A coumarin derivative and a method for preparing the same
The [2+2] cycloaddition reaction of coumarin with a four-membered bridged ring compound, catalyzed by a photosensitizer and driven by visible light, solves the problems of poor substrate universality and low yield in the prior art, and realizes the efficient synthesis of fused-ring coumarin.
Patent Information
- Application Number
- CN202411281209.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2024-09-13
- Publication Date
- 2025-12-05
- Estimated Expiration
- 2044-09-13
AI Technical Summary
In the existing technology, the cycloaddition reaction of coumarin with bridged ring compounds has the problems of poor substrate universality and low yield, especially when the four-membered bridged ring substituent is sulfone, the reaction conversion rate is poor.
Coumarin derivatives were prepared by the [2+2] cycloaddition reaction of coumarin with a four-membered bridged ring compound under visible light, using a photosensitizer as a catalyst. Iridium photosensitive catalysts such as bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bi(4-tert-butylpyridine)]iridium di(hexafluorophosphate) or 2,4,5,6-tetra(9-carbazolyl)-isophthalonitrile were used as catalysts, and anhydrous acetonitrile, tetrahydrofuran, or toluene were used as solvents. The reaction conditions were optimized to improve the yield.
This method improves the reaction yield and substrate versatility, enabling the efficient synthesis of fused-ring coumarins under simple and mild conditions.
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Abstract
Description
Technical Field
[0001] This invention relates to the field of organic chemistry, and in particular to a coumarin derivative and its preparation method. Background Technology
[0002] The coumarin skeleton is a common structural unit in many natural products and synthetic molecules, possessing diverse biological and pharmacological activities such as antitumor, antioxidant, anti-inflammatory, and antibacterial properties, thus finding wide applications in various fields, including medicine and optoelectronics. When the coumarin skeleton is combined with a cycloalkane skeleton, the resulting fused-ring coumarins exhibit interesting biological activities, such as Herbertenolide, a pemonate compound first isolated from the bryophyte *Herberta adunca*, whose extracts show significant inhibitory effects on certain plant pathogenic fungi. Furthermore, naturally occurring aflatoxins, Aflatoxin B1 and Aflatoxin B2, also have similar skeleton structures. Therefore, the synthesis of fused-ring coumarins is of great research significance.
[0003]
[0004] Currently, the synthesis of polycyclic coumarins is mainly achieved through cycloaddition. For example, in an article published by Li-Zhu Wu's research group (DOI: 10.1002 / chem.201501176), it was reported that a series of cyclobutanones were prepared in moderate to good yields by visible light-driven intermolecular [2+2] cycloaddition reactions of coumarin-3-carboxylic acid esters and acrylamide compounds under the catalysis of the iridium complex Firpic.
[0005]
[0006] In 2021, Chun-Hao Yuan's research group published an article (DOI: 10.1039 / d1ra03387e) reporting the [3+2] cycloaddition reaction of 3-high acylcoumarin with cyclic 1-azadiene under DBU catalysis, which yielded highly functionalized cyclopentane-fused coumarin under mild conditions with good diastereoselectivity.
[0007]
[0008] Meanwhile, quaternary bridged ring compounds, as synthons, play a crucial role in the construction of complex molecular skeletons and have been extensively studied by scientists. However, there are few reports on the cycloaddition reaction of coumarin with bridged ring compounds to obtain fused-ring coumarins. In 2022, Glorius's research group published an article in Science (DOI: 10.1038 / s41586-022-04636-x) reporting a visible light-driven [2+2] cycloaddition reaction of coumarin with quaternary bridged ring compounds under TXT catalysis. This reaction yielded a series of fused-ring compounds via an energy transfer pathway. However, when the quaternary bridged ring substituent was sulfone, the corresponding product was only obtained in a 12% yield, which poses a challenge to the substrate universality of the reaction.
[0009]
[0010] Therefore, based on extensive literature review and experimental research, we proposed a photosensitizer-catalyzed, visible light-driven [2+2] cycloaddition reaction of coumarin with four-membered bridged ring compounds, yielding a series of coumarin derivatives. Compared with previous methods, this approach improves the reaction yield, broadens the substrate range, and provides a powerful method for the synthesis of fused-ring compounds involving bridged ring compounds, showing strong application prospects. Summary of the Invention
[0011] To address the aforementioned deficiencies in the existing technology, the technical solution provided by this invention is as follows:
[0012] This invention first provides a coumarin derivative compound A, with the following structural formula:
[0013]
[0014] in:
[0015] R 1 Substituents include H or alkyl, alkoxy, acyl, alkyl-substituted acyl, alkyl-substituted ester, wherein the alkyl group can be methyl, ethyl, propyl, or isopropyl;
[0016] R 2 for
[0017] The specific structure of the coumarin derivative compound A can be as follows:
[0018]
[0019]
[0020] Another aspect of the present invention provides a method for preparing a coumarin derivative compound of formula A. This method includes a cycloaddition reaction between a compound of formula C and a four-membered bridged ring compound of formula B in the presence of a photocatalyst to prepare the coumarin derivative compound of formula A. The specific reaction formula is as follows:
[0021]
[0022] Wherein, formula C is a coumarin compound, and R 1 Substituents include H or alkyl, alkoxy, acyl, alkyl-substituted acyl, alkyl-substituted ester, wherein the alkyl group can be methyl, ethyl, propyl, or isopropyl;
[0023] R 2 for
[0024] In this invention, R 2 for Compound A can be obtained through R 1 Compound C, which is H or alkyl, alkoxy, acyl, alkyl-substituted acyl, or alkyl-substituted ester group, and compound B are prepared by the following reaction process: First, compound C and quaternary bridged ring compound B are mixed with a photosensitizer in a photoreaction tube. Under visible light-driven conditions, a certain amount of solvent is added to carry out a cycloaddition reaction. After concentration under reduced pressure, separation, purification and drying are performed to obtain coumarin derivative compound A.
[0025] In some specific embodiments, the compound of formula C can be any one of 1,2-benzopyranone, 7-methyl-1,2-benzopyranone, 6-methyl-1,2-benzopyranone, 3-methyl-1,2-benzopyranone, 3-ethoxyformyl-1,2-benzopyranone, and 3-formyl-1,2-benzopyranone. In some specific embodiments, the quaternary bridged B-ring compound includes, but is not limited to, 1-(phenylsulfonyl)bicyclo[1,1,0]butane.
[0026] In some specific embodiments, the catalyst is a photosensitive catalyst, which can be bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bi(4-tert-butylpyridine)]iridium di(hexafluorophosphate) salt, or 2,4,5,6-tetra(9-carbazolyl)-isophthalonitrile (abbreviated as 4CzIPN). In some specific embodiments, the reaction solvent can be any one of anhydrous acetonitrile, tetrahydrofuran, and toluene. In this invention, the photosensitive catalyst is the key factor in realizing the reaction under visible light. During the experiment, the inventors found that under TXT catalysis, when the substituent of the four-membered bridged ring compound is phenyl, the corresponding product yield is only 12%, which poses a challenge to the universality of the reaction substrate and results in poor reaction conversion. This invention uses a photosensitizer as a catalyst, thus broadening the range of reaction substrates.
[0027] In some specific embodiments, the ratio of the compound of formula C, the four-membered bridged ring compound B, the photosensitizer, and the solvent is in the range of 1.1 mmol–1.3 mmol: 0.1 mmol–0.3 mmol: 0.003 mmol–0.006 mmol: 5 mL–10 mL, preferably 1 mmol: 0.2 mmol: 0.004 mmol: 4 mL. In some specific embodiments, the mass-to-volume ratio of the compound of formula C and the solvent is 0.018 g: 5 mL–10 mL, preferably 0.018 g: 6 mL–8 mL.
[0028] In this invention, the reactants and solvents are mixed and added to a photoreaction tube, and the reaction is preferably carried out under irradiation with 50W, 456nm blue light. In some specific embodiments, the reaction is carried out at room temperature with stirring after passing visible light through the tube. This invention does not impose any special limitations on the room temperature; for example, it can be 20–40°C or 25–30°C, i.e., no heating or cooling is required, and the temperature under normal environmental conditions is acceptable. This invention does not impose any special limitations on the stirring speed. The reaction time is preferably 16h–24h, more preferably 16h.
[0029] The preferred preparation method of the coumarin derivative compound A of the present invention is as follows: Step (1): In a glove box, compound C, quaternary bridged ring compound B and iridium photosensitizer are added sequentially to a dry 25mL photoreaction tube; Step (2): Anhydrous acetonitrile is added to the tube, and the reaction is carried out at room temperature for 16h under irradiation with 50W, 456nm blue light; Step (3): After the reaction is complete as monitored by TLC, the reaction solution is concentrated under reduced pressure, purified by column chromatography, and the target product is obtained after rotary evaporation and vacuuming.
[0030] Compared with existing technologies, the advantages of this invention are as follows: This invention uses coumarin compounds and four-membered bridged ring compounds as raw materials, and a photosensitizer as a catalyst, to prepare a coumarin derivative through a cycloaddition reaction under visible light irradiation. This process is simple to operate, has mild reaction conditions, high substrate versatility, and exhibits high yield and purity. Detailed Implementation
[0031] The preferred embodiments of the present invention will be described in detail below so that the advantages and features of the present invention can be more easily understood by those skilled in the art, thereby making a clearer and more explicit definition of the scope of protection of the present invention.
[0032] Example 1
[0033]
[0034] The reaction was carried out in a glove box. Compound B-1 (38.85 mg, 0.2 mmol, 1.0 eq.), compound C-1 (1.0 mmol, 5.0 eq.), and iridium photosensitizer (4.48 mg, 0.004 mmol, 0.02 eq.) were added to a dry 25 mL photoreaction tube. Then, 4 mL of anhydrous acetonitrile was added to the tube. The reaction was carried out at room temperature for 16 h under 50 W, 456 nm blue light irradiation. After the reaction was completed by TLC monitoring, the reaction solution was transferred to a 50 mL single-necked flask, silica gel was added, and the solution was concentrated under reduced pressure. The solution was then purified by column chromatography using n-Hexane:EA as the eluent. The eluent was collected, evaporated to dryness, and vacuum was applied to obtain the target compound A-1, with a yield of 50%. (A-1, 34.0mg, 50% yield, white solid); 1H NMR (400MHz, CDCl3) δ7.88(d,J=7.6Hz,1H),7.81(d,J=8.0Hz,2H),7.64(t,J=8.0Hz,1H),7.54(t,J=7.6Hz,2H),7.29(t,J=7.6Hz,1H),7.17 (t,J=7.6Hz,1H),7.00(d,J=8.0Hz,1H),4.21(d,J=9.2Hz,1H),3.49(d,J=9.2Hz,1H),3.01(s,1H),1.84–1.75(m,3H),1.69–1.67(m,1H).13C NMR(101MHz, CDCl3)δ168.3,150.9,137.9,134.1,132.8,130.0,129.3,128.9,124.5,117.4,117.2,72.1,44.1,43.9,41.5,41.2,36.1.HRMS(ESI)calc'd for C19H16NaO4S[M+Na]+363.0622,found363.0622.
[0035] Example 2
[0036]
[0037] The reaction was carried out in a glove box. Compound B-2 (38.85 mg, 0.2 mmol, 1.0 eq.), compound C-2 (1.0 mmol, 5.0 eq.), and iridium photosensitizer (4.48 mg, 0.004 mmol, 0.02 eq.) were added to a dry 25 mL photoreaction tube. Then, 4 mL of anhydrous acetonitrile was added to the tube. The reaction was carried out under 50 W, 456 nm blue light irradiation and stirred continuously at room temperature for 16 h. After the reaction was monitored by TLC until complete, the reaction solution was transferred to a 50 mL single-necked flask, silica gel was added, and the solution was concentrated under reduced pressure. The solution was then purified by column chromatography using n-Hexane:EA as the eluent. The eluent was collected, evaporated to dryness, and vacuum was applied to obtain the target compound A-2 in 51% yield. (A-2, 37.8 mg, 51% yield, white solid); 1H NMR (400MHz, CDCl3) δ7.81(d,J=7.2Hz,2H),7.76(d,J=8.4Hz,1H),7.64(t,J=7.2Hz,1H),7.54(t,J=7.6Hz,2H), 6.73(dd,J=8.8,2.8Hz,1H),6.51(d,J=2.4Hz,1H),4.14(dd,J=9.2,2.4Hz,1H),3.78(s,3H),3.45(d,J=9.6Hz,1H ),2.97(d,J=2.4Hz,1H),1.81–1.73(m,3H),1.65–1.62(m,1H).13CNMR(101MHz,CDCl3)δ168.3,160.7,151.7,137 .9,134.0,133.5,129.3,128.9,110.9,109.2,102.1,71.6,55.6,44.0,43.8,41.4,40.7,36.0.HRMS(ESI)calc'd for C20H18KO5S[M+K]+409.0507,found 409.0507.
[0038] Example 3
[0039]
[0040] The reaction was carried out in a glove box. Compound B-3 (38.85 mg, 0.2 mmol, 1.0 eq.), compound C-3 (1.0 mmol, 5.0 eq.), and iridium photosensitizer (4.48 mg, 0.004 mmol, 0.02 eq.) were added to a dry 25 mL photoreaction tube. Then, 4 mL of anhydrous acetonitrile was added to the tube. The reaction was carried out under 50 W, 456 nm blue light irradiation and stirred continuously at room temperature for 16 h. After the reaction was completed by TLC monitoring, the reaction solution was transferred to a 50 mL single-necked flask, silica gel was added, and the solution was concentrated under reduced pressure. The solution was then purified by column chromatography using n-Hexane:EA as the eluent. The eluent was collected, evaporated to dryness, and vacuum was applied to obtain the target compound A-3 in a yield of 64%. (A-3, 52.8 mg, 64% yield, white solid). 1 H NMR (400MHz, CDCl3) δ7.89(d,J=7.6Hz,1H),7.79(d,J=7.6Hz,2H),7.64(t,J=7.6Hz,1H),7.53(t,J=8.0Hz,2H),7.32(t,J=8.0Hz,1H),7.21(t,J=7.6H z,1H),7.05(d,J=8.0Hz,1H),4.28–4.13(m,3H),3.19(t,J=3.2Hz,1H),2.1 0–2.06(m,1H),1.91–1.88(m,1H),1.80–1.74(m,2H),1.19(t,J=7.2Hz,3H). 13 C NMR (101MHz, CDCl3) δ168.7,165.8,150.2,137.6,134.2,132.8,130.3,129.3,129.0, 124.9,117.2,116.3,70.8,62.6,58.6,46.4,44.2,43.1,37.1,14.0.HRMS(ESI)calc'd for C 22 H 20 NKO6S[M+K] + 451.0612, found 451.0612.
[0041] Example 4
[0042]
[0043] The reaction was carried out in a glove box. Compound B-4 (38.85 mg, 0.2 mmol, 1.0 eq.), compound C-4 (1.0 mmol, 5.0 eq.), and photosensitizer (4.48 mg, 0.004 mmol, 0.02 eq.) were added to a dry 25 mL photoreaction tube. Then, 4 mL of anhydrous acetonitrile was added to the tube. The reaction was carried out under 50 W, 456 nm blue light irradiation, and stirred continuously at room temperature for 16 h. After the reaction was completed by TLC monitoring, the reaction solution was transferred to a 50 mL single-necked flask, silica gel was added, and the solution was concentrated under reduced pressure. The solution was then purified by column chromatography using n-Hexane:EA as the eluent. The eluent was collected, evaporated to dryness, and vacuum was applied to obtain the target compound A-4 in a yield of 48%. (A-4, 35.6 mg, 48% yield, white solid). 1 H NMR (400MHz, CDCl3) δ7.89(d,J=7.6Hz,1H),7.73(d,J=8.8Hz,1H),7.30(t,J=7.6Hz,1H),7.18(t,J=7.6Hz,1H) ,7.01-6.98(m,3H),4.19(d,J=9.2Hz,1H),3.87(s,1H),3.48(d,J=9.2Hz,1H),3.00(s,1H),1.81–1.67(m,4H). 13 C NMR (101MHz, CDCl3) δ168.4,164.0,150.9,132.9,131.2,130.0,129.4,124.5, 117.6,117.2,114.5,55.8,44.3,43.9,41.5,41.2,36.0.HRMS(ESI)calc'dfor C 20 H 18 NNaO4S[M+K] + 409.0507, found 409.0503.
[0044] The above description is merely an embodiment of the present invention and does not limit the patent scope of the present invention. Any equivalent structural or procedural transformations made based on the content of the present invention specification, or direct or indirect applications in other related technical fields, are similarly included within the patent protection scope of the present invention.
Claims
1. A method for preparing a coumarin derivative compound of formula A, characterized in that, The coumarin derivative of formula A is prepared by a cycloaddition reaction of a compound of formula C with a tetra-cyclic ring compound of formula B in a solvent in the presence of a photo-catalyst, and the specific reaction formula is as follows: Wherein: R 1 is H or alkyl, alkoxy, acyl, alkyl substituted acyl, alkyl substituted ester; R 2 For The catalyst is the photosensitive catalyst bis[2-(2,4-difluorophenyl)-5- trifluoromethylpyridine][2-2'-bi(4-tert-butylpyridine)]iridium bis(hexafluorophosphate).
2. A method for preparing a coumarin derivative, characterized by, The coumarin derivative is prepared by a cycloaddition reaction of a compound of formula C-3, a compound of formula C-4 or a compound of formula C-5 with a tetra-cyclic ring compound of formula B-3 in a solvent in the presence of a photo-catalyst, The coumarin derivative has the structural formula: The catalyst is a photo-sensitive catalyst, namely, bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bi(4-tert-butylpyridine)]iridium dihexafluorophosphate.
3. The production method according to claim 1 or 2, characterized by, The solvent is any one of anhydrous acetonitrile, tetrahydrofuran or toluene.
4. The method of claim 1, wherein, The ratio of the compound of formula C, the tetra-cyclic ring compound of formula B, the catalyst and the solvent is 1 mmol:0.2 mmol:0.004 mmol:4 mL.
5. The preparation method according to claim 1, characterized in that, The mass-volume ratio of the compound of formula C and the solvent is 0.018 g:5 mL-10 mL.
6. The production method according to claim 1 or 2, characterized by, The reaction temperature is 20-40 DEG C.
7. The preparation method according to claim 1, characterized in that, The preparation is carried out by the following steps: step (1): feeding in a glove box, sequentially adding the compound of formula C, the tetra-cyclic ring compound of formula B and the photo-sensitive agent into a dry 25 mL photo-reaction tube; step (2): adding anhydrous acetonitrile into the tube, under the irradiation of 50 W, 456 nm blue light, continuously stirring the reaction at room temperature for 16 h; step (3): after the reaction is completed as monitored by TLC, concentrating the reaction solution under reduced pressure, purifying by column chromatography, and obtaining the target product, the coumarin derivative of formula A after drying and vacuumizing.
8. The method of claim 1, wherein, The alkyl group is methyl, ethyl, propyl or isopropyl.
9. The method of claim 1, wherein, The structural formula of the coumarin derivative compound of formula A is: