Method for synthesizing 1, 7-dicarbonyl compound
The free radical coupling reaction of α-ketoic acid and vinylcyclopropane compounds was catalyzed by photocatalytic system, and the existing complications of cumbersome and harsh conditions of 1,7-dicarbonyl compounds were solved, and efficient and gentle synthesis of β,γ-unsaturated 1,7-dicarbonyl compounds were achieved.
Patent Information
- Application Number
- CN202510516568.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-04-23
- Publication Date
- 2025-07-25
AI Technical Summary
The existing synthesis method of 1,7-dicarbonyl compounds has problems such as cumbersome steps, harsh conditions and many by-products, making it difficult to achieve efficient and highly selective construction.
The photoredox catalytic method driven by visible light is used to catalyze the radical coupling reaction of α-ketoacid compounds and vinylcyclopropane compounds through a photocatalytic system to synthesize β,γ-unsaturated 1,7-dicarbonyl compounds.
It has achieved efficient construction of a variety of β,γ-unsaturated 1,7-dicarbonyl compounds under mild conditions, overcome the shortcomings of the traditional method, and has the advantages of safe operation, mild reaction conditions and wide universality of substrates.
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Abstract
Description
Technical Field
[0001] The present invention belongs to the field of organic synthesis and relates to a method for β,γ-unsaturated 1,7-dicarbonyl compounds. Background Art
[0002] 1,7-Dicarbonyl compounds widely exist in bioactive molecules and natural products and can serve as precursors for many natural products and drug molecules. Research shows that such compounds and their structural analogs exhibit significant bioactivities, such as various pharmacological effects including anti-tumor, anti-cancer, anti-thrombosis, and neuroprotection. However, the reported methods for such compounds generally have drawbacks such as long reaction steps, harsh conditions, or many by-products.
[0003] In recent years, α-keto acids have become important research objects in modern organic synthetic chemistry due to their unique reactivity. α-Keto acids can selectively decarboxylate under mild conditions to efficiently generate highly reactive acyl radical intermediates. Such highly reactive intermediates can participate in various radical coupling processes to complete the construction of C-C bonds or C-X bonds. And by introducing acyl functional groups into complex molecular skeletons, the biological activities of organic molecules can be regulated and their pharmacokinetic properties can be improved.
[0004] Therefore, developing an intermolecular radical coupling reaction based on the decarboxylation of α-keto acids to achieve the efficient and highly selective construction of 1,7-dicarbonyl compounds has potential application value and important significance, but also poses challenges. Summary of the Invention
[0005] In order to overcome the deficiencies of the prior art, one of the purposes of the present invention is to provide a method for synthesizing β,γ-unsaturated 1,7-dicarbonyl compounds. The present invention proposes a visible light-driven photoredox catalytic method to achieve the efficient synthesis of β,γ-unsaturated 1,7-dicarbonyl compounds.
[0006] The technical solution of the present invention is as follows:
[0007] 1. A method for synthesizing β,γ-unsaturated 1,7-dicarbonyl compounds, comprising the following steps:
[0008] Under a nitrogen atmosphere, in an organic solvent, α-keto acid compound I, vinylcyclopropane compound II or III undergoes a radical coupling reaction catalyzed by a photocatalytic system to obtain β,γ-unsaturated 1,7-dicarbonyl compound IV; the photocatalytic system consists of blue light and a photocatalyst Ir-III, and the photocatalyst has the structure shown by formula Ir-III; wherein, the structures of each formula are as follows:
[0009]
[0010] Among compound I, R is an aryl group; R is a heterocyclic group; R is an alkyl group;
[0011] Among compound II, R 1 is -OEt, R 2 is -COO t Bu; R 1 is -OEt, R 2 is -COOEt; R 1 is -Ph, R 2 is -COPh; R 1 is -OMe, R 2 is -COOMe; R 1 is -OEt, R 2 is -H; R 1 is -OMe, -NHPh; R 2 is -CN;
[0012] In compound II, R 1 is -OCH2CF3, R 2 is -COOCH2CF3;
[0013] Compound III is a spiro compound, namely benzolactam and benzocyclopentanedione respectively.
[0014] 2. Preferably according to the present invention, the solvent is one of dichloroethane, dichloromethane, toluene, tetrahydrofuran, ethyl acetate, 1,4-dioxane, N,N-dimethylformamide, dimethylacetamide or ethylene glycol dimethyl ether.
[0015] 3. Preferably according to the present invention, the base is one of cesium carbonate, sodium carbonate, potassium carbonate, potassium hydrogen phosphate or triethylamine.
[0016] 4. Preferably according to the present invention, the photocatalyst is bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bi(4-tert-butylpyridine)]iridium bis(hexafluorophosphate).
[0017] Compared with the prior art, the beneficial effects of the present invention are as follows:
[0018] The present invention develops a photocatalytic decarboxylative allylation strategy to efficiently construct various β,γ-unsaturated 1,7-dicarbonyl compounds through a one-step radical coupling reaction. This method overcomes the disadvantages of harsh reaction conditions and cumbersome steps in the traditional synthesis route, and has the advantages of safe operation, mild reaction conditions and wide substrate generality. Specific embodiments
[0019] The following further illustrates the present invention in conjunction with specific embodiments, but is not limited thereto.
[0020] Meanwhile, the experimental methods described in the following examples are all conventional methods unless otherwise specified; the reagents, materials and equipment, unless otherwise specified, can all be obtained from commercial sources.
[0021] The yield mentioned in the examples is the molar yield.
[0022] The reaction route is as follows:
[0023] Example 1
[0024] The synthesis steps of 1c are as follows:
[0025]
[0026] Under a nitrogen atmosphere, 1a (45.0 mg, 0.3 mmol), 1b (64.0 mg, 0.2 mmol), Cs2CO3 (65.2 mg, 0.2 mmol), photocatalyst (4.0 mg, 2 mol%) and 2 mL of dichloroethane solution were successively added to a 4 mL reaction flask. The mixture was reacted under blue light irradiation at room temperature for 16 h. The reaction solution was filtered and concentrated by rotary evaporation, and the target product 1c was obtained by silica gel column chromatography. The eluent was ethyl acetate and petroleum ether (volume ratio 5:1), and the yield was 66%.
[0027] The characterization data of the obtained product 1c are as follows:
[0028] 1 H NMR (400 MHz, CDCl3): δ (ppm) 7.93 (d, J = 7.9 Hz, 2H), 7.57 (t, J = 7.3 Hz, 1H), 7.46 (t, J = 7.6 Hz, 2H), 5.89–5.82 (m, 1H), 5.61–5.54 (m, 1H), 4.52 (q, J = 8.2 Hz, 4H), 3.68 (dd, J = 16.7, 7.1 Hz, 3H), 2.74 (t, J = 7.2 Hz, 2H).
[0029] 13 C NMR (100 MHz, CDCl3): δ (ppm) 197.8, 166.6, 136.6, 133.4, 128.8, 128.4, 128.3, 127.5, 124.1, 121.3, 61.2 (q, J = 37.1 Hz), 51.1, 42.1, 31.8.
[0030] 19 F NMR (376 MHz, CDCl3): δ (ppm) -73.84.
[0031] Example 2
[0032]
[0033] Under a nitrogen atmosphere, 1a (45.0 mg, 0.3 mmol), 2b (48.0 mg, 0.2 mmol), Cs2CO3 (65.2 mg, 0.2 mmol), a photocatalyst (4.0 mg, 2 mol%), and 2 mL of dichloroethane solution were successively added to a 4 mL reaction flask. The mixture was reacted under blue light irradiation at room temperature for 16 h. The reaction solution was filtered and concentrated by rotary evaporation, and the target product 2c was obtained by silica gel column chromatography. The eluent was ethyl acetate and petroleum ether (volume ratio 5:1), and the yield was 76%.
[0034] The characterization data of the obtained product 2c are as follows:
[0035] 1 H NMR (400 MHz, CDCl3): δ (ppm) 7.94 (d, J = 7.4 Hz, 2H), 7.56 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.6 Hz, 2H), 5.85–5.78 (m, 1H), 5.63–5.56 (m, 1H), 4.23–4.09 (m, 2H), 3.69 (d, J = 6.7 Hz, 2H), 3.30 (t, J = 7.5 Hz, 1H), 2.61 (t, J = 7.2 Hz, 2H), 1.43 (s, 9H), 1.25 (t, J = 7.1 Hz, 3H).
[0036] 13 C NMR (100 MHz, CDCl3): δ (ppm) 198.1, 169.4, 168.1, 136.7, 133.3, 130.3, 128.8, 128.4, 125.6, 82.0, 61.3, 53.0, 42.5, 31.9, 28.0, 14.3.
[0037] Example 3
[0038]
[0039] Under a nitrogen atmosphere, 1a (45.0 mg, 0.3 mmol), 3b (42.4 mg, 0.2 mmol), Cs2CO3 (65.2 mg, 0.2 mmol), a photocatalyst (4 mg, 2 mol%), and 2 mL of dichloroethane solution were successively added to a 4 mL reaction flask. The mixture was reacted under blue light irradiation at room temperature for 16 h. The reaction solution was filtered and concentrated by rotary evaporation, and the target product 3c was obtained by silica gel column chromatography. The eluent was ethyl acetate and petroleum ether (volume ratio 5:1), and the yield was 75%.
[0040] The characterization data of the obtained product 3c are as follows:
[0041] 1 1H NMR (400 MHz, CDCl3): δ (ppm) 7.93 (d, J = 8.5 Hz, 2H), 7.55 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.6 Hz, 2H), 5.85–5.78 (m, 1H), 5.62–5.55 (m, 1H), 4.20–4.12 (m, 4H), 3.68 (d, J = 6.6 Hz, 2H), 3.40 (t, J = 7.5 Hz, 1H), 2.65 (t, J = 7.1 Hz, 2H), 1.24 (t, J = 7.1 Hz, 6H).
[0042] 13 13C NMR (100 MHz, CDCl3): δ (ppm) 198.0, 168.9, 136.5, 133.2, 129.9, 128.6, 128.3, 125.8, 61.4, 51.9, 42.3, 31.8, 14.1.
[0043] Example 4
[0044]
[0045] Under a nitrogen atmosphere, 1a (45.0 mg, 0.3 mmol), 4b (30.2 mg, 0.2 mmol), Cs2CO3 (65.2 mg, 0.2 mmol), a photocatalyst (4.0 mg, 2 mol%), and 2 mL of dichloroethane solution were successively added to a 4 mL reaction flask. The mixture was reacted under blue light irradiation at room temperature for 16 h. The reaction solution was filtered and concentrated by rotary evaporation, and the target product 4c was obtained by silica gel column chromatography with ethyl acetate and petroleum ether (volume ratio 2:1) as the eluent, with a yield of 72%.
[0046] The characterization data of the obtained product 4c are as follows:
[0047] 1 1H NMR (400 MHz, CDCl3): δ (ppm) 7.95 (d, J = 7.7 Hz, 2H), 7.58 (t, J = 7.3 Hz, 1H), 7.47 (t, J = 7.7 Hz, 2H), 6.01–5.94 (m, 1H), 5.67–5.60 (m, 1H), 3.80 (s, 3H), 3.78–3.75 (m, 2H), 3.57 (t, J = 6.7 Hz, 1H), 2.72 (t, J = 7.3 Hz, 2H).
[0048] 1313C NMR (100 MHz, CDCl3): δ (ppm) 197.5, 166.0, 136.4, 133.3, 128.7, 128.2, 127.0, 116.0, 53.5, 42.0, 37.6, 32.9.
[0049] Example 5
[0050]
[0051] Under a nitrogen atmosphere, 1a (45.0 mg, 0.3 mmol), 5b (55.2 mg, 0.2 mmol), Cs2CO3 (65.2 mg, 0.2 mmol), photocatalyst (4.0 mg, 2 mol%), and 2 mL of dichloroethane solution were successively added to a 4 mL reaction flask. The mixture was reacted under blue light irradiation at room temperature for 16 h. The reaction solution was filtered and concentrated by rotary evaporation, and the target product 5c was obtained by silica gel column chromatography. The eluent was ethyl acetate and petroleum ether (volume ratio 5:1), and the yield was 61%.
[0052] The characterization data of the obtained product 5c are as follows:
[0053] 1 1H NMR (400 MHz, CDCl3): δ (ppm) 7.96–7.88 (m, 6H), 7.57 (s, 4H), 7.43 (t, J = 7.6 Hz, 5H), 5.84–5.77 (m, 1H), 5.74–5.65 (m 1H), 5.29 (t, J = 6.7 Hz, 1H), 3.65 (d, J = 6.4 Hz, 2H), 2.88 (t, J = 6.7 Hz, 2H).
[0054] 13 13C NMR (100 MHz, CDCl3): δ (ppm) 198.2, 195.7, 136.1, 133.7, 133.3, 131.1, 129.0, 128.7, 128.4, 125.6, 57.2, 42.3, 32.6.
[0055] Example 6
[0056]
[0057] Under a nitrogen atmosphere, 1a (45.0 mg, 0.3 mmol), 6b (36.8 mg, 0.2 mmol), Cs2CO3 (65.2 mg, 0.2 mmol), photocatalyst (4.0 mg, 2 mol%), and 2 mL of dichloroethane solution were successively added to a 4 mL reaction flask. The mixture was reacted for 16 h at room temperature under blue light irradiation. The reaction solution was filtered and concentrated by rotary evaporation, and the target product 6c was obtained by silica gel column chromatography. The eluent was ethyl acetate and petroleum ether (volume ratio 5:1), and the yield was 84%.
[0058] The characterization data of the obtained product 6c are as follows:
[0059] 1 1H NMR (400 MHz, CDCl3): δ (ppm) 7.93 (d, J = 8.0 Hz, 2H), 7.55 (t, J = 7.3 Hz, 1H), 7.45 (t, J = 7.6 Hz, 2H), 5.84–5.77 (m, 1H), 5.61–5.54 (m, 1H), 3.69 (d, J = 11.5 Hz, 8H), 3.44 (t, J = 7.5 Hz, 1H), 2.65 (t, J = 7.2 Hz, 2H).
[0060] 13 13C NMR (100 MHz, CDCl3): δ (ppm) 198.0, 169.4, 136.6, 133.3, 129.8, 128.7, 128.4, 126.2, 52.6, 51.7, 42.4, 32.0.
[0061] Example 7
[0062]
[0063] Under a nitrogen atmosphere, 1a (45.0 mg, 0.3 mmol), 7b (33.4 mg, 0.2 mmol), Cs2CO3 (65.2 mg, 0.2 mmol), photocatalyst (4.0 mg, 2 mol%), and 2 mL of dichloroethane solution were successively added to a 4 mL reaction flask. The mixture was reacted for 16 h at room temperature under blue light irradiation. The reaction solution was filtered and concentrated by rotary evaporation, and the target product 7c was obtained by silica gel column chromatography. The eluent was ethyl acetate and petroleum ether (volume ratio 5:1), and the yield was 72%.
[0064] The characterization data of the obtained product 7c are as follows:
[0065] 11H NMR (400 MHz, CDCl3): δ (ppm) 7.99 (s, 1H), 7.94 (d, J = 7.2 Hz, 2H), 7.61–7.31 (m, 10H), 7.17 (t, J = 7.4 Hz, 1H), 6.01–5.97 (m, 1H), 5.63–5.56 (m, 1H), 3.77 (d, J = 6.7 Hz, 2H), 3.62 (t, J = 6.6 Hz, 1H), 2.81 (t, J = 6.9 Hz, 2H).
[0066] 13 13C NMR (100 MHz, CDCl3): δ (ppm) 197.8, 162.1, 136.7, 136.4, 133.4, 129.1, 128.7, 128.3, 127.7, 125.5, 120.5, 117.6, 41.9, 39.8, 33.0.
[0067] Example 8
[0068]
[0069] Under a nitrogen atmosphere, 1a (45.0 mg, 0.3 mmol), 8b (28.0 mg, 0.2 mmol), Cs2CO3 (65.2 mg, 0.2 mmol), photocatalyst (4.0 mg, 2 mol%), and 2 mL of dichloroethane solution were successively added to a 4 mL reaction flask. The mixture was reacted under blue light irradiation at room temperature for 16 h. The reaction solution was filtered and concentrated by rotary evaporation, and the target product 8c was obtained by silica gel column chromatography. The eluent was ethyl acetate and petroleum ether (volume ratio 20:1), and the yield was 58%.
[0070] The characterization data of the obtained product 8c are as follows:
[0071] 1 1H NMR (400 MHz, CDCl3): δ (ppm) 8.04–7.93 (m, 2H), 7.58 (d, J = 7.3 Hz, 1H), 7.47 (t, J = 7.5 Hz, 2H), 5.82–5.73 (m, 1H), 5.69–5.60 (m, 1H), 4.12 (q, J = 7.1 Hz, 2H), 3.71 (d, J = 6.5 Hz, 2H), 2.40 (s, 4H), 1.25 (t, J = 7.1 Hz, 3H).
[0072] 1313C NMR (100 MHz, CDCl3): δ (ppm) 198.4, 173.2, 133.3, 132.8, 129.3, 128.8, 128.4, 127.9, 123.8, 60.5, 42.5, 34.1, 28.1, 14.4.
[0073] Example 9
[0074]
[0075] Under a nitrogen atmosphere, 1a (45.0 mg, 0.3 mmol), 9b (42.4 mg, 0.2 mmol), Cs2CO3 (65.2 mg, 0.2 mmol), photocatalyst (4.0 mg, 2 mol%), and 2 mL of dichloroethane solution were successively added to a 4 mL reaction flask. The mixture was reacted under blue light irradiation at room temperature for 16 h. The reaction solution was filtered and concentrated by rotary evaporation, and the target product 9c was obtained by silica gel column chromatography with ethyl acetate and petroleum ether (volume ratio 5:1) as the eluent, with a yield of 74%.
[0076] The characterization data of the obtained product 9c are as follows:
[0077] Yellow solid (45.0 mg)
[0078] 1 1H NMR (400 MHz, CDCl3): δ (ppm) 7.94 (d, J = 8.1 Hz, 2H), 7.89–7.77 (m, 4H), 7.52 (t, J = 7.3 Hz, 1H), 7.40 (t, J = 7.5 Hz, 2H), 5.86–5.79 (m, 1H), 5.63–5.56 (m, 1H), 3.59 (d, J = 6.7 Hz, 2H), 3.09 (t, J = 5.9 Hz, 1H), 2.75 (t, J = 6.4 Hz, 2H)..
[0079] 13 13C NMR (100 MHz, CDCl3): δ (ppm) 200.2, 197.9, 142.6, 136.6, 135.8, 133.2, 128.9, 128.7, 128.4, 126.8, 123.3, 53.6, 42.4, 29.9.
[0080] Example 10
[0081]
[0082] Under a nitrogen atmosphere, 1a (45.0 mg, 0.3 mmol), 10b (42.6 mg, 0.2 mmol), Cs2CO3 (65.2 mg, 0.2 mmol), a photocatalyst (4.0 mg, 2 mol%), and 2 mL of dichloroethane solution were successively added to a 4 mL reaction flask. The mixture was reacted under blue light irradiation at room temperature for 16 h. The reaction solution was filtered and concentrated by rotary evaporation, and the target product 10c was obtained by silica gel column chromatography. The eluent was ethyl acetate and petroleum ether (volume ratio 5:1), and the yield was 74%.
[0083] The characterization data of the obtained product 10c are as follows:
[0084] 1 1H NMR (400 MHz, CDCl3): δ (ppm) 7.91 (d, J = 7.4 Hz, 2H), 7.55 (t, J = 7.4 Hz, 1H), 7.46 (t, J = 7.5 Hz, 2H), 7.24 (dd, J = 12.6, 5.4 Hz, 2H), 7.00 (d, J = 7.5 Hz, 1H), 6.77 (d, J = 7.7 Hz, 1H), 5.79–5.72 (m, 1H), 5.62–5.55 (m, 1H), 3.65 (d, J = 5.6 Hz, 2H), 3.48–3.42 (m, 1H), 3.15 (s, 3H), 2.81 (dd, J = 12.5, 6.5 Hz, 1H), 2.55 (dd, J = 14.7, 7.4 Hz, 1H).
[0085] 13 13C NMR (100 MHz, CDCl3): δ (ppm) 198.1, 177.2, 144.3, 136.6, 133.2, 130.2, 128.7, 128.4, 128.0, 126.1, 124.3, 122.4, 108.0, 45.4, 42.4, 34.0, 26.2.
[0086] The above are only some embodiments of the present invention, and do not impose any formal limitations on the present invention. Any simple modifications, equivalent changes, and modifications made to the above embodiments based on the technical essence of the invention all belong to the scope of the technical solution of the present invention.
Claims
1. A method for preparing β,γ-unsaturated 1,7-dicarbonyl compounds, comprising the following steps: In a nitrogen atmosphere, in an organic solvent, under the catalysis of a photocatalytic system, α-keto acid compounds I, vinylcyclopropane compounds II or III undergo a radical coupling reaction to obtain β,γ-unsaturated 1,7-dicarbonyl compounds IV; the photocatalytic system consists of blue light and a photocatalyst Ir-III, and the photocatalyst has the structure shown by formula Ir-III; wherein, The structures of various formulas are as follows: Among them, in compound I, R is an aryl group; R is a heterocyclic group; R is an alkyl group; Among compound II, R 1 is -OEt, R 2 is -COO t Bu; R 1 is -OEt, R 2 is -COOEt; R 1 is -Ph, R 2 is -COPh; R 1 is -OMe, R 2 is -COOMe; R 1 is -OEt, R 2 is -H; R 1 is -OMe, -NHPh; R 2 is -CN, In compound II, R 1 is -OCH2CF3, and R 2 is -COOCH2CF3; Compound III is a spiro compound, which are benzolactam and benzocyclopentadione respectively.
2. Preferably according to the present invention, the solvent is one of dichloroethane, dichloromethane, toluene, tetrahydrofuran, ethyl acetate, 1,4-dioxane, N,N-dimethylformamide, dimethylacetamide or ethylene glycol dimethyl ether.
3. Preferably according to the present invention, the base is one of cesium carbonate, sodium carbonate, potassium carbonate, potassium hydrogen phosphate or triethylamine.
4. Preferably according to the present invention, the photocatalyst is bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bi(4-tert-butylpyridine)]iridium bis(hexafluorophosphate).