Palladium-catalyzed synthesis of isocoumarin derivatives containing aldehyde groups and synthesis method

Abstract

The application discloses a palladium catalytic synthesis method of isocoumarin derivatives containing aldehyde groups, which is characterized by the following steps: taking aryl formic acid and ethylene carbonate as raw materials, Pd(OAc)2 as a catalyst, K2S2O8 as an oxidant, Ag2CO3 and MS as additives, 2-hydroxy-3-nitro-5-trifluoromethyl pyridine as a ligand, and hexafluoroisopropanol as a solvent, and then reacting at 100 DEG C for 24 hours to obtain novel isocoumarin derivatives containing aldehyde groups. The synthesis method provided by the application has the advantages of easy raw material acquisition, short reaction steps, one-step completion, and medium to good yield.

Description

Technical Field

[0001] This invention relates to a palladium-catalyzed synthesis of isocoumarin derivatives containing aldehyde groups and a synthesis method thereof, belonging to the field of organic synthesis technology. Background Technology

[0002] Natural products and their analogues containing isocoumarin structural units are widely found in nature and have attracted much attention from organic synthetic chemists due to their various biological activities and potential clinical applications. For example, caldosporin, isolated from Cladosporium and Aspergillus flavus in 1971, has good antitumor and antimalarial activities (Das P, Babbar P, Malhotra N, et al. Specific stereoisomeric conformations determine the drug potency of cladosporin scaffold against malarial parasite[J]. Journal of Medicinal Chemistry, 2018, 61(13): 5664-5678.). Fusarentin 6-methyl ether and its analogues, isolated from *Fusarium larvarum* in 1979, can be used as insecticides, etc. (Fang B, Xie X, Zhao C, et al. Asymmetric total synthesis of fusarentin 6-methyl ether and its biomimetic transformation into fusarentin 6,7-dimethyl ether, 7-O-demethylmonocerin, and (+)-monocerin[J]. The Journal of Organic Chemistry, 2013, 78(12): 6338-6343.). Furthermore, isocoumarin derivatives are often used as key intermediates in the synthesis of some natural products. Therefore, the efficient synthesis of functionally diverse isocoumarin derivatives has significant application prospects.

[0003] Aromatic acids are an important class of organic compounds, not only as important raw materials for organic synthesis, but also as common in natural products and drug molecules. The isocoumarin skeleton can be constructed by reacting aromatic acids with different coupling reagents. In 1998, Miura's group first achieved the synthesis of isocoumarin derivatives under transition metal catalysis. In this work, Pd(OAc)2 and Cu(OAc)2 were used as catalysts, and aromatic acids and styrene were used as substrates. The yield was moderate, the substrate range was narrow, and it was only applicable to benzoic acid, 4-methoxybenzoic acid and 2-naphthoic acid (Miura M, Tsuda T, Satoh T, et al. Oxidative cross-coupling of N-(2'-Phenylphenyl)benzene-sulfonamides or benzoic and naphthoic acids with alkenes using a palladium-copper catalyst system under air[J].The Journal of Organic Chemistry,1998,63(15):5211-5215). Subsequently, Lee et al. modified the structures of aromatic acids and styrene, obtaining good isocumarin yields under similar combinations of Pd(OAc)2 and Ag2O. In this work, when the ortho-substituent of the aromatic acid was hydrogen, the product was an isocumarin derivative; when the ortho-substituent was an electron-donating group (-CH3 or -OCH3), the product was a phthalide derivative (Nandi D, Ghosh D, Chen S, et al. One-step synthesis of isocumarins and 3-benzylidenephthalides via ligandless Pd-catalyzed oxidative coupling of benzoic acids and vinylarenes[J].The Journal of Organic Chemistry,2013,78(7):3445-3451.).In 2009, Yu's research group reported the alkylation / lactoneation reaction of aryl carboxylic acids with dichloroethane as the alkyl source, synthesizing isocoumarin derivatives without the need for silver salts as iodide scavengers. Dichloroethane was used as both an alkylating agent and a solvent (Zhang Y, Shi B, Yu, JQ. Palladium(II)-catalyzed ortho alkylation of benzoic acids with alkyl halides[J]. Angewandte Chemie International Edition, 2009, 48(33): 6097-6100). In 2017, Jiang's research group achieved a nucleophilic addition / oxidative cyclization reaction of bromoalkynes with benzoic acid under Pd(TFA)2 catalysis, providing an effective strategy for the synthesis of 3-substituted isocoumarin derivatives. Cis-nucleophilic addition and CH bond activation functionalization are the key steps of this reaction (Jiang G, Li J, Zhu C, et al. Palladium-catalyzed sequential nucleophilic addition / oxidative annulation of bromoalkynes with benzoic acids to construct functionalized isocoumarins[J]. Organic Letters, 2017, 19(17):4440-4443.). Although isocoumarin skeletons can be constructed by CH bond activation functionalization using aromatic acids as substrates, these reaction conditions are relatively harsh, and existing methods cannot synthesize isocoumarin derivatives with aliphatic aldehyde structural units. Therefore, it is necessary to find a method with readily available raw materials and high efficiency to synthesize isocoumarin derivatives containing aldehyde groups. Summary of the Invention

[0004] The technical problem to be solved by this invention is to provide a palladium-catalyzed synthesis of isocoumarin derivatives containing aldehyde groups and a synthesis method thereof, using arylformic acid and ethylene ethylene carbonate as raw materials, Pd(OAc)2 as catalyst, K2S2O8 as oxidant, and Ag2CO3 and MS was used as an additive, 2-hydroxy-3-nitro-5-trifluoromethylpyridine as a ligand, and hexafluoroisopropanol as a reaction solvent. The reaction was carried out in sealed tubes at 100°C for 24 hours to generate the target product. The reaction steps were short and could be completed in one step, with a medium to good yield.

[0005] To solve the above-mentioned technical problems, the technical solution of the present invention is as follows:

[0006] An innovative method for the palladium-catalyzed synthesis of isocoumarin derivatives containing aldehyde groups is as follows: The palladium-catalyzed synthesis of isocoumarin derivatives containing aldehyde groups is as follows:

[0007]

[0008] in:

[0009] In Formula I, R is one or two of methyl, methoxy, tert-butyl, fluorine, chlorine, and bromine.

[0010] A method for the palladium-catalyzed synthesis of isocoumarin derivatives containing aldehyde groups, comprising the following steps:

[0011]

[0012] Wherein: the compound with the structure of formula II is arylcarboxylic acid, and the compound with the structure of formula III is ethylene carbonate;

[0013] The aforementioned aryl carboxylic acid and ethylene carbonate were reacted with palladium acetate (Pd(OAc)2) as a catalyst, potassium persulfate (K2S2O8) as an oxidant, and silver carbonate (Ag2CO3) and... MS was used as an additive, 2-hydroxy-3-nitro-5-trifluoromethylpyridine was used as a ligand, and hexafluoroisopropanol was used as a reaction solvent. The reaction was carried out in sealed tubes at 100°C for 24 h. After the reaction was completed, the product was concentrated and purified by TLC on a thin-layer silica gel plate to obtain the palladium-catalyzed synthesis of isocoumarin derivatives containing aldehyde groups according to Formula I.

[0014] Preferably, the method for synthesizing the palladium-catalyzed isocoumarin derivative containing an aldehyde group is as follows:

[0015] Add 0.1 mmol of arylcarboxylic acid and 0.15 mmol of ethylene carbonate to a pressure-resistant tube, followed by 0.01 mmol of palladium acetate, 0.12 mmol of potassium persulfate, 0.05 mmol of silver carbonate, 0.03 mmol of 2-hydroxy-3-nitro-5-trifluoromethylpyridine, and 10 mg of [unspecified ingredient]. MS, add 1 mL of hexafluoroisopropanol, seal the tube, and heat at 100°C for 24 hours;

[0016] After the reaction was completed, the palladium-catalyzed isocoumarin derivative containing an aldehyde group was obtained by TLC on a thin-layer silica gel plate, concentration and purification.

[0017] The molar ratio of the aryl carboxylic acid to the ethylene carbonate is 1:1.5.

[0018] Preferably, the pressure-resistant tube is a 10mL pressure-resistant tube with a magnetic stir bar.

[0019] Preferably, the amount of palladium acetate Pd(OAc)2 used is 10% of the molar amount of the arylformic acid.

[0020] Preferably, the amount of oxidant K2S2O8 used is 120% of the molar amount of arylformic acid.

[0021] Preferably, the amount of silver carbonate Ag2CO3 used is 50% of the molar amount of arylformic acid.

[0022] Preferably, the compound of 2-hydroxy-3-nitro-5-trifluoromethylpyridine is

[0023]

[0024] The amount of 2-hydroxy-3-nitro-5-trifluoromethylpyridine used is 30% of the molar amount of the arylcarboxylic acid.

[0025] Preferably, the aryl carboxylic acid includes 3-methylbenzoic acid, 2-methylbenzoic acid, 4-methylbenzoic acid, benzoic acid, 2-methoxybenzoic acid, 3-methoxybenzoic acid, 2,3-dimethylbenzoic acid, 3,4-dimethylbenzoic acid, 2,4-dimethylbenzoic acid, and 3-methyl-4-methoxybenzoic acid.

[0026] Preferably, the concentration includes diluting the reaction with 30 mL of ethyl acetate, filtering the solid, and removing the solvent by rotary evaporation under reduced pressure.

[0027] The purification is carried out after the concentration process, and the purification is performed by separation and purification using a preparative plate. The developing solvent in the purification is a mixture of petroleum ether and ethyl acetate with a volume ratio of 4:1.

[0028] The advantages of this invention are as follows: This invention uses arylformic acid and ethylene ethylene carbonate as starting materials, palladium acetate as the catalyst, potassium persulfate as the oxidant, and silver carbonate and... MS, with 2-hydroxy-3-nitro-5-trifluoromethylpyridine as the ligand and hexafluoroisopropanol as the solvent, yielded isocoumarin derivatives containing aldehyde groups under palladium acetate catalysis. The reaction was short, completed in one step, and yielded moderate to good results. Detailed Implementation

[0029] The palladium-catalyzed synthesis of isocoumarin derivatives containing aldehyde groups in this invention is as follows:

[0030]

[0031] Wherein: In Formula I, R is one or two of methyl, methoxy, tert-butyl, fluorine, chlorine, and bromine.

[0032] A method for the palladium-catalyzed synthesis of isocoumarin derivatives containing aldehyde groups, used to prepare palladium-catalyzed isocoumarin derivatives containing aldehyde groups, includes the following steps:

[0033]

[0034] Wherein: the compound with the structure of formula II is arylcarboxylic acid, and the compound with the structure of formula III is ethylene carbonate;

[0035] The aforementioned aryl carboxylic acid and ethylene carbonate were reacted with palladium acetate (Pd(OAc)2) as a catalyst, potassium persulfate (K2S2O8) as an oxidant, and silver carbonate (Ag2CO3) and... MS was used as an additive, 2-hydroxy-3-nitro-5-trifluoromethylpyridine was used as a ligand, and hexafluoroisopropanol was used as a reaction solvent. The reaction was carried out in sealed tubes at 100°C for 24 h. After the reaction was completed, the product was concentrated and purified by TLC on a thin-layer silica gel plate to obtain the palladium-catalyzed synthesis of isocoumarin derivatives containing aldehyde groups according to Formula I.

[0036] This invention uses arylformic acid and ethylene carbonate as starting materials, palladium acetate as catalyst, potassium persulfate as oxidant, and silver carbonate and [other additives]. MS, with 2-hydroxy-3-nitro-5-trifluoromethylpyridine as the ligand and hexafluoroisopropanol as the solvent, yielded isocoumarin derivatives containing aldehyde groups under palladium acetate catalysis. The reaction was short, completed in one step, and yielded moderate to good results.

[0037] Specifically, the method for synthesizing isocoumarin derivatives containing aldehyde groups using palladium catalysis is as follows:

[0038] Add 0.1 mmol of arylcarboxylic acid and 0.15 mmol of ethylene carbonate to a pressure-resistant tube, followed by 0.01 mmol of palladium acetate, 0.12 mmol of potassium persulfate, 0.05 mmol of silver carbonate, 0.03 mmol of 2-hydroxy-3-nitro-5-trifluoromethylpyridine, and 10 mg of [unspecified ingredient]. MS, then add 1 mL of hexafluoroisopropanol, seal the tube, and heat the reaction at 100 °C for 24 hours; after the reaction is completed, follow the reaction by thin-layer silica gel plate TLC, concentrate and purify to obtain the palladium-catalyzed synthesis of isocoumarin derivative containing aldehyde group of formula I; wherein, the molar ratio of the arylformic acid and the ethylene carbonate is 1:1.5.

[0039] The pressure-resistant tube mentioned above is a 10 mL pressure-resistant tube equipped with a magnetic stir bar; the amount of palladium acetate Pd(OAc)2 used is 10% of the molar amount of the arylformic acid; the amount of oxidant K2S2O8 used is 120% of the molar amount of the arylformic acid; and the amount of silver carbonate Ag2CO3 used is 50% of the molar amount of the arylformic acid.

[0040] The above-mentioned compound, 2-hydroxy-3-nitro-5-trifluoromethylpyridine, is

[0041]

[0042] In addition, the amount of 2-hydroxy-3-nitro-5-trifluoromethylpyridine used is 30% of the molar amount of the arylcarboxylic acid.

[0043] The aforementioned aryl carboxylic acids include 3-methylbenzoic acid, 2-methylbenzoic acid, 4-methylbenzoic acid, benzoic acid, 2-methoxybenzoic acid, 3-methoxybenzoic acid, 2,3-dimethylbenzoic acid, 3,4-dimethylbenzoic acid, 2,4-dimethylbenzoic acid, and 3-methyl-4-methoxybenzoic acid.

[0044] The above concentration process includes diluting the reaction with 30 mL of ethyl acetate, filtering the solid, and removing the solvent by rotary evaporation under reduced pressure. The purification process is carried out after the concentration process is completed, and the purification is performed by separation and purification using a preparative plate. The developing solvent in the purification process is a mixture of petroleum ether and ethyl acetate in a volume ratio of 4:1.

[0045] Example 1

[0046] Preparation of 2-(7-methyl-1-oxoisobenzodihydropyran-3-yl)acetaldehyde: 3-methylbenzoic acid 3-CH3 (0.1 mmol), ethylene carbonate (0.15 mmol), palladium acetate (0.01 mmol), potassium persulfate (0.12 mmol), silver carbonate (0.05 mmol), 2-hydroxy-3-nitro-5-trifluoromethylpyridine (0.03 mmol), and 10 mg of [unspecified ingredient] were added to a 10 mL pressure-resistant tube equipped with a magnetic stir bar. MS was added, followed by 1 mL of hexafluoroisopropanol. The tube was sealed and heated at 100 °C for 24 hours. The reaction was monitored by thin-layer silica gel plate (TLC). After the reaction was completed, the reaction system was diluted with 30 mL of ethyl acetate, the solid was filtered, the solvent was removed by rotary evaporation under reduced pressure, and the solid was purified by preparative plate separation (petroleum ether: ethyl acetate = 4:1).

[0047] The characterization data of the obtained compounds are as follows:

[0048] 2-(7-Methyl-1-oxoisobenzodihydropyran-3-yl)acetaldehyde (3a)

[0049] Yellow oil; 1H NMR (400MHz, CDCl3) δ (ppm) 9.87 (s, 1H), 7.98 (d, J = 7.9Hz, 1H), 7.21 (d, J = 8.0Hz, 1H), 7.05 (s, 1H), 5.15-4 .90(m,1H),3.10(dd,J=17.6,6.2Hz,1H),3.00(d,J=6.4Hz,2H),2.87(dd,J=17.7,6.3Hz,1H),2.41(s,3H); 13 C{ 1 H}NMR (100MHz, CDCl3) δ (ppm) 198.43, 165.03, 137.91, 135.32, 134.88, 130.62, 127.32, 124.44, 73.33, 48.30, 32.63, 20.99; IR (KBr) (ν, cm -1 )3420,2925,2854,1725,1618,1595,1502,1422,1285,1195,1142,1084,775; HRMS(APCI-TOF)m / z:[M+H] + Calcd for C 12 H 13 O3 + 205.0859; Found 205.0851.

[0050] The aryl carboxylic acid was obtained by using 3-methylbenzoic acid (3-CH3), and the resulting palladium-catalyzed synthesis of isocoumarin derivatives containing aldehyde groups yielded 75%.

[0051] Example 2

[0052] Preparation of 2-(8-methyl-1-oxoisobenzodihydropyran-3-yl)acetaldehyde: In a 10 mL pressure-resistant tube equipped with a magnetic stir bar, add 2-methylbenzoic acid 2-CH3 (0.1 mmol), ethylene carbonate (0.15 mmol), 0.01 mmol of palladium acetate, 0.12 mmol of potassium persulfate, 0.05 mmol of silver carbonate, 0.03 mmol of 2-hydroxy-3-nitro-5-trifluoromethylpyridine, and 10 mg of... MS was added, followed by 1 mL of hexafluoroisopropanol. The tube was sealed and heated at 100 °C for 24 hours. The reaction was monitored by thin-layer silica gel plate (TLC). After the reaction was completed, the reaction system was diluted with 30 mL of ethyl acetate, the solid was filtered, the solvent was removed by rotary evaporation under reduced pressure, and the solid was purified by preparative plate separation (petroleum ether: ethyl acetate = 4:1).

[0053] The characterization data of the obtained compounds are as follows:

[0054] 2-(8-Methyl-1-oxoisobenzodihydropyran-3-yl)acetaldehyde (3b)

[0055] Yellow oil; 1 H NMR (400MHz, CDCl3) δ (ppm) 9.88 (s, 1H), 7.39 (t, 1H), 7.22 (d, J = 7.7Hz, 1H), 7.08 (d, J = 7.5Hz, 1H), 5.07-4 .89(m,1H),3.10(dd,J=17.6,6.5Hz,1H),3.01(d,J=7.2Hz,2H),2.85(dd,J=17.7,6.2Hz,1H),2.67(s,3H); 13 C{ 1 H}NMR (100MHz, CDCl3) δ (ppm) 198.54, 164.08, 143.18, 139.37, 132.89, 131.35, 125.26, 123.35, 72.49, 48.20, 34.21, 22.13; IR (KBr) (ν, cm -1 )3421,2925,2853,1724,1597,1472,1399,1245,1210,1115,1065,932,777,574; HRMS(APCI-TOF)m / z:[M+H] + Calcd for C 12 H 13 O3 + 205.0859; Found 205.0850.

[0056] Arylformic acid was obtained by using 2-methylbenzoic acid 2-CH3, and the resulting palladium-catalyzed synthesis of isocoumarin derivatives containing aldehyde groups yielded 57%.

[0057] Example 3

[0058] Preparation of 2-(8-methyl-1-oxoisobenzodihydropyran-3-yl)acetaldehyde: 4-methylbenzoic acid (4-CH3) (0.1 mmol), ethylene carbonate (0.15 mmol), palladium acetate (0.01 mmol), potassium persulfate (0.12 mmol), silver carbonate (0.05 mmol), 2-hydroxy-3-nitro-5-trifluoromethylpyridine (0.03 mmol), and 10 mg of [unspecified ingredient] were added to a 10 mL pressure-resistant tube equipped with a magnetic stir bar. MS was added, followed by 1 mL of hexafluoroisopropanol. The tube was sealed and heated at 100 °C for 24 hours. The reaction was monitored by thin-layer silica gel plate (TLC). After the reaction was completed, the reaction system was diluted with 30 mL of ethyl acetate, the solid was filtered, the solvent was removed by rotary evaporation under reduced pressure, and the solid was purified by preparative plate separation (petroleum ether: ethyl acetate = 4:1).

[0059] The characterization data of the obtained compounds are as follows:

[0060] 2-(6-Methyl-1-oxoisobenzodihydropyran-3-yl)acetaldehyde (3c)

[0061] Yellow oil; 1 H NMR (400MHz, CDCl3) δ (ppm) 9.87 (s, 1H), 7.98 (d, J = 7.9Hz, 1H), 7.21 (d, J = 8.0Hz, 1H), 7.05 (s, 1H), 5.27 -4.67(m,1H),3.10(dd,J=17.6,6.2Hz,1H),3.00(d,J=6.4Hz,2H),2.89(dd,J=6.3Hz,1H),2.41(s,3H); 13 C{ 1 H}NMR (100MHz, CDCl3) δ (ppm) 198.45, 164.90, 145.07, 138.31, 130.46, 128.87, 127.98, 122.04, 73.15, 48.31, 32.99, 21.76; IR (KBr) (ν, cm -1 )3428,2924,1724,1615,1384,1361,1288,1159,1138,1080,840,777; HRMS(APCI-TOF)m / z:[M+H] + Calcd for C 12 H 13 O3 + 205.0859; Found 205.0854.

[0062] Arylformic acid was obtained by using 4-methylbenzoic acid (4-CH3), and the resulting palladium-catalyzed synthesis of isocoumarin derivatives containing aldehyde groups yielded 56%.

[0063] Example 4

[0064] Preparation of 2-(8-methyl-1-oxoisobenzodihydropyran-3-yl)acetaldehyde: Benzoic acid H (0.1 mmol), ethylene carbonate (0.15 mmol), palladium acetate (0.01 mmol), potassium persulfate (0.12 mmol), silver carbonate (0.05 mmol), 2-hydroxy-3-nitro-5-trifluoromethylpyridine (0.03 mmol), and 10 mg of [unspecified ingredient] were added to a 10 mL pressure-resistant tube equipped with a magnetic stir bar. MS was added, followed by 1 mL of hexafluoroisopropanol. The tube was sealed and heated at 100 °C for 24 hours. The reaction was monitored by thin-layer silica gel plate (TLC). After the reaction was completed, the reaction system was diluted with 30 mL of ethyl acetate, the solid was filtered, the solvent was removed by rotary evaporation under reduced pressure, and the solid was purified by preparative plate separation (petroleum ether: ethyl acetate = 4:1).

[0065] The characterization data of the obtained compounds are as follows:

[0066] 2-(1-Oxoisobenzodihydropyran-3-yl)acetaldehyde (3d)

[0067] Yellow oil; 1 H NMR (400MHz, CDCl3) δ (ppm) 9.88 (s, 1H), 8.10 (d, J = 7.6Hz, 1H), 7.56 (t, J = 7.6Hz, 1H), 7.42 ( t,J=7.7Hz,1H),7.26(d,J=7.6Hz,1H),5.18-4.95(m,1H),3.13(dd,J=17.7,6.0Hz,1H),3.09 -2.97(m,2H),2.89(dd,J=17.7,6.3Hz,1H); 13 C{ 1 H}NMR (100MHz, CDCl3) δ (ppm) 198.33, 164.75, 138.31, 134.01, 130.43, 127.98, 127.45, 124.74, 73.22, 48.30, 33.00; IR (KBr) (ν, cm -1 )3421,2925,2854,1717,1635,1500,1471,1244,1056,820,783,657; HRMS(APCI-TOF)m / z:[M+Na] + Calcd for C 11 H 10 O3Na + 213.0522; Found 213.0514

[0068] Arylcarboxylic acid was synthesized using benzoic acid H, and the resulting palladium-catalyzed synthesis of isocoumarin derivatives containing aldehyde groups yielded 50%.

[0069] Example 5

[0070] Preparation of 2-(8-methyl-1-oxoisobenzodihydropyran-3-yl)acetaldehyde: 2-methyloxybenzoic acid 2-OCH3 (0.1 mmol), ethylene carbonate (0.15 mmol), palladium acetate (0.01 mmol), potassium persulfate (0.12 mmol), silver carbonate (0.05 mmol), 2-hydroxy-3-nitro-5-trifluoromethylpyridine (0.03 mmol), and 10 mg of [unspecified ingredient] were added to a 10 mL pressure-resistant tube equipped with a magnetic stir bar. MS was added, followed by 1 mL of hexafluoroisopropanol. The tube was sealed and heated at 100 °C for 24 hours. The reaction was monitored by thin-layer silica gel plate (TLC). After the reaction was completed, the reaction system was diluted with 30 mL of ethyl acetate, the solid was filtered, the solvent was removed by rotary evaporation under reduced pressure, and the solid was purified by preparative plate separation (petroleum ether: ethyl acetate = 4:1).

[0071] The characterization data of the obtained compounds are as follows:

[0072] 2-(8-methoxy-1-oxoisobenzodihydropyran-3-yl)acetaldehyde (3e)

[0073] Yellow oil; 1 H NMR (400MHz, CDCl3) δ (ppm) 9.86 (s, 1H), 7.47 (t, J = 8.0Hz, 1H), 6.94 (d, J = 8.5Hz, 1H), 6.82 (d, J = 7.4Hz, 1H), 5.0 1-4.82(m,1H),3.95(s,3H),3.09(dd,J=17.7,6.2Hz,1H),2.98(d,J=10.1Hz,2H),2.83(dd,J=17.7,6.3Hz,1H); 13 C{ 1 H}NMR (100MHz, CDCl3) δ (ppm) 198.57, 161.78, 161.26, 141.06, 134.78, 119.29, 113.35, 111.15, 72.31, 56.18, 48.05, 34.16; IR (KBr) (ν, cm -1 )2923,2849,2359,1727,1599,1585,1477,1356,1279,1236,1083,1061,804,700; HRMS(APCI-TOF)m / z:[M+H] + Calcd for C 12 H 13 O4 +221.0808; Found 221.0801.

[0074] Arylformic acid was used in the synthesis of isocoumarin derivatives containing aldehyde groups using palladium catalysis with a yield of 53%.

[0075] Example 6

[0076] Preparation of 2-(8-methyl-1-oxoisobenzodihydropyran-3-yl)acetaldehyde: 3-methyloxybenzoic acid 3-OCH3 (0.1 mmol), ethylene carbonate (0.15 mmol), palladium acetate (0.01 mmol), potassium persulfate (0.12 mmol), silver carbonate (0.05 mmol), 2-hydroxy-3-nitro-5-trifluoromethylpyridine (0.03 mmol), and 10 mg of [unspecified ingredient] were added to a 10 mL pressure-resistant tube equipped with a magnetic stir bar. MS was added, followed by 1 mL of hexafluoroisopropanol. The tube was sealed and heated at 100 °C for 24 hours. The reaction was monitored by thin-layer silica gel plate (TLC). After the reaction was completed, the reaction system was diluted with 30 mL of ethyl acetate, the solid was filtered, the solvent was removed by rotary evaporation under reduced pressure, and the solid was purified by preparative plate separation (petroleum ether: ethyl acetate = 4:1).

[0077] The characterization data of the obtained compounds are as follows:

[0078] 2-(7-methoxy-1-oxoisobenzodihydropyran-3-yl)acetaldehyde (3f)

[0079] Yellow oil; 1 H NMR (400MHz, CDCl3) δ (ppm) 9.89 (s, 1H), 7.71 (d, J = 7.7Hz, 1H), 7.36 (t, J = 8.1Hz, 1H), 7.09 (d, J = 8.1Hz, 1H), 5.15 -4.85(m,1H),3.87(s,3H),3.28(d,J=19.1Hz,1H),3.11(dd,1H),2.88(dd,J=17.6,5.8Hz,1H),2.81-2.62(m,1H); 13 C{ 1 H}NMR (100MHz, CDCl3) δ (ppm) 198.42, 164.78, 155.58, 128.20, 127.32, 125.63, 121.92, 114.99, 73.05, 55.75, 48.46, 26.76; IR (KBr) (ν, cm -1)3427,2924,2852,1723,1591,1482,1441,1386,1276,1171,1140,1060,959,753; HRMS(APCI-TOF)m / z:[M+Na] + Calcd for C 12 H 13 O4Na + 243.0628; Found 243.0619.

[0080] The aryl carboxylic acid was 3-methoxybenzoic acid 3-OCH3, and the resulting palladium-catalyzed synthesis of isocoumarin derivatives containing aldehyde groups yielded 65%.

[0081] Example 7

[0082] Preparation of 2-(8-methyl-1-oxoisobenzodihydropyran-3-yl)acetaldehyde: In a 10 mL pressure-resistant tube equipped with a magnetic stir bar, add 2,3-dimethylbenzoic acid 2,3-(CH3)2 (0.1 mmol), ethylene carbonate (0.15 mmol), 0.01 mmol of palladium acetate, 0.12 mmol of potassium persulfate, 0.05 mmol of silver carbonate, 0.03 mmol of 2-hydroxy-3-nitro-5-trifluoromethylpyridine, and 10 mg of... MS was added, followed by 1 mL of hexafluoroisopropanol. The tube was sealed and heated at 100 °C for 24 hours. The reaction was monitored by thin-layer silica gel plate (TLC). After the reaction was completed, the reaction system was diluted with 30 mL of ethyl acetate, the solid was filtered, the solvent was removed by rotary evaporation under reduced pressure, and the solid was purified by preparative plate separation (petroleum ether: ethyl acetate = 4:1).

[0083] The characterization data of the obtained compounds are as follows:

[0084] 2-(7,8-Dimethyl-1-oxoisobenzodihydropyran-3-yl)acetaldehyde (3g)

[0085] Yellow oil; 1 H NMR (400MHz, CDCl3) δ (ppm) 9.87 (s, 1H), 7.29 (d, J = 7.6Hz, 1H), 6.97 (d, J = 7.6Hz, 1H), 4.92 (m, J = 6.5Hz, 1H), 3.08(dd,J=17.6,6.6Hz,1H),2.95(d,J=6.9Hz,2H),2.83(dd,J=17.7,6.0Hz,1H),2.57(s,3H),2.32(s,3H); 13 C{ 1H}NMR (100MHz, CDCl3) δ (ppm) 198.64, 164.53, 141.24, 137.73, 136.85, 134.42, 124.42, 123.82, 72.55, 48.10, 34.29, 20.59, 17.11; IR (KBr) (ν, cm -1 )3410,3315,2944,1724,1560,1478,1460,1263,1212,1148,1111,1052,1025,838; HRMS(APCI-TOF)m / z:[M+H] + Calcd for C 13 H 15 O3 + 219.1016; Found 219.1010.

[0086] The aryl carboxylic acid used was 2,3-dimethylbenzoic acid 2,3-(CH3)2, and the resulting palladium-catalyzed synthesis of isocoumarin derivatives containing aldehyde groups yielded 63%.

[0087] Example 8

[0088] Preparation of 2-(8-methyl-1-oxoisobenzodihydropyran-3-yl)acetaldehyde: 3,4-dimethylbenzoic acid 3,4-(CH3)2 (0.1 mmol), ethylene carbonate (0.15 mmol), palladium acetate (0.01 mmol), potassium persulfate (0.12 mmol), silver carbonate (0.05 mmol), 2-hydroxy-3-nitro-5-trifluoromethylpyridine (0.03 mmol), and 10 mg of [unspecified ingredient] were added to a 10 mL pressure-resistant tube equipped with a magnetic stir bar. MS was added, followed by 1 mL of hexafluoroisopropanol. The tube was sealed and heated at 100 °C for 24 hours. The reaction was monitored by thin-layer silica gel plate (TLC). After the reaction was completed, the reaction system was diluted with 30 mL of ethyl acetate, the solid was filtered, the solvent was removed by rotary evaporation under reduced pressure, and the solid was purified by preparative plate separation (petroleum ether: ethyl acetate = 4:1).

[0089] The characterization data of the obtained compounds are as follows:

[0090] 2-(6,7-Dimethyl-1-oxoisobenzodihydropyran-3-yl)acetaldehyde (3h)

[0091] Yellow oil; 1H NMR (400MHz, CDCl3) δ (ppm) 9.87 (s, 1H), 7.85 (s, 1H), 7.01 (s, 1H), 5.27-4.72 (m, 1H), 3.08 (dd,J=17.7,6.0Hz,1H),3.03-2.90(m,3H),2.88(dd,J=6.1Hz,1H),2.30(d,J=8.1Hz,6H); 13 C{ 1 H}NMR (100MHz, CDCl3) δ (ppm) 198.55, 165.13, 143.92, 136.64, 135.80, 131.05, 128.51, 122.12, 73.30, 48.33, 32.53, 20.10, 19.35; IR (KBr) (ν, cm -1 )3427,2924,1720,1619,1498,1456,1414,1355,1266,1229,1149,1090,1046,781,581; HRMS(APCI-TOF)m / z:[M+H] + Calcd for C 13 H 15 O3 + 219.1016; Found 219.1009.

[0092] The aryl carboxylic acid used was 3,4-dimethylbenzoic acid 3,4-(CH3)2, and the resulting palladium-catalyzed synthesis of isocoumarin derivatives containing aldehyde groups yielded 73%.

[0093] Example 9

[0094] Preparation of 2-(8-methyl-1-oxoisobenzodihydropyran-3-yl)acetaldehyde: In a 10 mL pressure-resistant tube equipped with a magnetic stir bar, add 2,4-dimethylbenzoic acid 2,4-(CH3)2 (0.1 mmol), ethylene carbonate (0.15 mmol), palladium acetate (0.01 mmol), potassium persulfate (0.12 mmol), silver carbonate (0.05 mmol), 2-hydroxy-3-nitro-5-trifluoromethylpyridine (0.03 mmol), and 10 mg of [unspecified ingredient]. MS was added, followed by 1 mL of hexafluoroisopropanol. The tube was sealed and heated at 100 °C for 24 hours. The reaction was monitored by thin-layer silica gel plate (TLC). After the reaction was completed, the reaction system was diluted with 30 mL of ethyl acetate, the solid was filtered, the solvent was removed by rotary evaporation under reduced pressure, and the solid was purified by preparative plate separation (petroleum ether: ethyl acetate = 4:1).

[0095] The characterization data of the obtained compounds are as follows:

[0096] 2-(6,8-Dimethyl-1-oxoisobenzodihydropyran-3-yl)acetaldehyde (3i)

[0097] Yellow oil; 1 H NMR (400MHz, CDCl3) δ (ppm) 9.86 (s, 1H), 7.02 (s, 1H), 6.88 (s, 1H), 5.06-4.80 (m, 1H), 3.07 (dd, J =17.6,6.5Hz,1H),2.95(d,J=7.2Hz,2H),2.82(dd,J=17.6,6.1Hz,1H),2.62(s,3H),2.34(s,3H); 13 C{ 1 H}NMR (100MHz, CDCl3) δ (ppm) 198.67, 164.23, 143.73, 143.13, 139.43, 132.16, 125.92, 120.58, 72.39, 48.19, 34.14, 22.03, 21.43; IR (KBr) (ν, cm -1 )3421,2925,1721,1612,1578,1429,1357,1382,1256,1214,1169,1077,858,571; HRMS(APCI-TOF)m / z:[M+H] + Calcd for C 13 H 15 O3 + 219.1016; Found 219.1010.

[0098] The aryl carboxylic acid used was 2,4-dimethylbenzoic acid 2,4-(CH3)2, and the resulting palladium-catalyzed synthesis of isocoumarin derivatives containing aldehyde groups yielded 65%.

[0099] Example 10

[0100] Preparation of 2-(8-methyl-1-oxoisobenzodihydropyran-3-yl)acetaldehyde: 3-methyl-4-methoxybenzoic acid (3-CH3,4-OCH3) (0.1 mmol), ethylene carbonate (0.15 mmol), palladium acetate (0.01 mmol), potassium persulfate (0.12 mmol), silver carbonate (0.05 mmol), 2-hydroxy-3-nitro-5-trifluoromethylpyridine (0.03 mmol), and 10 mg of [unspecified ingredient] were added to a 10 mL pressure-resistant tube equipped with a magnetic stir bar. MS was added, followed by 1 mL of hexafluoroisopropanol. The tube was sealed and heated at 100 °C for 24 hours. The reaction was monitored by thin-layer silica gel plate (TLC). After the reaction was completed, the reaction system was diluted with 30 mL of ethyl acetate, the solid was filtered, the solvent was removed by rotary evaporation under reduced pressure, and the solid was purified by preparative plate separation (petroleum ether: ethyl acetate = 4:1).

[0101] The characterization data of the obtained compounds are as follows:

[0102] 2-(6-methoxy-7-methyl-1-oxoisobenzodihydropyran-3-yl)acetaldehyde (3j)

[0103] Yellow oil; 1 H NMR (400MHz, CDCl3) δ (ppm) 9.86 (s, 1H), 7.84 (s, 1H), 6.61 (s, 1H), 5.25-4.75 (m, 1H), 3.88 (s, 3H) ),3.09(dd,J=17.7,6.2Hz,1H),2.99(d,J=5.8Hz,3H),2.86(dd,J=17.7,6.4Hz,1H),2.21(s,3H); 13 C{ 1 H}NMR(100MHz,CDCl3)δ(ppm)198.65,165.00,162.35,138.47,132.44,126.95, 116.35,107.97,73.03,55.64,48.31,33.17,15.83; HRMS(APCI-TOF)m / z:[M+H] + Calcd for C 13 H 15 O4 + 235.0965; Found 235.0957.

[0104] The aryl carboxylic acid was obtained by using 3-methyl-4-methoxybenzoic acid (3-CH3,4-OCH3), and the resulting palladium-catalyzed synthesis of isocoumarin derivatives containing aldehyde groups yielded 55%.

[0105] The reaction principles, reaction conditions, and yields of each example in Examples 1-10 are shown in Table 1.

[0106] Table 1. Reaction principles, reaction conditions, and yields of Examples 1-10

[0107]

[0108] As shown in Table 1, the method of the present invention uses readily available raw materials, is simple and safe to operate, has a high yield, and is convenient for post-processing. Therefore, it has great implementation value and potential social and economic benefits.

[0109] The above description is merely an embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principle of the present invention should be included within the scope of the claims of the present invention.

Claims

1. A method for synthesizing isocoumarin derivatives containing aldehyde groups using palladium catalysis, characterized in that: The palladium-catalyzed synthesis of isocoumarin derivatives containing aldehyde groups is as follows: Wherein: In Formula I, R is a methoxy group; A palladium-catalyzed method for synthesizing isocoumarin derivatives containing aldehyde groups includes the following steps: Wherein: the compound with the structure of formula II is arylcarboxylic acid, and the compound with the structure of formula III is ethylene carbonate; The above-mentioned aryl carboxylic acid and ethylene carbonate were reacted in a sealed tube at 100 °C for 24 h using palladium acetate Pd(OAc)2 as a catalyst, potassium persulfate K2S2O8 as an oxidant, silver carbonate Ag2CO3 and 3Å MS as additives, 2-hydroxy-3-nitro-5-trifluoromethylpyridine as a ligand, and hexafluoroisopropanol as a reaction solvent. After the reaction was completed, the product was concentrated and purified by TLC on a thin-layer silica gel plate to obtain the palladium-catalyzed synthesis of isocoumarin derivatives containing aldehyde groups according to Formula I. The amount of palladium acetate Pd(OAc)2 used is 10% of the molar amount of arylformic acid; the amount of oxidant K2S2O8 used is 120% of the molar amount of arylformic acid; and the amount of silver carbonate Ag2CO3 used is 50% of the molar amount of arylformic acid.

2. The method for synthesizing isocoumarin derivatives containing aldehyde groups using palladium catalysis as described in claim 1, characterized in that, The method for synthesizing isocoumarin derivatives containing aldehyde groups using palladium catalysis is as follows: Add 0.1 mmol of arylcarboxylic acid and 0.15 mmol of ethylene carbonate to a pressure-resistant tube, followed by 0.01 mmol of palladium acetate, 0.12 mmol of potassium persulfate, 0.05 mmol of silver carbonate, 0.03 mmol of 2-hydroxy-3-nitro-5-trifluoromethylpyridine, 10 mg of 3Å MS, and then add 1 mL of hexafluoroisopropanol. Seal the tube and heat it at 100 °C for 24 hours. After the reaction was completed, the palladium-catalyzed isocoumarin derivative containing an aldehyde group was obtained by TLC on a thin-layer silica gel plate, concentration and purification. The molar ratio of the aryl carboxylic acid to the ethylene carbonate is 1:1.

5.

3. The method for synthesizing isocoumarin derivatives containing aldehyde groups using palladium catalysis as described in claim 2, characterized in that: The pressure-resistant tube is a 10 mL pressure-resistant tube equipped with a magnetic stir bar.

4. The method for synthesizing isocoumarin derivatives containing aldehyde groups using palladium catalysis as described in claim 2, characterized in that: The compound of 2-hydroxy-3-nitro-5-trifluoromethylpyridine is The amount of 2-hydroxy-3-nitro-5-trifluoromethylpyridine used is 30% of the molar amount of the arylcarboxylic acid.

5. The method for synthesizing isocoumarin derivatives containing aldehyde groups using palladium catalysis as described in claim 2, characterized in that: The concentration process includes diluting the reaction with 30 mL of ethyl acetate, filtering the solid, and removing the solvent by rotary evaporation under reduced pressure. The purification is carried out after the concentration process, and the purification is performed by separation and purification using a preparative plate. The developing solvent in the purification is a mixture of petroleum ether and ethyl acetate with a volume ratio of 4:1.

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