Method for efficiently synthesizing indanone compound

Abstract

The invention discloses a method for efficiently synthesizing an indanone compound, which comprises the following steps: sequentially adding benzamide and norbornene into a reaction container according to a molar ratio of 1: 2, then adding a solvent, then adding 10.0% of a catalyst Pd (PPh3) 2Cl2, 20.0% of a ligand PCy3, 300% of an oxidant Cu (OAc) 2, 200% of alkali K2CO3 and 100% of the molar weight of benzamide, reacting for 24 hours in 5 mL of toluene in an air atmosphere under the condition of 130 DEG C oil bath, cooling to room temperature, adding water, and reacting for 2 hours at the temperature of 120 DEG C to obtain the indanone compound. And extracting with ethyl acetate for three times, combining organic layers, concentrating under reduced pressure, and purifying the product by column chromatography to obtain the indanone compound. The reaction substrate is wide in source, commercially available, good in yield, good in selectivity, easy to separate and purify, less in pollution and simple in operation step, a coupling reaction among molecules of raw materials can be avoided, and the generated indanone compound is widely applicable to organic synthesis design of organic chemical reaction, bioactive intermediates, advanced materials and pesticides.

Description

Technical Field

[0001] The invention relates to the synthesis of organic matter, and in particular to a method for efficiently synthesizing indanone compounds. Background Art

[0002] Indone compounds have a wide range of applications in the following areas due to their unique biological, physical and chemical properties: 1. Indone compounds are important pharmaceutical intermediates and can be used in the synthesis of many drugs. Such as acetylcholinesterase inhibitors (AChE inhibitors) for Alzheimer's disease, topoisomerase I inhibitors (Indotecan LMP-400), Donepezil hydrochloride, Gallic acid indanone, Mangiferin xanthone and Camptothecin. 2. Indone compounds are also important intermediates in organic chemistry and are widely found in natural products. 3. Their derivatives are also widely used in polymers, advanced materials, pesticides and other fields. Indone compounds have broad application prospects and special biological activities, such as important physiological and pharmacological activities, and other biological activities such as anti-inflammatory and antibacterial. As a result, people's research on it has become more and more in-depth. The main methods for synthesizing indanone compounds are as follows: 1. Synthesis method of cyclization reaction of ortho-difunctional aromatic hydrocarbons (J.Org.Chem., 2002, 67, 9276, J.Am.Chem.Soc., 1999, 121, 3238, Org.Lett., 2005, 7, 3339, Org.Lett., 2006, 8, 2867, J.Am.Chem.Soc., 2007, 129, 5766, Org.Biomol.Chem., 2021, 19, 10210). This method mainly synthesizes indanone compounds by cyclization reaction of ortho-difunctional aromatic hydrocarbons and norbornene under transition metal catalysis conditions. The advantage of this method is that the synthetic route is simple, but the reaction conditions are relatively demanding. Generally, the substrate needs to be pre-functionalized in advance, and the method has poor tolerance to many functional groups, and the expansion of the substrate range is subject to certain restrictions. Therefore, the application of this synthetic route in organic synthesis is greatly limited. 2. Synthesis method of reaction of aryl halide with norbornene (Adv.Synth.Catal., 2004, 346, 1765, Chem.–Eur.J., 2020, 26, 12972, Adv.Synth.Catal., 2017, 359, 240). This method has good selectivity, but aryl acyl halide compounds are expensive, highly toxic, unstable and difficult to synthesize, which also limits the practical application of this method. 3. Directing group-assisted transition metal-catalyzed synthesis method (Org. Lett., 2019, 21, 1774, Org. Chem. Front., 2024, 11, 769). This method has the advantages of high efficiency and good functional group tolerance.Benzamide is a commercially available, stable, low-toxic chemical reagent, widely used in CH activation functionalization reactions. Compared with other reagents, benzamide has the advantages of commercial availability, low price, wide source, insensitivity to air and water, relatively stable properties, and easy storage. In recent years, indanone compounds have played an important role in the creation of new drugs, and the research on their synthesis methods has also made great progress.

[0003] In the past few years, directing group (DG)-assisted C-H activation has become an effective scheme for direct C-C bond formation, which has greatly attracted the interest of chemists. So far, some excellent strategies for achieving indanones through directing group-assisted transition metal-catalyzed ortho-C-H activation reactions have been developed. For example, in 2019, Chatani's group developed the use of 8-aminoquinoline as a pre-installed directing group to Ni(II)-catalyzed cyclization of aromatic amides with bicyclic olefins to produce indanone compounds (Org. Lett., 2019, 21, 1774). In 2024, Luo and colleagues described a synthetic strategy for indanones, namely, the direct cyclization of benzaldehyde with norbornene catalyzed by Pd, assisted by aniline as a monodentate transient directing group (Org. Chem. Front., 2024, 11, 769). At present, the Catellani reaction has become an increasingly useful method for the synthesis of polysubstituted aromatics and benzo-fused compounds. Catellani et al. first discovered this (Angew.Chem., Int.Ed.Engl.1997,36,119), and this reaction allows the ortho- and iso-position continuous functionalization of aryl halides (Nat.Chem.2015,7,863,Acc.Chem.Res.2016,49,1389,Chem.Rev.2019,119,7478,Chin.J.Chem.2021,39,1690,Acc.Chem.Res.2023,56,573). However, most of the methods that have been developed are limited to palladium (0)-catalyzed aryl halides Catellani-type CH functionalization and directing group-assisted palladium (II)-catalyzed aromatic compounds Catellani-type selective CH functionalization. So far, the method of using norbornene as a directing group-assisted palladium (II)-catalyzed aromatic cyclization reaction to obtain polycyclic compounds is still very insufficient. As is known to all, amides are widely used as directing groups in the field of organic synthesis (Org. Lett. 2024, 26, 2495, J. Org. Chem. 2016, 81, 12499, J. Org. Chem. 2012, 77, 3341), most of which focus on ortho-CH functionalization. Inspired by these, we believe that using amides as directing groups for ortho-CH bond activation of benzamides, followed by insertion of NBE derivatives, and then oxidative addition of metal centers to CN bonds can achieve a divergent synthesis of indanones by adjusting the chemical selectivity of NBE derivatives. Summary of the invention

[0004] In view of the problems existing in the existing methods for synthesizing indanone compounds, the present invention aims to provide a method for synthesizing indanone compounds which is simple to operate, has cheap raw materials and is efficient.

[0005] The technical solution adopted by the present invention is: a method for efficiently synthesizing indanone compounds, comprising the following steps:

[0006] Benzamide and norbornene were added to a reaction vessel in a molar ratio of 1:2, and the solvent was added at a ratio of 0.5mmol benzamide to 5mL of solvent. Then, catalyst Pd(PPh3)2Cl2, ligand PCy3, oxidant Cu(OAc)2, base K2CO3, and additive DABCO were added in amounts of 10.0%, 20.0%, 300%, 200%, and 100% of the molar amount of benzamide, respectively. 5mL of toluene was added, and the mixture was reacted under air atmosphere and oil bath conditions at 130°C for 24h. The mixture was cooled to room temperature, and water was added. The mixture was extracted three times with ethyl acetate. The organic layers were combined and concentrated under reduced pressure. The product was purified by column chromatography to obtain the product indanone compound.

[0007] The general reaction formula of the synthesis method is as follows:

[0008]

[0009] Indane compounds, the general chemical structure is as follows:

[0010]

[0011] Among them, R1 is hydrogen, methoxy, methyl, ethyl, tert-butyl, fluoro, chloro, trifluoromethyl, nitro; R2 is hydrogen, methoxy, methyl, chloro, trifluoromethyl, nitro; R2 is hydrogen or fluoro.

[0012] According to the above-mentioned synthesis method of indanone compound, the benzamide is replaced by 4-methoxybenzamide, 4-methylbenzamide, 4-ethylbenzamide, 4-tert-butylbenzamide, 4-fluorobenzamide, 4-chlorobenzamide, 4-trifluoromethylbenzamide, 4-nitrobenzamide, 3-methoxybenzamide, 3-methylbenzamide, 3-chlorobenzamide, 3-trifluoromethylbenzamide, 3-nitrobenzamide or 2-fluorobenzamide.

[0013] According to the above-mentioned synthesis method of indanone compound, the base is K2CO3, K3PO4 or t Bu OK.

[0014] According to the above-mentioned method for synthesizing indanone compounds, the solvent is toluene or acetonitrile.

[0015] According to the above-mentioned synthesis method of indanone compound, the column chromatography conditions are: 200-300 mesh silica gel column, and the eluent is petroleum ether and ethyl acetate in a volume ratio of 100:1.

[0016] The present invention adopts a method for efficiently synthesizing indanone compounds designed by the above technical scheme, which has the following beneficial effects:

[0017] 1. The present invention uses benzamide to replace the use of traditional raw materials ortho-difunctional aromatic hydrocarbons and halogenated aromatic hydrocarbon substrates, and the reaction operation is relatively simple; the reaction substrate is simple and has a wide source, and is suitable for benzamides substituted with various functional groups, and the electronic effect has little influence on the reaction;

[0018] 2. The reaction substrate of the present invention is cheap, has high yield, good selectivity, is easy to separate and purify, has little pollution, and has simple steps. The protection and deprotection synthesis steps of functional groups can be omitted. The target product indanone compound is widely applicable to organic intermediates, drug intermediates, advanced materials and pesticides in organic chemical reactions. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 The H NMR spectrum of Example 1 of the present invention is shown;

[0020] Figure 2 The NMR carbon spectrum of Example 1 of the present invention is shown;

[0021] Figure 3 The nuclear magnetic hydrogen spectrum of Example 2 of the present invention is shown;

[0022] Figure 4 The NMR carbon spectrum of Example 2 of the present invention is shown. DETAILED DESCRIPTION

[0023] The following is a detailed description of a method for efficiently synthesizing indanone compounds according to the present invention in conjunction with embodiments.

[0024] Example 1

[0025] A method for synthesizing 1,2,3,4,4a,9a-hexahydro-9H-1,4-methylfluorene-9-one (3a) comprises the following steps:

[0026] In a 25 mL Schlenk reaction tube, 0.5 mmol (60.5 mg) of benzamide and 1.0 mmol (94 mg) of norbornene were added, followed by 35.1 mg of bis(triphenylphosphine)palladium dichloride, 452.5 mg of anhydrous copper acetate, 138 mg of potassium carbonate, 112 mg of triethylenediamine, and 5 mL of toluene. The mixture was stirred at 130° C. for 24 hours. After the reaction (monitored by TLC), the mixture was cooled to room temperature, the reaction solution was filtered, and the organic layer was dried under reduced pressure using a rotary evaporator. Finally, the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 100: 1) to obtain 84 mg of the desired target product (3a) as a colorless oily liquid. After drying under vacuum conditions, the yield was calculated to be 85% and the purity was 99.9%. 1H NMR(500MHz, CDCl3, δppm) δ7.70(d,J=7.68Hz,1H),7.60(t,J=7.68Hz,1H),7.49( d,J=7.68Hz,1H),7.35(d,J=7.41Hz,1H),3.14(d,J=6.04Hz,1H),2.59(d,J=2.47 Hz,1H),2.49(d,J=6.04Hz,1H),2.40(d,J=2.74Hz,1H),1.75-1.65(m,2H),1.49- 1.43(m,1H),1.39-1.37(m,1H),0.93(d,J=10.43Hz,1H),0.79(d,J=10.43Hz,1H). 13 C{ 1 H}NMR (100MHz, CDCl3) δ208.9,157.2,139.0,134.9,127.4,126.1,123.1,55.8,48.0,41.2,40.3,32.2,28.8,28.6.

[0027] The general chemical structure of 1,2,3,4,4a,9a-hexahydro-9H-1,4-methylfluorene-9-one (3a) is:

[0028]

[0029] Example 2

[0030] A method for synthesizing (4aR, 9aS)-6-methoxy-1,2,3,4-4a,9a-hexahydro-9H-1,4-methanefluorene-9-one (3b) comprises the following steps:

[0031] In a 25 mL Schlenk reaction tube, 0.5 mmol (75.5 mg) of 4-methoxybenzamide and 1.0 mmol (94 mg) of norbornene were added, followed by 35.1 mg of bis(triphenylphosphine)palladium dichloride, 452.5 mg of anhydrous copper acetate, 138 mg of potassium carbonate, 112 mg of triethylenediamine, and 5 mL of toluene. The mixture was stirred at 130° C. for 24 hours. After the reaction (monitored by TLC), the mixture was cooled to room temperature, the reaction solution was filtered, and the organic layer was dried under reduced pressure using a rotary evaporator. Finally, the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 100: 1) to obtain 82 mg of the desired target product (3b) as a colorless oily liquid. After drying under vacuum conditions, the yield was calculated to be 72% and the purity was 99.9%. 1H NMR (500MHz, CDCl3, δppm) δ7.63 (d, J=8.51Hz, 1H), 6.90 (s, 1H), 6.87 (d, J= 8.51Hz,1H),3.88(s,3H),3.07(d,J=6.04Hz,1H),2.57(d,J=1.92Hz,1H),2. 47(d,J=6.04Hz,1H),2.39(s,1H),1.71-1.62(m,2H),1.42(d,J=9.88Hz,1H ), 1.36 (d, J = 9.88Hz, 1H), 0.94 (d, J = 10.70Hz, 1H), 0.83 (d, J = 10.43Hz, 1H). 13 C{ 1 H}NMR (100MHz, CDCl3) δ207.0,165.5,160.2,132.4,124.8,115.3,109.1,56.2,55.6,48.0,41.2,40.1,32.2,28.8,28.7.

[0032] The chemical structure of (4aR, 9aS)-6-methoxy-1,2,3,4-4a,9a-hexahydro-9H-1,4-methanefluorene-9-one (3b) is as follows:

[0033]

[0034] Example 3

[0035] A method for synthesizing (4aR, 9aS)-6-methyl-1,2,3,4-4a,9a-hexahydro-9H-1,4-methylfluorene-9-one (3c) comprises the following steps:

[0036] In a 25 mL Schlenk reaction tube, 0.5 mmol (67.5 mg) of 4-methylbenzamide and 1.0 mmol (94 mg) of norbornene were added, followed by 35.1 mg of bis(triphenylphosphine)palladium dichloride, 452.5 mg of anhydrous copper acetate, 138 mg of potassium carbonate, 112 mg of triethylenediamine, and 5 mL of toluene. The mixture was stirred at 130° C. for 24 hours. After the reaction (monitored by TLC), the mixture was cooled to room temperature, the reaction solution was filtered, and the organic layer was dried under reduced pressure using a rotary evaporator. Finally, the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 100: 1) to obtain 88 mg of the desired target product (3c) as a colorless oily liquid. After drying under vacuum conditions, the yield was calculated to be 83% and the purity was 99.9%. 1H NMR (500MHz, CDCl3, δppm) δ7.60(d,J=7.73Hz,1H),7.28(s,1H),7.16(d,J=7.73Hz,1H),3.08(d,J=5.76Hz,1H),2.58(s,1H),2.48(d,J=6.04 Hz,1H),2.44(s,3H),2.39(s,1H),1.69-1.63(m,2H),1.45-1.42(m,1H ),1.38-1.36(m,1H),0.93(d,J=10.70Hz,1H),0.81(d,J=10.43Hz,1H). 13 C{ 1 H}NMR (100MHz, CDCl3) δ208.4,157.8,146.1,136.8,128.7,126.5,123.0,56.0,47.8,41.2,40.2,32.2,28.9,28.7,22.1.

[0037] The chemical structure of (4aR, 9aS)-6-methyl-1,2,3,4-4a,9a-hexahydro-9H-1,4-methylfluorene-9-one (3c) is as follows:

[0038]

[0039] Example 4

[0040] A method for synthesizing (4aR, 9aS)-6-ethyl-1,2,3,4,4a,9a-hexahydro-9H-1,4-methanefluorene-9-one (3d), comprising the following steps:

[0041] In a 25 mL Schlenk reaction tube, 0.5 mmol (74.5 mg) of 4-ethylbenzamide and 1.0 mmol (94 mg) of norbornene were added, followed by 35.1 mg of bis(triphenylphosphine)palladium dichloride, 452.5 mg of anhydrous copper acetate, 138 mg of potassium carbonate, 112 mg of triethylenediamine, and 5 mL of toluene. The mixture was stirred at 130° C. for 24 hours. After the reaction (monitored by TLC), the mixture was cooled to room temperature, the reaction solution was filtered, and the organic layer was dried under reduced pressure using a rotary evaporator. Finally, the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 100: 1) to obtain 96 mg of the desired target product (3d) as a colorless oily liquid. After drying under vacuum conditions, the yield was calculated to be 85% and the purity was 99.9%. 1H NMR (500MHz, CDCl3, δppm) δ7.61(d,J=7.68Hz,1H),7.30(s,1H),7.18(d,J=7.68Hz,1H) ,3.09(d,J=5.76Hz,1H),2.73(dd,J=15.09Hz,7.68Hz,2H),2.58(d,J=2.47Hz,1H),2.4 7(d,J=6.04Hz,1H),2.39(d,J=3.02Hz,1H),1.70-1.62(m,2H),1.44-1.42(m,1H),1.38 -1.35(m,1H),1.28(d,J=7.68Hz,3H),0.93(d,J=10.43Hz,1H),0.81(d,J=10.43Hz,1H). 13 C{ 1 H}NMR (100MHz, CDCl3) δ208.4,157.8,152.3,137.0,127.6,125.1,123.1,56.1,47.9,41.2,40.2,32.2,29.3,28.9,28.7,15.2.

[0042] The chemical structure of (4aR, 9aS)-6-ethyl-1,2,3,4,4a,9a-hexahydro-9H-1,4-methanefluorene-9-one (3d) is as follows:

[0043]

[0044] Example 5

[0045] A method for synthesizing (4aR, 9aS)-6-(tert-butyl)-1,2,3,4,4a,9a-hexahydro-9H-1,4-methylfluorene-9-one (3e), comprising the following steps:

[0046] In a 25 mL Schlenk reaction tube, 0.5 mmol (88.5 mg) of 4-tert-butylbenzamide and 1.0 mmol (94 mg) of norbornene were added, followed by 35.1 mg of bis(triphenylphosphine)palladium dichloride, 452.5 mg of anhydrous copper acetate, 138 mg of potassium carbonate, 112 mg of triethylenediamine, and 5 mL of toluene. The mixture was stirred at 130° C. for 24 hours. After the reaction (monitored by TLC), the mixture was cooled to room temperature, the reaction solution was filtered, and the organic layer was dried under reduced pressure using a rotary evaporator. Finally, the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 100: 1) to obtain 112 mg of the desired target product (3e) as a colorless oily liquid. After drying under vacuum conditions, the yield was calculated to be 88% and the purity was 99.9%. 1H NMR (500MHz, CDCl3, δppm) δ7.63(d,J=8.23Hz,1H),7.48(s,1H),7.39(d,J=8.23 Hz,1H),3.10(d,J=6.04Hz,1H),2.58(d,J=2.74Hz,1H),2.58(d,J=2.47Hz,1H),2 .47(d,J=6.04Hz,1H),2.41(d,J=3.02Hz,1H),1.71-1.62(m,2H),1.45-1.43(m, 1H), 1.35 (s, 9H), 1.25 (s, 1H), 0.93 (d, J = 10.43Hz, 1H), 0.83 (d, J = 10.43Hz, 1H). 13 C{ 1 H}NMR (100MHz, CDCl3) δ208.5,159.1,157.6,136.7,125.2,122.7,122.5,56.1,48.1,41.2,40.2,35.5,32.2,31.2,28.9,28.7.

[0047] The chemical structure of (4aR, 9aS)-6-(tert-butyl)-1,2,3,4,4a,9a-hexahydro-9H-1,4-methylfluorene-9-one (3e) is as follows:

[0048]

[0049] Example 6

[0050] A method for synthesizing (4aR, 9aS)-6-fluoro-1,2,3,4-4a,9a-hexahydro-9H-1,4-methanefluorene-9-one (3f) comprises the following steps:

[0051] In a 25 mL Schlenk reaction tube, 0.5 mmol (69.5 mg) of 4-fluorobenzamide and 1.0 mmol (94 mg) of norbornene were added, followed by 35.1 mg of bis(triphenylphosphine)palladium dichloride, 452.5 mg of anhydrous copper acetate, 138 mg of potassium carbonate, 112 mg of triethylenediamine, and 5 mL of toluene. The mixture was stirred at 130° C. for 24 hours. After the reaction (monitored by TLC), the mixture was cooled to room temperature, the reaction solution was filtered, and the organic layer was dried under reduced pressure using a rotary evaporator. Finally, the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 100: 1) to obtain 76 mg of the desired target product (3f) as a colorless oily liquid. After drying under vacuum conditions, the yield was calculated to be 70% and the purity was 99.9%. 1H NMR (500MHz, CDCl3, δppm) δ8.52(s,1H),8.48-8.45(m,1H),7.68(d,J=8.46Hz,1H),3.26(d,J=5.96Hz,1H),2.67(d,J=2.69Hz,1H),2.64(d,J=6.15 Hz,1H),2.49(s,1H),1.78-1.74(m,1H),1.69-1.67(m,1H),1.54-1.52(m, 1H),1.43-1.41(m,1H),1.03(d,J=10.57Hz,1H),0.78(d,J=10.69Hz,1H). 13 C{ 1 H}NMR (100MHz, CDCl3) δ206.6,162.7,147.8,140.1,129.2,127.3,118.5,56.4,48.2,41.4,40.8,32.5,28.9,28.4.

[0052] The chemical structure of (4aR, 9aS)-6-fluoro-1,2,3,4-4a,9a-hexahydro-9H-1,4-methanefluorene-9-one (3f) is as follows:

[0053]

[0054] Example 7

[0055] A method for synthesizing (4aR, 9aS)-6-chloro-1,2,3,4,4a,9a-hexahydro-9H-1,4-methylfluorene-9-one (3g) comprises the following steps:

[0056] In a 25 mL Schlenk reaction tube, 0.5 mmol (77.5 mg) of 4-chlorobenzamide and 1.0 mmol (94 mg) of norbornene were added, followed by 35.1 mg of bis(triphenylphosphine)palladium dichloride, 452.5 mg of anhydrous copper acetate, 138 mg of potassium carbonate, 112 mg of triethylenediamine, and 5 mL of toluene. The mixture was stirred at 130° C. for 24 hours. After the reaction (monitored by TLC), the mixture was cooled to room temperature, the reaction solution was filtered, and the organic layer was dried under reduced pressure using a rotary evaporator. Finally, the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 100: 1) to obtain 90 mg of the desired target product (3 g) as a colorless oily liquid. After drying under vacuum conditions, the yield was calculated to be 78% and the purity was 99.9%. 1H NMR (500MHz, CDCl3, δppm) δ7.62 (d, J = 8.06Hz, 1H), 7.48 (s, 1H), 7.32 (d, J = 8. 06Hz,1H),3.11(d,J=5.97Hz,1H),2.59(d,J=2.99Hz,1H),2.50(d,J=6.27Hz, 1H),2.40(d,J=2.99Hz,1H),1.72-1.69(m,1H),1.66-1.62(m,1H),1.45-1.42 (m,1H),1.38-1.36(m,1H),0.96(d,J=10.75Hz,1H),0.79(d,J=10.75Hz,1H). 13 C{ 1 H}NMR (100MHz, CDCl3) δ207.3,158.6,141.4,137.5,128.2,126.4,124.3,56.0,47.7,41.2,40.4,32.2,28.8,28.5.

[0057] The chemical structure of (4aR, 9aS)-6-chloro-1,2,3,4,4a,9a-hexahydro-9H-1,4-methylfluorene-9-one (3g) is as follows:

[0058]

[0059] Example 8

[0060] A method for synthesizing (4aR, 9aS)-6-(trifluoromethyl)-1,2,3,4,4a,9a-hexahydro-9H-1,4-methylfluorene-9-one (3h), comprising the following steps:

[0061] In a 25 mL Schlenk reaction tube, 0.5 mmol (94.5 mg) of 4-trifluoromethylbenzamide and 1.0 mmol (94 mg) of norbornene were added, followed by 35.1 mg of bis(triphenylphosphine)palladium dichloride, 452.5 mg of anhydrous copper acetate, 138 mg of potassium carbonate, 112 mg of triethylenediamine, and 5 mL of toluene. The mixture was stirred at 130° C. for 24 hours. After the reaction (monitored by TLC), the mixture was cooled to room temperature, the reaction solution was filtered, and the organic layer was dried under reduced pressure using a rotary evaporator. Finally, the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 100: 1) to obtain 96 mg of the desired target product (3h) as a colorless oily liquid. After drying under vacuum conditions, the yield was calculated to be 72% and the purity was 99.9%. 1H NMR (500MHz, CDCl3, δppm) δ7.80 (d, J = 8.05Hz, 1H), 7.78 (s, 1H), 7.60 (d, J = 7. 95Hz,1H),3.21(d,J=5.99Hz,1H),2.63(d,J=2.79Hz,1H),2.57(d,J=6.09Hz, 1H),2.46(d,J=2.99Hz,1H),1.76-1.71(m,1H),1.68-1.65(m,1H),1.49-1.46 (m,1H),1.42-1.39(m,1H),0.99(d,J=10.63Hz,1H),0.78(d,J=10.63Hz,1H). 13 C{ 1 H}NMR (100MHz, CDCl3) δ207.9, 157.2, 141.6, 136.2 (d, J = 30.63Hz), 123.7 (d, J = 272.90Hz), 124.5 (q, J=3.75Hz), 123.7, 123.4 (q, J=3.75Hz), 56.0, 48.0, 41.3, 40.7, 32.3, 28.8, 28.5.

[0062] The chemical structure of (4aR, 9aS)-6-(trifluoromethyl)-1,2,3,4,4a,9a-hexahydro-9H-1,4-methylfluorene-9-one (3h) is as follows:

[0063]

[0064] Example 9

[0065] A method for synthesizing (4aR, 9aS)-6-nitro-1,2,3,4-4a,9a-hexahydro-9H-1,4-methanefluorene-9-one (3i), comprising the following steps:

[0066] In a 25 mL Schlenk reaction tube, 0.5 mmol (83 mg) of 4-nitrobenzamide and 1.0 mmol (94 mg) of norbornene were added, followed by 35.1 mg of bis(triphenylphosphine)palladium dichloride, 452.5 mg of anhydrous copper acetate, 138 mg of potassium carbonate, 112 mg of triethylenediamine, and 5 mL of toluene. The mixture was stirred at 130° C. for 24 hours. After the reaction (monitored by TLC), the mixture was cooled to room temperature, the reaction solution was filtered, and the organic layer was dried under reduced pressure using a rotary evaporator. Finally, the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 100: 1) to obtain 81 mg of the desired target product (3i) as a colorless oily liquid. After drying under vacuum conditions, the yield was calculated to be 67% and the purity was 99.9%. 1H NMR (500MHz, CDCl3, δppm) δ8.20(dd,J=6.95Hz,1.50Hz,1H),7.89(d,J=8.86Hz,1H),7.83(d,J=8.27Hz,1H),3.27(d,J=6.08Hz,1H),2.66-2.62(m,2H) ,2.50(d,J=3.65Hz,1H),1.78-1.74(m,1H),1.71-1.67(m,1H),1.53-1.48( m,1H),1.44-1.41(m,1H),1.03(d,J=10.82Hz,1H),0.77(d,J=10.70Hz,1H). 13 C{ 1 H} NMR (100MHz, CDCl3) δ207.1, 157.8, 152.1, 143.1, 133.4, 124.2 (q, J = 14.81Hz), 122.3 (q, J = 128.01Hz), 56.4, 48.0, 41.4, 40.9, 32.4, 28.7, 28.5.

[0067] The general chemical structure of (4aR, 9aS)-6-nitro-1,2,3,4-4a,9a-hexahydro-9H-1,4-methanefluorene-9-one (3i) is:

[0068]

[0069] Example 10

[0070] A method for synthesizing (4aR, 9aS)-7-methoxy-1,2,3,4-4a,9a-hexahydro-9H-1,4-methoxyfluorene-9-one (3j) comprises the following steps:

[0071] In a 25 mL Schlenk reaction tube, 0.5 mmol (75.5 mg) of 3-methoxybenzamide and 1.0 mmol (94 mg) of norbornene were added, followed by 35.1 mg of bis(triphenylphosphine)palladium dichloride, 452.5 mg of anhydrous copper acetate, 138 mg of potassium carbonate, 112 mg of triethylenediamine, and 5 mL of toluene. The mixture was stirred at 130° C. for 24 hours. After the reaction (monitored by TLC), the mixture was cooled to room temperature, the reaction solution was filtered, and the organic layer was dried under reduced pressure using a rotary evaporator. Finally, the crude product was purified by column chromatography (petroleum ether:ethyl acetate=100:1) to obtain 83 mg of the desired target product (3j) as a colorless oily liquid. After drying under vacuum conditions, the yield was calculated to be 73% and the purity was 99.9%. 1H NMR (500MHz, CDCl3, δppm) δ7.63(d,J=8.51Hz,1H),6.90-6.87(m,2H),3.88(s,3H),3.07(d,J=6.04Hz,1H),2.56(d,J=1.93Hz,1H),2.47( d,J=6.04Hz,1H),2.39(s,1H),1.71-1.62(m,2H),1.43-1.41(m,1H),1.37-1.35(m,1H),0.93(d,J=10.70Hz,1H),0.83(d,J=10.43Hz,1H). 13 C{ 1 H}NMR (100MHz, CDCl3) δ207.0,165.5,160.2,132.4,124.8,115.3,109.1,56.2,55.6,48.0,41.2,40.1,32.2,28.8,28.7.

[0072] The chemical structure of (4aR, 9aS)-7-methoxy-1,2,3,4-4a,9a-hexahydro-9H-1,4-methoxyfluorene-9-one (3j) is as follows:

[0073]

[0074] Embodiment 11

[0075] A method for synthesizing (4aR, 9aS)-7-methyl-1,2,3,4,4a,9a-hexahydro-9H-1,4-methanefluorene-9-one (3k) comprises the following steps:

[0076] In a 25 mL Schlenk reaction tube, 0.5 mmol (67.5 mg) of 3-methylbenzamide and 1.0 mmol (94 mg) of norbornene were added, followed by 35.1 mg of bis(triphenylphosphine)palladium dichloride, 452.5 mg of anhydrous copper acetate, 138 mg of potassium carbonate, 112 mg of triethylenediamine, and 5 mL of toluene. The mixture was stirred at 130° C. for 24 hours. After the reaction (monitored by TLC), the mixture was cooled to room temperature, the reaction solution was filtered, and the organic layer was dried under reduced pressure using a rotary evaporator. Finally, the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 100: 1) to obtain 72 mg of the desired target product (3k) as a colorless oily liquid. After drying under vacuum conditions, the yield was calculated to be 68% and the purity was 99.9%. 1H NMR (500MHz, CDCl3, δppm) δ7.50(s,1H),7.42(d,J=7.91Hz,1H),7.37(d,J=7.54Hz,1H),3.09(d,J=5.65Hz,1H),2.58(s,1H),2.48(d,J =6.03Hz,1H),2.39(s,4H),1.70-1.67(m,2H),1.44-1.42(m,1H),1.38-1.35(m,1H),0.92(d,J=10.55Hz,1H),0.79(d,J=10.55Hz,1H). 13 C{ 1 H}NMR (100MHz, CDCl3) δ209.0,154.7,139.2,137.3,136.2,125.8,123.1,56.2,47.7,41.2,40.3,32.1,28.8,28.6,21.1.

[0077] The chemical structure of (4aR, 9aS)-7-methyl-1,2,3,4,4a,9a-hexahydro-9H-1,4-methanefluorene-9-one (3k) is as follows:

[0078]

[0079] Example 12

[0080] A method for synthesizing (4aR, 9aS)-7-chloro-1,2,3,4,4a,9a-hexahydro-9H-1,4-methylfluorene-9-one (3l) comprises the following steps:

[0081] In a 25 mL Schlenk reaction tube, 0.5 mmol (77.5 mg) of 3-chlorobenzamide and 1.0 mmol (94 mg) of norbornene were added, followed by 35.1 mg of bis(triphenylphosphine)palladium dichloride, 452.5 mg of anhydrous copper acetate, 138 mg of potassium carbonate, 112 mg of triethylenediamine, and 5 mL of toluene. The mixture was stirred at 130° C. for 24 hours. After the reaction (monitored by TLC), the mixture was cooled to room temperature, the reaction solution was filtered, and the organic layer was dried under reduced pressure using a rotary evaporator. Finally, the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 100: 1) to obtain 85 mg of the desired target product (3l) as a colorless oily liquid. After drying under vacuum conditions, the yield was calculated to be 73% and the purity was 99.9%. 1H NMR (500MHz, CDCl3, δppm) δ7.65 (d, J=1.89Hz, 1H), 7.55 (dd, J=8.14Hz, 2.01H z,1H),7.43(d,J=8.03Hz,1H),3.11(d,J=5.90Hz,1H),2.59(d,J=3.31Hz,1H) ,2.52(d,J=5.90Hz,1H),2.39(d,J=2.42Hz,1H),1.72-1.66(m,2H),1.45-1.4 2(m,1H),1.39-1.36(m,1H),0.96(d,J=10.58Hz,1H),0.78(d,J=10.58Hz,1H). 13 C{ 1 H}NMR (100MHz, CDCl3) δ207.5,155.2,140.5,134.9,133.8,127.4,123.0,56.3,47.6,41.2,40.5,32.2,28.8,28.5.

[0082] The chemical structure of (4aR, 9aS)-7-chloro-1,2,3,4,4a,9a-hexahydro-9H-1,4-methylfluorene-9-one (3l) is as follows:

[0083]

[0084] Embodiment 13

[0085] A method for synthesizing (4aR, 9aS)-7-(trifluoromethyl)-1,2,3,4,4a,9a-hexahydro-9H-1,4-methylfluorene-9-one (3m) comprises the following steps:

[0086] In a 25 mL Schlenk reaction tube, 0.5 mmol (94.5 mg) of 3-trifluoromethylbenzamide and 1.0 mmol (94 mg) of norbornene were added, followed by 35.1 mg of bis(triphenylphosphine)palladium dichloride, 452.5 mg of anhydrous copper acetate, 138 mg of potassium carbonate, 112 mg of triethylenediamine, and 5 mL of toluene. The mixture was stirred at 130° C. for 24 hours. After the reaction (monitored by TLC), the mixture was cooled to room temperature, the reaction solution was filtered, and the organic layer was dried under reduced pressure using a rotary evaporator. Finally, the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 100: 1) to obtain 93 mg of the desired target product (3m) as a colorless oily liquid. After drying under vacuum conditions, the yield was calculated to be 70% and the purity was 99.9%. 1H NMR (500MHz, CDCl3, δppm) δ7.96 (s, 1H), 7.83 (d, J = 7.88Hz, 1H), 7.63 (d, J = 8. 06Hz,1H),3.21(d,J=5.96Hz,1H),2.62(d,J=2.80Hz,1H),2.56(d,J=6.13Hz, 1H),2.44(d,J=3.33Hz,1H),1.74-1.71(m,1H),1.69-1.65(m,1H),1.49-1.46 (m,1H),1.41-1.38(m,1H),0.98(d,J=10.51Hz,1H),0.77(d,J=10.69Hz,1H). 13 C{ 1 H}NMR(100MHz, CDCl3)δ207.5,160.2,139.4,131.3(q,J=3.35Hz),130.1(d,J=32.00Hz),12 6.9, 123.8 (d, J = 272.01Hz), 120.4 (q, J = 3.98Hz), 56.0, 48.1, 41.3, 40.6, 32.3, 28.8, 28.5.

[0087] The chemical structure of (4aR, 9aS)-7-(trifluoromethyl)-1,2,3,4,4a,9a-hexahydro-9H-1,4-methylfluorene-9-one (3m) is as follows:

[0088]

[0089] Embodiment 14

[0090] A method for synthesizing (4aR, 9aS)-7-nitro-1,2,3,4-4a,9a-hexahydro-9H-1,4-methanefluorene-9-one (3n), comprising the following steps:

[0091] In a 25 mL Schlenk reaction tube, 0.5 mmol (83 mg) of 3-nitrobenzamide and 1.0 mmol (94 mg) of norbornene were added, followed by 35.1 mg of bis(triphenylphosphine)palladium dichloride, 452.5 mg of anhydrous copper acetate, 138 mg of potassium carbonate, 112 mg of triethylenediamine, and 5 mL of toluene. The mixture was stirred at 130° C. for 24 hours. After the reaction (monitored by TLC), the mixture was cooled to room temperature, the reaction solution was filtered, and the organic layer was dried under reduced pressure using a rotary evaporator. Finally, the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 100: 1) to obtain 68 mg of the desired target product (3n) as a colorless oily liquid. After drying under vacuum conditions, the yield was calculated to be 56% and the purity was 99.9%. 1H NMR (500MHz, CDCl3, δppm) δ7.70 (dd, J=8.48Hz, 5.48Hz, 1H), 7.14 (dd, J=8.48Hz, 1.94H z,1H),7.43(td,J=8.66Hz,2.12Hz,1H),3.12(d,J=6.01Hz,1H),2.59(d,J=3.18Hz,1H) ,2.52(d,J=6.18Hz,1H),2.40(d,J=3.36Hz,1H),1.73-1.70(m,1H),1.66-1.63(m,1H), 1.45-1.43(m,1H),1.39-1.36(m,1H),0.97(d,J=10.60Hz,1H),0.81(d,J=10.60Hz,1H). 13 C{ 1 H}NMR(100MHz, CDCl3)δ206.9,167.4(d,J=261.62Hz),160.1(d,J=9.77Hz),135.5,125.4(d,J=10.28Hz ), 115.7 (d, J = 24.16Hz), 112.6 (d, J = 22.10Hz), 56.1, 47.8 (d, J = 2.03Hz), 41.2, 40.3, 32.2, 28.8, 28.6.

[0092] The chemical structure of (4aR, 9aS)-7-nitro-1,2,3,4-4a,9a-hexahydro-9H-1,4-methanefluorene-9-one (3n) is as follows:

[0093]

[0094] Embodiment 15

[0095] A method for synthesizing (4aR, 9aS)-8-fluoro-1,2,3,4-4a,9a-hexahydro-9H-1,4-methanefluorene-9-one (3o) comprises the following steps:

[0096] In a 25 mL Schlenk reaction tube, 0.5 mmol (69.5 mg) of 2-fluorobenzamide and 1.0 mmol (94 mg) of norbornene were added, followed by 35.1 mg of bis(triphenylphosphine)palladium dichloride, 452.5 mg of anhydrous copper acetate, 138 mg of potassium carbonate, 112 mg of triethylenediamine, and 5 mL of toluene. The mixture was stirred at 130° C. for 24 hours. After the reaction (monitored by TLC), the mixture was cooled to room temperature, the reaction solution was filtered, and the organic layer was dried under reduced pressure using a rotary evaporator. Finally, the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 100: 1) to obtain 87 mg of the desired target product (3o) as a colorless oily liquid. After drying under vacuum conditions, the yield was calculated to be 81% and the purity was 99.9%. 1 H NMR (500MHz, CDCl3, δppm) δ7.58-7.53(m,1H),7.25(d,J=3.10Hz,1H),6.94(t,J=8.74Hz,1H),3.14(d,J=6.06Hz,1H),2.62(d,J=2.11Hz,1H),2.50( d,J=6.06Hz,1H),2.40(d,J=2.40Hz,1H),1.65-1.62(m,2H),1.44-1.41(m ,1H),1.37-1.35(m,1H),0.97(d,J=10.87Hz,1H),0.87(d,J=10.25Hz,1H). 13 C{ 1 H}NMR (100MHz, CDCl3) δ205.2, 159.7 (d, J = 25.14Hz), 157.2, 136.8 (d, J = 8.21Hz), 126. 8,121.9(d,J=4.33Hz),114.2(d,J=19.51Hz),56.2,48.0,41.5,40.6,32.2,28.8,28.5.

[0097] The general chemical structure of (4aR, 9aS)-8-fluoro-1,2,3,4-4a,9a-hexahydro-9H-1,4-methanefluorene-9-one (3o) is:

[0098]

Claims

1. A method for efficiently synthesizing an indanone compound, characterized in that The following steps are involved: Benzamide and norbornene were added to a reaction vessel in a molar ratio of 1:2, and the solvent was added at a ratio of 0.5mmol benzamide to 5mL of solvent. Then, catalyst Pd(PPh3)2Cl2, ligand PCy3, oxidant Cu(OAc)2, base K2CO3, and additive DABCO were added in amounts of 10.0%, 20.0%, 300%, 200%, and 100% of the molar amount of benzamide, respectively. 5mL of toluene was added, and the mixture was reacted under air atmosphere and oil bath conditions at 130°C for 24h. The mixture was cooled to room temperature, and water was added. The mixture was extracted three times with ethyl acetate. The organic layers were combined and concentrated under reduced pressure. The product was purified by column chromatography to obtain the product indanone compound. The general reaction formula of the synthesis method is as follows: Indane compounds, the general chemical structure is as follows: Among them, R1 is hydrogen, methoxy, methyl, ethyl, tert-butyl, fluoro, chloro, trifluoromethyl, nitro; R2 is hydrogen, methoxy, methyl, chloro, trifluoromethyl, nitro; R2 is hydrogen or fluoro.

2. The method for efficiently synthesizing an indanone compound according to claim 1, characterized in that The benzamide is replaced by 4-methoxybenzamide, 4-methylbenzamide, 4-ethylbenzamide, 4-tert-butylbenzamide, 4-fluorobenzamide, 4-chlorobenzamide, 4-trifluoromethylbenzamide, 4-nitrobenzamide, 3-methoxybenzamide, 3-methylbenzamide, 3-chlorobenzamide, 3-trifluoromethylbenzamide, 3-nitrobenzamide or 2-fluorobenzamide.

3. A method for efficiently synthesizing indanone compounds according to claim 1, characterized in that The base is K2CO3, K3PO4 or t Bu OK.

4. The method for efficiently synthesizing indanone compounds according to claim 1, characterized in that The solvent is toluene or acetonitrile.

5. The method for efficiently synthesizing indanone compounds according to claim 1, characterized in that The column chromatography conditions are: 200-300 mesh silica gel column, and the eluent is petroleum ether and ethyl acetate in a volume ratio of 100:1.

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