mixture was diluted with EA and washed 3-4 times with saturated brine. The organic layer was separated, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography. The yield of 3-methyl-1-(2-naphthyl)-1-butanone was 74%. 1 H NMR(400MHz, CDCl3)δ8.46(d,J=1.8Hz,1H),8.07–7.93(m,2H),7.88(t,J=7.7Hz,2H) ,7.64–7.50(m,2H),2.97(d,J=6.9Hz,2H),2.52–2.30(m,1H),1.05(d,J=6.7Hz,6H). 13C NMR (101MHz, CDCl3) δ200.14,135.45,134.73,132.52,129.61,129.49,128.33,128.27,127.70,126.65,123.95,47.51,25.29,22.78.

[0066] Example 7: Synthesis of 1-(2-naphthyl)-2-(1-phenylcyclopropyl)ethan-1-one [1-(naphthalen-2-yl)-2-(1-phenylcyclopropyl)ethan-1-one] (3 g)

[0067]

[0068] In a glove box, 2-(1-azidovinyl)naphthalene (58.5 mg, 0.3 mmol), tert-butyl NHPI ester (111 mg, 0.45 mmol), and 2,6-dimethyl-3,5-diacetyl-1,4-dihydropyridine (86.8 mg, 0.45 mmol) were accurately weighed and added to an 8 mL reaction vial. DMSO (3.0 mL) and H₂O (8.1 μL, 0.45 mmol) were then added. The resulting mixture was stirred at room temperature under irradiation with a blue LED (456 nm, 10 W) for 18 hours. After completion of the reaction, the reaction mixture was diluted with EA and washed 3-4 times with saturated brine. The organic layer was separated, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography. The yield of 1-(2-naphthyl)-2-tert-butylethanone was 54%. 1 H NMR (400MHz, CDCl3) δ8.45(s,1H),8.03(dd,J=8.6,1.8Hz,1H),7.97(d,J=8.0Hz,1H),7.92–7.85(m,2H),7.63–7.50(m,2H),3.00(s,2H),1.12(s,9H). 13 C NMR (101MHz, CDCl3) δ200.36,135.92,135.37,132.50,129.79,129.54,128.30,128.25,127.68,126.64,124.09,50.11,31.52,30.13.HRMS m / z(ESI)calcd for C 16 H 18 O(M+H) + 227.1430, found 227.1435.

[0069] Example 8: Synthesis of 2-((1S,3R,5S)-adamantan-1-yl)-1-(naphthalen-2-yl)ethan-1-one [2-((1S,3R,5S)-adamantan-1-yl)-1-(naphthalen-2-yl)ethan-1-one] (3h)

[0070]

[0071] In a glove box, 2-(1-azidovinyl)naphthalene (58.5 mg, 0.3 mmol), adamantane NHPI ester (146 mg, 0.45 mmol), and di-tert-butyl 2,6-dimethyl-3,5-dicarboxylate-1,4-dihydropyridine (92.7 mg, 0.3 mmol) were accurately weighed and added to an 8 mL reaction vial. DMSO (2.0 mL) and H₂O (8.1 μL, 0.45 mmol) were also added. The resulting mixture was stirred at room temperature under irradiation with a blue LED (456 nm, 10 W) for 24 hours. After completion of the reaction, the reaction mixture was diluted with EA and washed 3-4 times with saturated brine. The organic layer was separated, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography. The yield of 1-(2-naphthyl)-2-(1-adamantyl)-1-ethanone was 58%. 1 H NMR (400MHz, CDCl3) δ8.46(s,1H),8.04(dd,J=8.6,1.8Hz,1H),7.98(d,J=7.9Hz,1H),7. 92–7.83(m,2H),7.66–7.50(m,2H),2.85(s,2H),2.03–1.90(m,3H),1.75–1.63(m,12H). 13 C NMR (101MHz, CDCl3) δ200.17,136.18,135.34,132.44,130.03,129.57,128. 24,127.65,126.59,124.16,51.27,43.01,36.69,34.02,28.82,28.67.HRMS m / z(ESI)calcd for C 22 H 24 O(M+H) + 305.1900,found305.1908.

[0072] Example 9: Synthesis of 3-(4-isobutylphenyl)-1-(naphthalen-2-yl)butan-1-one (3i)

[0073]

[0074] In a glove box, 2-(1-azidovinyl)naphthalene (58.5 mg, 0.3 mmol), 2-({2-[4-(2-methylpropyl)phenyl]propionyl}oxy)isoindole-1,3-dione (126 mg, 0.36 mmol), and 2,6-dimethyl-3,5-diacetyl-1,4-dihydropyridine (86.8 mg, 0.45 mmol) were accurately weighed and added to an 8 mL reaction vial. CH3CN (3.0 mL) and H2O (8.1 μL, 0.45 mmol) were also added. The resulting mixture was stirred at room temperature under irradiation with a blue LED (440 nm, 10 W) for 8 hours. After completion of the reaction, the reaction mixture was diluted with EA and washed 3-4 times with saturated brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography. The yield of 3-[4-(2-methylpropyl)phenyl]-1-(2-naphthyl)-1-butanone was 63%. 1 H NMR (400MHz, CDCl3) δ8.44 (s, 1H), 8.03 (dd, J = 8.6, 1.8Hz, 1H), 7.98–7.92 (m, 1H), 7. 87(dd,J=8.3,3.3Hz,2H),7.64–7.48(m,2H),7.30–7.20(m,2H),7.20–7.08(m,2H),3 .67–3.48(m,1H),3.44(dd,J=16.2,5.6Hz,1H),3.31(dd,J=16.2,8.4Hz,1H),2.46(d ,J=7.2Hz,2H),1.96–1.71(m,1H),1.40(d,J=6.9Hz,3H),0.91(dd,J=6.6,0.9Hz,6H). 13 CNMR(101MHz,CDCl3)δ199.16,143.77,139.56,135.46,134.58,132.48,129.67,129.49,129 .21,128.32,127.69,126.65,126.53,123.89,47.27,44.99,35.42,30.14,22.35,21.82.HRMS m / z(ESI)calculated for C 24 H 26 O(M+H) + 331.2056, found 331.2071.

[0075] Example 10: 6-(2,5-dimethylphenoxy)-3,3-dimethyl-1-(naphthalen-2-yl)hexan-1-one

[0076] Synthesis of [6-(2,5-dimethylphenoxy)-3,3-dimethyl-1-(naphthalen-2-yl)hexan-1-one](3j)

[0077]

[0078] In a glove box, 2-(1-azidovinyl)naphthalene (58.5 mg, 0.3 mmol), 2-({5-[(2,5-dimethylphenyl)oxy]-2,2-dimethyl-1-oxopentyl}oxy)isoindole-1,3-dione (119 mg, 0.30 mmol), and 2,6-dimethyl-3,5-diacetyl-1,4-dihydropyridine (86.8 mg, 0.45 mmol) were accurately weighed and added to an 8 mL reaction vial. DMSO (3.0 mL) and H₂O (8.1 μL, 0.45 mmol) were also added. The resulting mixture was stirred at room temperature under irradiation with a blue LED (456 nm, 40 W) for 8 hours. After completion of the reaction, the reaction mixture was diluted with EA and washed 3-4 times with saturated brine. The organic layer was separated, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography. The yield of 6-[(2,5-dimethylphenyl)oxy]-3,3-dimethyl-1-(2-naphthyl)-1-hexanone was 54%. 1 H NMR (400MHz, CDCl3) δ8.49(s,1H),8.08(d,J=8.6Hz,1H),8.00(d,J=7.9Hz,1H),7.91(t,J=7.9Hz,2H),7.74–7.55(m,2H),7.05(d,J=7.5Hz ,1H),6.77–6.64(m,2H),3.97(t,J=6.5Hz,2H),3.08(s,2H),2.35(s,3H),2.24(s,3H),2.01–1.82(m,2H),1.77–1.62(m,2H),1.18(s,6H). 13C NMR (101MHz, CDCl3) δ200.13,156.99,136.36,135.95,135.36,132.48,130.22,129.63,129.51,128.32,128.25 ,127.66,126.64,123.99,123.52,120.60,112.02,68.35,48.02,38.64,33.85,27.66,24.47,21.34,15.73.HRMS m / z(ESI)calculated for C 26 H 30 O2(M+H) + 375.2319, found 375.2337.

[0079] Example 11: Synthesis of Tert-butyl 4-(2-(naphthalen-2-yl)-2-oxoethyl)piperidine-1-carboxylate (3k)

[0080] In a glove box, accurately weigh 2-(1-azidovinyl)naphthalene (58.5 mg, 0.3 mmol), 1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2,4,6-triphenylpyridine-1-tetrafluoroborate (260 mg, 0.45 mmol), and 2,6-dimethyl-3,5-diacetyl-1,4-dihydropyridine (86.8 mg, 0.45 mmol) into an 8 mL reaction vial. DMSO (3.0 mL) and H₂O (8.1 μL, 0.45 mmol) were then added. The resulting mixture was stirred at room temperature for 12 hours under irradiation with a blue LED (456 nm, 10 W). After completion of the reaction, the reaction mixture was diluted with EA and washed 3-4 times with saturated brine. The organic layer was separated, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography. The yield of tert-butyl 4-(2-(2-naphthyl)-2-oxoethyl)piperidine-1-carboxylate was 46%. 1H NMR(400MHz,CDCl3)δ8.44(s,1H),8.01(dd,J=8.6,1.8Hz,1H),7.96(d,J=8.0Hz,1H),7.88(t,J=7.8Hz,2H),7.66–7.49(m,2H),4.24–3.96(m,2H),3.01(d,J=6.7Hz,2H),2.76(t,J=12.9Hz,2H),2.28–2.13(m,1H),1.85–1.69(m,2H),1.46(s,9H),1.31–1.22(m,2H). 13 C NMR(101MHz,CDCl3)δ199.14,154.81,135.55,134.52,132.48,129.66,129.52,128.46,127.74,126.78,123.78,79.26,45.00,43.85,32.53,32.18,28.42。

Claims

1. A method for preparing an asymmetric ketone compound, characterized in that: Here are the steps: At room temperature, the reducing agent, vinyl azide, NHPI ester or Katritzky salt, solvent, and H2O were added to the reaction flask in sequence, and the reaction was placed under blue light; The synthetic route is as follows: ； wherein R1 of the vinyl azide is a naphthalene ring or a benzene ring, wherein the benzene ring is further substituted by a halogen; R2 of the NHPI ester is phenylpropyl, 10-undecenyl, furanyl, isopropyl, tert-butyl or adamantyl; R3 of the Katritzk salt is 1-tert-butoxycarbonyl-4-piperidinyl; Wherein, the concentration of vinyl azide in the reaction system is 0.1 M-0.3 M; The molar ratio of vinyl azide to NHPI ester is 1:1.0 to 1:2.0; The molar ratio of vinyl azide to reducing agent is 1:1.0 to 1:2.0; The molar ratio of vinyl azide to H2O is 1:1.0~1:2.0; The reaction time ranges from 8 to 24 h; Light intensity ranges from 10W to 40W; The wavelength range is 390 nm-456 nm; The reducing agent is selected from 2,6-dimethyl-3,5-diacetyl-1,4-dihydropyridine, 2,6-diphenyl-3,5-dibenzoyl-1,4-dihydropyridine, 2,6-dimethyl-3,5-dicarboxylic acid di-tert-butyl ester-1,4-dihydropyridine, 2,6-dimethyl-3,5-dicyano-1,4-dihydropyridine and 2,4,6-trimethyl-3,5-diacetyl-1,4-dihydropyridine.

2. The method for preparing an asymmetric ketone compound according to claim 1, wherein: The solvent is selected from one or a mixture of two or more of toluene, n-hexane, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, dichloromethane, acetone and acetonitrile.

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