CN115894141A - Synthesis method of acylindene derivatives - Google Patents

Synthesis method of acylindene derivatives Download PDF

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CN115894141A
CN115894141A CN202211255386.1A CN202211255386A CN115894141A CN 115894141 A CN115894141 A CN 115894141A CN 202211255386 A CN202211255386 A CN 202211255386A CN 115894141 A CN115894141 A CN 115894141A
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acylindane
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CN115894141B (en
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严小威
张兴国
严文婧
张小红
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Wenzhou University
Hezhou University
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Hezhou University
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Abstract

The invention relates to a synthesis method of acylindene derivatives, which comprises the following steps: taking aryl cyclobutane and o-dihalogenated benzene as reaction substrates, palladium acetate as a catalyst, bis (2-diphenylphosphinophenyl) ether as a ligand, cesium carbonate as an alkali and ultra-dry toluene as a solvent, and dissolving the mixture in a solvent of 120 DEG o C was stirred to react for 8 hours under nitrogen atmosphere. The method has the advantages of simple and easily obtained raw materials and reaction stripThe method has the advantages of relatively mild components, wide substrate universality, novel preparation process, less pollution, low energy consumption and the like.

Description

Synthesis method of acylindene derivatives
Technical Field
The present invention relates to a process for the preparation of acylindane derivatives.
Background
Indene compounds are common structural skeletons in organic synthesis and are also important components of many medicines, natural products and functional materials. The core structure of many commercial drugs and materials on the market is indene alkyl compound. For example, novel tricyclic indene derivatives as melatonin receptor agonists (A)Journal of Medicinal Chem.2002, 454222-4239), which has certain metabolic stability, and can be used for treating insomnia and circadian rhythm disorder; the indene derivatives also play an important medical role as endothelin antagonists, such as peptide-leading new-generation non-peptide antagonists (Bioorganic & MedicinalChemistry, 2001, 9255-268); novel indane-1, 3-dione derivatives are effective modulators of tomato wilt disease: (Arabian Journal of Chemistry,2022, 15, 103731-103754). The indenedione derivative can be used as antiplatelet compound, has coagulation effect, and can be used for treating blood coagulation disorder and Alzheimer diseaseMini-Rev. Med. Chem. 2018, 18, 1321-1330). However, the methods for preparing acylindane derivatives are very limited, and cyclization reactions activated by a catalyst to catalyze C-H bonds are one of the important methods for synthesizing acylindane derivatives, for example, synthesis of acylindane derivatives by Heck coupling reaction or typical intramolecular Friedel-Crafts reaction.
The above method has the disadvantages of multi-step reaction, low economy, low yield, etc. Therefore, it is highly desirable to find general and convenient methods for constructing acylindane skeletons from readily available starting materials.
Disclosure of Invention
Aiming at the defects existing in the prior stage, the invention provides the synthesis method of the acyl indene alkane derivatives, which takes the aryl cyclobutane and the o-dihalogenated benzene as reaction raw materials, has simple technical process, high yield, less pollution, environmental protection and safety.
In order to achieve the purpose, the invention adopts the technical scheme that:
a synthetic method of acylindene derivatives comprises the following steps: taking aryl cyclobutane and o-dihalogenated benzene as reaction substrates, palladium acetate or palladium chloride as a catalyst, bis (2-diphenylphosphinophenyl) ether, triphenylphosphine or tricyclohexylphosphorus as ligands, cesium carbonate, potassium phosphate or potassium hydroxide as an alkali, ultra-dry toluene, ultra-dry N, N-dimethylformamide, ultra-dry N, N-dimethylacetamide or N-methylpyrrolidone as a solvent, and dissolving the solvent in 100-120 o C, stirring and reacting for 8-10 hours under the nitrogen atmosphere, wherein the chemical reaction formula is as follows:
Figure 708858DEST_PATH_IMAGE001
the-X is chlorine atom, bromine atom or iodine atom;
the-Ar is phenyl, 5, 6-benzo [ b ], [ 2 ]d][1,3]One of dioxolane, 5-chlorophenyl, 5-fluorophenyl, 5-methylphenyl and 5-trifluoromethylphenyl; wherein 5, 6-benzo [ b ], [ 2 ]d][1,3]The dioxolane has the formula:
Figure 210246DEST_PATH_IMAGE002
；
the R is one of a hydrogen atom and a phenyl;
the-R' is phenyl, 2-methylphenyl, 3, 5-dimethylphenyl, 4-tert-butylphenyl, 4-fluorophenyl, 4-chlorophenyl 4-bromophenyl, 4-methoxyphenyl, 3-trifluoromethylphenyl, 2-naphthyl, 5-benzo [ 2 ], [d][1,3]One of dioxolane and 2-thiophene; wherein the 2-naphthyl group is represented by:
Figure DEST_PATH_IMAGE003
5-benzo [ 2 ]d][1,3]The dioxolane has the formula: />
Figure 689769DEST_PATH_IMAGE004
The expression of 2-thiophene is: />
Figure DEST_PATH_IMAGE005
。
The preparation method adopted by the invention is that the acyl indene alkane derivatives are synthesized by the reaction of o-dihalogenated benzene and aryl cyclobutanol under the promotion of palladium acetate as a catalyst, bis (2-diphenylphosphinophenyl) ether as a ligand, cesium carbonate as an alkali and ultra-dry toluene as a solvent, the process is simple, special instruments or modes are not needed, the method is very suitable for operation of people in the field, and the method has the advantages of simple operation, easy product obtaining and the like.
In a further embodiment of the present invention, the catalyst is palladium acetate.
In a further embodiment of the present invention, the ligand is bis (2-diphenylphosphinophenyl) ether.
In a further embodiment of the invention, the base is cesium carbonate.
In a further embodiment of the present invention, the solvent is ultra-dry toluene.
The method can directly synthesize the target product without separating intermediate products, and can obtain the target product by a simple separation method, the yield can reach 93 percent at most, the process engineering is greatly simplified, the energy consumption is reduced, and the yield is excellent; in addition, the waste solution is less in the reaction process, and other polluted gases and liquid are not discharged, so that the method reduces the discharge of the waste solution, and has the advantages of protecting the environment and ensuring the health of operators; in addition, a series of acylindene alkane derivatives can be prepared, and the method has better substrate universality. Thus, the invention fills the blank of the method for preparing the acylindene derivatives at the present stage and promotes the development of the acylindene derivatives.
The mechanism of the invention is as follows: firstly, carrying out oxidation addition reaction on 1, 2-dibromobenzene and Pd (0) species to obtain an intermediate A, then carrying out ligand exchange on A and cyclobutanol anions with proton loss to obtain B, eliminating B through beta-C to obtain an alkyl palladium species C, carrying out reduction elimination on C, carrying out oxidation addition on C and Pd (0) to obtain a Pd (II) intermediate D, deprotonating under the action of alkali, carrying out ligand exchange again to obtain a cyclopalladium intermediate F, finally carrying out reduction elimination to obtain an indene ring compound, and regenerating Pd (0) species. Possible reaction mechanisms the chemical reaction formula is as follows:
Figure 923304DEST_PATH_IMAGE006
Detailed Description
The invention discloses a synthesis method of acylindene derivatives, which takes aryl cyclobutane and o-dihalogenated benzene as reaction substrates, palladium acetate or palladium chloride as catalysts, bis (2-diphenylphosphinophenyl) ether, triphenylphosphine or tricyclohexylphosphorus as ligands, cesium carbonate, potassium phosphate or potassium hydroxide as alkali, ultra-dry toluene, ultra-dry N, N-dimethylformamide, ultra-dry N, N-dimethylacetamide or N-methylpyrrolidone as solvent, and the reaction is carried out in 100-120 o C, stirring and reacting for 8-10 hours under the nitrogen atmosphere, wherein the chemical reaction formula is as follows:
Figure 347332DEST_PATH_IMAGE007
the-X is chlorine atom, bromine atom or iodine atom;
the group-Ar is phenyl, 5, 6-benzo [ 2 ]d][1,3]One of dioxolane, 5-chlorophenyl, 5-fluorophenyl, 5-methylphenyl and 5-trifluoromethylphenyl; wherein 5,6-benzo [ 2 ]d][1,3]The dioxolane is represented by the formula:
Figure 324516DEST_PATH_IMAGE008
；
the R is one of a hydrogen atom and a phenyl;
the-R' is phenyl, 2-methylphenyl, 3, 5-dimethylphenyl, 4-tert-butylphenyl, 4-fluorophenyl, 4-chlorophenyl 4-bromophenyl, 4-methoxyphenyl, 3-trifluoromethylphenyl, 2-naphthyl, 5-benzo [ 2 ], [d][1,3]One of dioxolane and 2-thiophene; wherein the 2-naphthyl group is represented by:
Figure 392966DEST_PATH_IMAGE009
5-benzo [ 2 ]d][1,3]The dioxolane has the formula: />
Figure 797402DEST_PATH_IMAGE010
2-thiophene meterThe expression is as follows: />
Figure 380830DEST_PATH_IMAGE011
。
After the reaction, filtration was performed, the filtrate was washed with a saturated sodium chloride solution, extracted with ethyl acetate and dried over anhydrous sodium sulfate, and the combined organic layers were subjected to rotary evaporation using a rotary evaporator to remove the solvent to obtain a residue. And (3) eluting the residue by a silica gel column by using an eluent prepared from ethyl acetate and petroleum ether according to a volume ratio (1).
The first embodiment is as follows: 2-bromochlorobenzene (0.2 mmol), 1-phenylcyclobutanol (0.2 mmol), palladium acetate (4.5 mg), bis (2-diphenylphosphinophenyl) ether (21.5 mg), cesium carbonate (130.3 mg) were added to extra dry toluene (2 mL) at 120 deg.C o The reaction was stirred under nitrogen for 8 hours. The reaction solution was filtered to obtain a filtrate and washed with a saturated sodium chloride solution, ethyl acetate was extracted and then dried over anhydrous sodium sulfate, and the filtrate was subjected to solvent removal using a rotary evaporator to obtain a residue, which was eluted through a silica gel column with an eluent prepared from ethyl acetate and petroleum ether at a volume ratio of 1. 1 H NMR (400 MHz, CDCl 3 ) δ 8.06 (d, J = 7.2 Hz, 2H), 7.60 (t, J = 7.2 Hz, 1H), 7.50 (t, J = 7.2 Hz, 2H), 7.27 (d, J = 7.2 Hz, 1H), 7.18 (t, J = 7.2 Hz, 1H), 7.11-7.04 (m, 2H), 5.04 (t, J = 7.2 Hz, 1H), 3.19-3.11 (m, 1H), 3.04-2.96 (m, 1H), 2.54-2.38 (m, 2H); 13 C NMR (125 MHz, CDCl 3 ) δ 200.4, 144.6, 141.4, 136.9, 133.1, 128.8, 128.7, 127.2, 126.2, 125.0, 124.7, 52.4, 31.9, 29.5。
The second embodiment is as follows: 1, 2-dibromobenzene (0.2 mmol) and 1-Phenylcyclobutanol (0.2 mmol), palladium acetate (4.5 mg), bis (2-diphenylphosphinophenyl) ether (21.5 mg), cesium carbonate (130.3 mg) were added to ultra-dry toluene (2 mL) at 120 o The reaction was stirred under nitrogen for 8 hours. The reaction solution was filtered to obtain a filtrate and washed with a saturated sodium chloride solution, ethyl acetate was extracted and then dried over anhydrous sodium sulfate, and the filtrate was subjected to solvent removal using a rotary evaporator to obtain a residue, which was eluted through a silica gel column with an eluent prepared from ethyl acetate and petroleum ether at a volume ratio of 1.
The third concrete embodiment: o-iodobromobenzene (0.2 mmol), 1-phenylcyclobutanol (0.2 mmol), palladium acetate (4.5 mg), bis (2-diphenylphosphinophenyl) ether (21.5 mg), cesium carbonate (130.3 mg) were added to ultra-dry toluene (2 mL) at 120 o The reaction was stirred under nitrogen for 8 hours. The reaction solution was filtered to obtain a filtrate and washed with a saturated sodium chloride solution, ethyl acetate was extracted and then dried over anhydrous sodium sulfate, and the filtrate was subjected to solvent removal using a rotary evaporator to obtain a residue, which was eluted through a silica gel column with an eluent prepared from ethyl acetate and petroleum ether at a volume ratio of 1.
The fourth concrete embodiment: 1, 2-dibromobenzene (0.2 mmol), 1-phenylcyclobutanol (0.2 mmol), palladium acetate (4.5 mg), bis (2-diphenylphosphinophenyl) ether (21.5 mg), cesium carbonate (130.3 mg) were added to extra dry toluene (2 mL) at 120 deg.C o And C, stirring and reacting for 10 hours in a nitrogen atmosphere. The reaction solution was filtered to obtain a filtrate and washed with a saturated sodium chloride solution, extracted with ethyl acetate and dried over anhydrous sodium sulfate, and the filtrate was subjected to solvent removal with a rotary evaporator to obtain a residue, which was passed through a silica gel column to prepare a reaction mixture by mixing ethyl acetate and petroleum ether in a volume ratio of 1Eluting the prepared eluent, collecting the effluent according to actual gradient, detecting by TLC, combining the effluent containing the target product, removing the solvent by rotating the combined effluent by a rotary evaporator, and drying in vacuum to obtain 35.1 mg of yellow oil drop (2, 3-dihydro-1H-inden-1-yl) (phenyl) ketone with the yield of 79 percent.
The fifth concrete embodiment: 1, 2-dibromobenzene (0.2 mmol), 1-phenylcyclobutanol (0.2 mmol), palladium acetate (4.5 mg), bis (2-diphenylphosphinophenyl) ether (21.5 mg), cesium carbonate (130.3 mg) were added to extra dry toluene (2 mL) at 100 o The reaction was stirred under nitrogen for 8 hours. The reaction solution was filtered to obtain a filtrate and washed with a saturated sodium chloride solution, ethyl acetate was extracted and then dried over anhydrous sodium sulfate, and the filtrate was subjected to solvent removal using a rotary evaporator to obtain a residue, which was eluted through a silica gel column with an eluent prepared from ethyl acetate and petroleum ether at a volume ratio of 1.
The sixth specific embodiment: 1, 2-dibromobenzene (0.2 mmol), 1- (o-tolyl) cyclobutane-1-ol (0.2 mmol), palladium acetate (4.5 mg), bis (2-diphenylphosphinophenyl) ether (21.5 mg), cesium carbonate (130.3 mg) were added to super-dry toluene (2 mL) at 120 deg.C o The reaction was stirred under nitrogen for 8 hours. The reaction solution was filtered to obtain a filtrate and washed with a saturated sodium chloride solution, ethyl acetate was extracted and then dried over anhydrous sodium sulfate, and the filtrate was subjected to solvent removal using a rotary evaporator to obtain a residue, which was eluted through a silica gel column with an eluent prepared from ethyl acetate and petroleum ether at a volume ratio of 1. 1 H NMR (400 MHz, CDCl 3 ) δ 7.67 (t, J = 7.6 Hz, 1H), 7.40 (q, J = 7.6 Hz, 1H), 7.35-7.25 (m, 3H), 7.20 (t, J = 7.6 Hz, 1H), 7.11-7.05 (m, 1H), 6.94 (t, J = 7.2 Hz, 1H), 4.89 (t, J = 8.0 Hz, 1H), 3.19-3.09 (m, 1H), 3.02-2.92 (m, 1H), 2.59-2.51 (m, 1H), 2.42-2.32 (m, 4H); 13 C NMR (125 MHz, CDCl 3 ) δ 204.4, 144.5, 140.9, 138.6, 138.1, 131.7, 130.9, 128.2, 127.3, 126.2, 125.6, 124.9, 124.8, 55.7, 31.8, 28.6, 20.7。
The seventh specific embodiment: 1, 2-dibromobenzene (0.2 mmol), 1- (3, 5-dimethylphenyl) cyclobutan-1-ol (0.2 mmol), palladium acetate (4.5 mg), bis (2-diphenylphosphinophenyl) ether (21.5 mg), cesium carbonate (130.3 mg) were added to super-dry toluene (2 mL) at 120 o The reaction was stirred under nitrogen for 8 hours. The reaction solution was filtered to obtain a filtrate and washed with a saturated sodium chloride solution, ethyl acetate was extracted and then dried over anhydrous sodium sulfate, and the filtrate was subjected to solvent removal using a rotary evaporator to obtain a residue, which was eluted through a silica gel column with an eluent prepared from ethyl acetate and petroleum ether at a volume ratio of 1. 1 H NMR (400 MHz, CDCl 3 ) δ 7.67-7.59 (m, 2H), 7.24-6.96 (m, 5H), 5.03 (t, J = 7.2 Hz, 1H), 3.18-3.07 (m, 1H), 3.03-2.88 (m, 1H), 2.52-2.35 (m, 8H); 13 C NMR (125 MHz, CDCl 3 ) δ 200.8, 144.6, 141.7, 138.3, 137.2, 134.8, 127.2, 126.6, 126.2, 124.9, 124.7, 52.3, 31.9, 29.6, 21.3, 21.2。
The eighth embodiment: 1, 2-dibromobenzene (0.2 mmol), 1- (4- (tert-butyl) phenyl) cyclobutan-1-ol (0.2 mmol), palladium acetate (4.5 mg), bis (2-diphenylphosphinophenyl) ether (21.5 mg), cesium carbonate (130.3 mg) were added to super-dry toluene (2 mL) at 120 o The reaction was stirred under nitrogen for 8 hours. Filtering the reaction solution to obtain filtrate, washing with saturated sodium chloride solution, extracting with ethyl acetate, drying with anhydrous sodium sulfate, removing solvent from the filtrate with rotary evaporator to obtain residue, passing the residue through silica gel column, eluting with ethyl acetate and petroleum etherEluting the eluent prepared from the product ratio of 1:60, collecting the effluent according to a practical gradient, detecting by TLC, combining the effluent containing the target product, removing the solvent by rotating the combined effluent by using a rotary evaporator, and drying in vacuum to obtain 40.6 mg of yellow oil drop (4- (tert-butyl) phenyl) (2, 3-dihydro-1H-inden-1-yl) ketone with the yield of 73%. 1 H NMR (400 MHz, CDCl 3 ) δ 8.02 (t, J = 6.2 Hz, 2H), 7.53 (t, J = 6.0 Hz, 2H), 7.32-7.26 (m, 1H), 7.20-7.18 (m, 1H), 7.10-7.08 (m, 2H), 5.03 (t, J = 6.4 Hz, 1H), 3.19-3.12 (m, 1H), 3.04-2.96 (m, 1H), 2.50-2.43 (m, 2H), 1.37 (s, 9H); 13 C NMR (125 MHz, CDCl 3 ) δ 200.1, 156.8, 144.6, 141.7, 134.3, 128.9, 127.2, 126.2, 125.6, 125.0, 124.7, 52.4, 35.1, 32.0, 31.1, 29.7。
The specific embodiment is nine: 1, 2-dibromobenzene (0.2 mmol), 1- (naphthalen-2-yl) cyclobutan-1-ol (0.2 mmol), palladium acetate (4.5 mg), bis (2-diphenylphosphinophenyl) ether (21.5 mg), cesium carbonate (130.3 mg) were added to super-dry toluene (2 mL) at 120 o The reaction was stirred under nitrogen for 8 hours. The reaction solution was filtered to obtain a filtrate and washed with a saturated sodium chloride solution, ethyl acetate was extracted and then dried over anhydrous sodium sulfate, and the filtrate was subjected to solvent removal using a rotary evaporator to obtain a residue, which was eluted through a silica gel column with an eluent prepared from ethyl acetate and petroleum ether at a volume ratio of 1. 1 H NMR (400 MHz, CDCl 3 ) δ 8.59 (s, 1H), 8.11 (d, J = 7.2 Hz, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.95-7.89 (m, 2H), 7.64-7.55 (m, 2H), 7.29 (d, J = 7.2 Hz, 1H), 7.21-7.17 (m, 1H), 7.10-7.05 (m, 2H), 5.21 (t, J = 7.2 Hz, 1H), 3.23-3.16 (m, 1H), 3.08-3.00 (m, 1H), 2.63-2.60 (m, 1H), 2.51-2.44 (m, 1H); 13 C NMR (125 MHz, CDCl 3 ) δ 200.3, 144.6, 141.5, 135.6, 134.4, 132.6, 130.6, 129.6, 128.6, 128.5, 127.8, 127.3, 126.8, 126.3, 125.0, 124.8, 124.6, 52.4, 32.0, 29.6。
The specific embodiment ten: 1, 2-dibromobenzene (0.2 mmol), 1- (4-methoxyphenyl) cyclobutan-1-ol (0.2 mmol), palladium acetate (4.5 mg), bis (2-diphenylphosphinophenyl) ether (21.5 mg), cesium carbonate (130.3 mg) were added to super-dry toluene (2 mL) at 120 o The reaction was stirred under nitrogen for 8 hours. The reaction solution was filtered to obtain a filtrate and washed with a saturated sodium chloride solution, ethyl acetate was extracted and then dried over anhydrous sodium sulfate, and the filtrate was subjected to solvent removal using a rotary evaporator to obtain a residue, which was eluted through a silica gel column with an eluent prepared from ethyl acetate and petroleum ether at a volume ratio of 1. 1 H NMR (400 MHz, CDCl 3 ) δ 8.10-8.04 (m, 2H), 7.32-7.25 (m, 1H), 7.23-7.15 (m, 1H), 7.13-6.96 (m, 4H), 5.02 (t, J = 7.2 Hz, 1H), 3.93 (s, 3H), 3.23-3.12 (m, 1H), 3.07-2.96 (m, 1H), 2.57-2.38 (m, 2H); 13 C NMR (125 MHz, CDCl 3 ) δ 199.0, 163.5, 144.6, 141.8, 131.2, 129.9, 127.2, 126.2, 124.9, 124.7, 113.8, 55.5, 52.1, 32.0, 29.6。
The concrete example eleven: 1, 2-dibromobenzene (0.2 mmol), 1- (3-methoxyphenyl) cyclobutan-1-ol (0.2 mmol), palladium acetate (4.5 mg), bis (2-diphenylphosphinophenyl) ether (21.5 mg), cesium carbonate (130.3 mg) were added to extra dry toluene (2 mL) at 120 deg.C o The reaction was stirred under nitrogen for 8 hours. Filtering the reaction solution to obtain a filtrate, washing the filtrate with saturated sodium chloride solution, extracting with ethyl acetate, drying with anhydrous sodium sulfate, removing the solvent from the filtrate by using a rotary evaporator to obtain a residue, eluting the residue through a silica gel column with an eluent prepared from ethyl acetate and petroleum ether according to a volume ratio of 1) 22.2 mg of methanone, 44% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 7.66 (d, J = 7.2 Hz, 1H), 7.57 (s, 1H), 7.46-7.41 (m, 1H), 7.28 (d, J = 7.6 Hz, 1H), 7.21-7.15 (m, 2H), 7.12-7.06 (m, 2H), 5.03 (t, J = 7.2 Hz, 1H), 3.86 (s, 3H), 3.20-3.13 (m, 1H), 3.05-2.97 (m, 1H), 2.55-2.39 (m, 2H); 13 C NMR (125 MHz, CDCl 3 ) δ 200.2, 159.9, 144.6, 141.4, 138.4, 129.6, 127.3, 126.3, 125.0, 124.8, 121.5, 119.6, 113.0, 52.6, 52.5, 32.0, 29.6。
The specific example twelve: 1, 2-dibromobenzene (0.2 mmol), 1- (benzo [ 2 ], ]d][1,3]Dioxolane) Cyclobutan-1-ol (0.2 mmol), palladium acetate (4.5 mg), bis (2-diphenylphosphinophenyl) ether (21.5 mg), cesium carbonate (130.3 mg) were added to ultra-dry toluene (2 mL) at 120 o The reaction was stirred under nitrogen for 8 hours. Filtering the reaction solution to obtain a filtrate, washing the filtrate with saturated sodium chloride solution, extracting with ethyl acetate, drying with anhydrous sodium sulfate, removing the solvent from the filtrate by using a rotary evaporator to obtain a residue, leaching the residue by using a silica gel column with an eluent prepared from ethyl acetate and petroleum ether according to a volume ratio of 1][1,3]Dioxolane (2, 3-dihydro-1H-inden-1-yl) methanone 40.0 mg, 75% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 7.69 (d, J = 7.6 Hz, 1H), 7.51 (s, 1H), 7.29-7.24 (m, 1H), 7.19-7.15 (m, 1H), 7.11-7.06 (m, 2H), 6.93-6.86 (m, 1H), 6.06 (s, 2H), 4.95 (t, J = 5.2 Hz, 1H), 3.18-3.10 (m, 1H), 3.02-2.95 (m, 1H), 2.51-2.38 (m, 2H); 13 C NMR (125 MHz, CDCl 3 ) δ 198.5, 151.8, 148.3, 144.6, 141.6, 131.8, 127.2, 126.2, 125.2, 124.9, 124.8, 108.6,, 107.9, 101.9, 52.1, 32.0, 29.7。
The specific example thirteen is as follows: 1, 2-dibromobenzene (0.2 mmol), 1- (thien-2-yl) cyclobutan-1-ol (0.2 mmol), palladium acetate (4.5 mg), bis (2-diphenylphosphinophenyl) ether (21.5 mg), cesium carbonate (130.3 mg) were added to super-dry toluene (2 mL) at 120 o Nitrogen under CThe reaction was stirred for 8 hours under an atmosphere. The reaction solution was filtered to obtain a filtrate and washed with a saturated sodium chloride solution, ethyl acetate was extracted and dried over anhydrous sodium sulfate, and the filtrate was subjected to solvent removal with a rotary evaporator to obtain a residue, which was eluted through a silica gel column with an eluent prepared from ethyl acetate and petroleum ether in a volume ratio of 1. 1 H NMR (400 MHz, CDCl 3 ) δ 7.86-7.83 (m, 1H), 7.73-7.72 (m, 1H), 7.33 (d, J = 7.2 Hz, 1H), 7.24-7.22 (m, 2H), 7.20-7.14 (m, 2H), 4.90 (t, J = 7.2 Hz, 1H), 3.28-3.20 (m, 1H), 3.10-3.02 (m, 1H), 2.63-2.44 (m, 2H); 13 C NMR (125 MHz, CDCl 3 ) δ 193.5, 144.6, 144.4, 141.4, 134.2, 132.6, 128.2, 127.4, 126.3, 124.81, 124.78, 54.1, 32.1, 29.8。
The specific embodiment fourteen: 1, 2-dibromobenzene (0.2 mmol), 1, 3-diphenylcyclobutan-1-ol (0.2 mmol), palladium acetate (4.5 mg), bis (2-diphenylphosphinophenyl) ether (21.5 mg), cesium carbonate (130.3 mg) were added to ultra-dry toluene (2 mL) at 120 deg.C o The reaction was stirred under nitrogen for 8 hours. Filtering the reaction liquid to obtain filtrate, washing the filtrate by saturated sodium chloride solution, extracting by ethyl acetate, drying by anhydrous sodium sulfate, removing the solvent from the filtrate by a rotary evaporator to obtain residue, eluting the residue by a silica gel column by using ethyl acetate and petroleum ether according to a volume ratio of 1. 1 H NMR (400 MHz, CDCl 3 ) δ 7.96 (d, J = 5.6 Hz, 2H), 7.56 (t, J = 6.4 Hz, 1H), 7.50-7.41 (m, 2H), 7.28-7.26 (m, 3H), 7.22-7.19 (m, 4H), 7.16-7.09 (m, 1H), 6.95-6.92 (m, 1H), 5.17 (t, J = 6.8 Hz, 1H), 4.27-4.22 (m, 1H), 3.62-3.52 (m, 1H), 3.28-3.18 (m, 1H); 13 C NMR (125 MHz, CDCl 3 ) δ 199.6, 144.2, 143.3, 141.2, 137.2, 133.3, 129.0, 128.7, 128.6, 127.6, 127.2, 126.7, 126.6, 124.7, 124.4, 60.4, 48.4, 40.3。
The specific embodiment fifteen: 2-bromo-4-chloro-1-iodobenzene (0.2 mmol), 1-phenylcyclobutanol (0.2 mmol), palladium acetate (4.5 mg), bis (2-diphenylphosphinophenyl) ether (21.5 mg), cesium carbonate (130.3 mg) were added to ultra-dry toluene (2 mL) at 120 deg.C o The reaction was stirred under nitrogen for 8 hours. The reaction solution was filtered to obtain a filtrate and washed with a saturated sodium chloride solution, ethyl acetate was extracted and then dried over anhydrous sodium sulfate, and the filtrate was subjected to solvent removal using a rotary evaporator to obtain a residue, which was eluted through a silica gel column with an eluent prepared from ethyl acetate and petroleum ether at a volume ratio of 1. 1 H NMR (500 MHz, CDCl 3 ) δ 8.05 (d, J = 9.0 Hz, 2H), 7.66-7.61 (m, 1H), 7.55-7.51 (m, 2H), 7.19-7.15 (m, 2H), 7.04 (s, 1H), 5.02 (t, J = 6.5 Hz, 1H), 3.14-3.07 (m, 1H), 3.00-2.92 (m, 1H), 2.51-2.45 (m, 2H); 13 C NMR (125 MHz, CDCl 3 ) δ 199.8, 143.4, 143.2, 136.7, 133.4, 132.0, 128.89, 128.85, 127.5, 125.7, 125.3, 52.3, 31.5, 30.2。
The specific embodiment is sixteen: 2-bromo-4-fluoro-1-iodobenzene (0.2 mmol), 1-phenylcyclobutanol (0.2 mmol), palladium acetate (4.5 mg), bis (2-diphenylphosphinophenyl) ether (21.5 mg), cesium carbonate (130.3 mg) were added to ultra-dry toluene (2 mL) at 120 deg.C o The reaction was stirred under nitrogen for 8 hours. Filtering the reaction solution to obtain filtrate, washing the filtrate by using saturated sodium chloride solution, extracting by using ethyl acetate, drying the ethyl acetate by using anhydrous sodium sulfate, removing the solvent from the filtrate by using a rotary evaporator to obtain residue, leaching the residue by using silica gel column by using eluent prepared by using ethyl acetate and petroleum ether according to the volume ratio of 1The combined effluent was subjected to rotary evaporation using a rotary evaporator to remove the solvent, and dried in vacuo to give 33.1 mg of yellow oil droplet (6-fluoro-2, 3-dihydro-1H-inden-1-yl) (phenyl) methanone in 69% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 8.07 (t, J = 7.2 Hz, 2H), 7.66 (t, J = 7.6 Hz, 1H), 7.56 (t, J = 7.6 Hz, 2H), 7.24-7.21 (m, 1H), 6.94-6.88 (m, 1H), 6.80-6.77 (m, 1H), 5.05 (t, J = 7.4 Hz, 1H), 3.17-3.10 (m, 1H), 3.03-2.95 (m, 1H), 2.56-2.51 (m, 2H); 13 C NMR (125 MHz, CDCl 3 ) δ 199.9, 162.8, 160.9 ( 1 J = 241.2 Hz), 143.4, 143.3 ( 3 J = 8.7 Hz), 140.0, 136.7, 133.4, 128.9, 125.6, 125.5 ( 3 J = 8.7 Hz), 114.4, 114.2 ( 2 J = 22.5 Hz), 112.3, 112.1 ( 2 J = 21.3 Hz), 52.5, 31.2, 30.3; 19 F NMR (470 MHz, CDCl 3 ) δ -117.044 (s, 1F)。
Specific example seventeen: 2-bromo-1-iodo-4- (trifluoromethyl) benzene (0.2 mmol), 1-phenylcyclobutanol (0.2 mmol), palladium acetate (4.5 mg), bis (2-diphenylphosphinophenyl) ether (21.5 mg), cesium carbonate (130.3 mg) were added to ultra-dry toluene (2 mL) at 120% o The reaction was stirred under nitrogen for 8 hours. The reaction solution was filtered to obtain a filtrate, which was washed with a saturated sodium chloride solution, extracted with ethyl acetate and then dried over anhydrous sodium sulfate, and the filtrate was subjected to solvent removal with a rotary evaporator to obtain a residue, which was eluted through a silica gel column with an eluent prepared from ethyl acetate and petroleum ether at a volume ratio of 1. 1 H NMR (500 MHz, CDCl 3 ) δ 8.06 (d, J = 7.5 Hz, 2H), 7.63 (t, J = 7.5 Hz, 1H), 7.54 (t, J = 7.5 Hz, 2H), 7.46 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.34 (s, 1H), 5.07 (t, J = 7.5 Hz, 1H), 3.21-3.15 (m, 1H), 3.08-3.02 (m, 1H), 2.58-2.53 (m, 1H), 2.51-2.44 (m, 1H); 13 C NMR (125 MHz, CDCl 3 ) δ 199.8, 148.9, 142.3, 136.5, 133.5, 129.1, 128.9, 128.8( 2 J = 31.3 Hz), 127.6, 125.5, 125.0, 124.6, 124.5( 3 J = 3.8 Hz), 123.3, 122.2, 122.1( 3 J = 3.8 Hz), 121.1( 1 J = 270.0 Hz), 52.2, 32.0, 30.2; 19 F NMR (470 MHz, CDCl 3 ) δ -61.938 (s, 3F)。
The specific embodiment eighteen: 1, 2-dibromo-4-toluene (0.2 mmol), 1-phenylcyclobutanol (0.2 mmol), palladium acetate (4.5 mg), bis (2-diphenylphosphinophenyl) ether (21.5 mg), and cesium carbonate (130.3 mg) were added to ultra-dry toluene (2 mL) at 120 deg.C o The reaction was stirred under nitrogen for 8 hours. The reaction solution was filtered to obtain a filtrate and washed with a saturated sodium chloride solution, the ethyl acetate was extracted and then dried over anhydrous sodium sulfate, and the filtrate was subjected to solvent removal by a rotary evaporator to obtain a residue, which was eluted through a silica gel column with an eluent prepared from ethyl acetate and petroleum ether at a volume ratio of 1. 1 H NMR (400 MHz, CDCl 3 ) δ 8.06-8.04 (m, 2H), 7.60-7.58 (m, 1H), 7.52-7.50 (m, 2H), 7.17-7.09 (m, 1H), 7.02-6.88 (m, 2H), 5.04-4.96 (m, 1H), 3.15-3.07 (m, 1H), 3.00-2.92 (m, 1H), 2.51-2.39 (m, 2H), 2.30 (s, 1.81H), 2.24 (s, 1.19H); 13 C NMR (125 MHz, CDCl 3 ) δ 200.8, 200.6, 144.9, 141.8, 141.7, 138.5, 137.1, 137.06, 136.0, 133.2, 133.1, 130.1, 129.0, 128.8, 128.7, 128.3, 128.2, 127.2, 125.7, 125.6, 124.8, 124.5, 52.4, 52.2, 31.9, 31.6, 30.2, 29.8, 21.3。
Nineteenth specific embodiment: 5,6-dibromo benzo [ 2 ]d][1,3]Dioxolane (0.2 mmol), 1-phenylcyclobutanol (0.2 mmol), palladium acetate (4.5 mg), bis (2-diphenylphosphinophenyl) ether (21.5 mg), cesium carbonate (130.3 mg) were added to ultra-dry toluene (2 mL) at 120 o C is belowThe reaction was stirred for 8 hours under nitrogen. Filtering the reaction solution to obtain filtrate, washing the filtrate with saturated sodium chloride solution, extracting with ethyl acetate, drying with anhydrous sodium sulfate, removing the solvent from the filtrate by using a rotary evaporator to obtain residue, leaching the residue by using a silica gel column with an eluent prepared from ethyl acetate and petroleum ether according to a volume ratio of 1d][1,3]Dioxolan-5-yl) (phenyl) methanone 25.6 mg, 48% yield. 1 H NMR (500 MHz, CDCl 3 ) δ 8.03 (d, J = 7.0 Hz, 2H), 7.60 (t, J = 6.5 Hz, 1H), 7.51 (t, J = 7.5 Hz, 2H), 6.72 (s, 1H), 6.52 (s, 1H), 5.88 (d, J = 11 Hz, 2H), 4.93 (t, J = 8.5 Hz, 1H), 3.09-3.00 (m, 1H), 2.94-2.85 (m, 1H), 2.51-2.41 (m, 2H); 13 C NMR (125 MHz, CDCl 3 ) δ 200.6, 147.3, 146.4, 137.6, 136.8, 133.8, 133.2, 128.8, 128.7, 105.5, 105.1, 101.0, 52.2, 31.8, 30.3。
In the embodiment of the invention, aryl cyclobutanol and o-dihalobenzene are taken as reaction substrates, palladium acetate is taken as a catalyst, bis (2-diphenylphosphinophenyl) ether is taken as a ligand, cesium carbonate is taken as an alkali, and ultra-dry toluene is taken as a solvent, and the reaction is carried out in the presence of a catalyst solution of 120 DEG C o C was stirred to react for 8 hours under nitrogen atmosphere. In the first to third examples, X is used as a variable, and the result proves that the effect is best when X is a bromine atom. The fourth embodiment takes the reaction time as a variable, and the result proves that the reaction has the best effect after eight hours. In the fourth embodiment, the reaction temperature is taken as a variable, and the reaction temperature is 120 DEG o The yield is highest at C. In the embodiments of six to thirteen, R' in the aryl cyclobutanol is substituted with various substituents as variables, and it is noted that when the substituent is methoxy, the yield of the product is greatly reduced. In the example, it is found that the reaction proceeds smoothly without being affected by steric hindrance, as shown by the results of the fourteen aryl cyclobutanols in which R is a variable. Fifteen to nineteen embodiments are those in which Ar in o-dihalobenzene is a variable, and an electron-withdrawing group or an electron-donating group is suitably attached to a benzene ring.
According to the invention, the intermediate product does not need to be separated, the target product can be directly synthesized by simple raw materials, the process is simplified, the energy consumption is low, the discharge of waste solution is reduced, the environmental pollution is reduced, and the yield reaches 93% at most; in the above embodiment, aryl cyclobutane and o-dihalogenated benzene containing different substituents are selected as reactants, and acylindene alkane derivatives can be prepared. The present invention is not limited to the above embodiments, and those skilled in the art can implement the present invention in other embodiments according to the disclosure of the present invention, or make simple changes or modifications on the design structure and idea of the present invention, and fall into the protection scope of the present invention.

Claims (7)

1. A synthetic method of acylindene derivatives comprises the following steps: taking aryl cyclobutane and o-dihalogenated benzene as reaction substrates, palladium acetate or palladium chloride as a catalyst, bis (2-diphenylphosphinophenyl) ether, triphenylphosphine or tricyclohexylphosphorus as ligands, cesium carbonate, potassium phosphate or potassium hydroxide as an alkali, ultra-dry toluene, ultra-dry N, N-dimethylformamide, ultra-dry N, N-dimethylacetamide or N-methylpyrrolidone as a solvent, and dissolving the solvent in 100-120 o C, stirring and reacting for 8-10 hours under the nitrogen atmosphere, wherein the chemical reaction formula is as follows:
Figure 204919DEST_PATH_IMAGE001
the-X is chlorine atom, bromine atom or iodine atom;
the group-Ar is phenyl, 5, 6-benzo [ 2 ]d][1,3]One of dioxolane, 5-chlorophenyl, 5-fluorophenyl, 5-methylphenyl and 5-trifluoromethylphenyl; wherein 5, 6-benzo [ b ], [ 2 ]d][1,3]The dioxolane has the formula:
Figure 883025DEST_PATH_IMAGE002
；
the R is one of a hydrogen atom and a phenyl;
the-R' is phenyl, 2-methylphenyl, 3, 5-dimethylphenyl, 4-tert-butylphenyl, 4-fluorophenyl, 4-chlorophenyl 4-bromophenyl, 4-methoxyphenyl, 3-trifluoromethylphenyl, 2-naphthyl, 5-benzo [ 2 ], [d][1,3]One of dioxolane and 2-thiophene; wherein the 2-naphthyl group is represented by the formula:
Figure 241850DEST_PATH_IMAGE003
5-benzo [ 2 ]d][1,3]The dioxolane has the formula: />
Figure 689012DEST_PATH_IMAGE004
The expression of 2-thiophene is: />
Figure 81947DEST_PATH_IMAGE005
。
2. The process for the synthesis of acylindane derivatives according to claim 1, wherein: the catalyst is palladium acetate.
3. The process for the synthesis of acylindane derivatives according to claim 1, wherein: the ligand is bis (2-diphenylphosphinophenyl) ether.
4. The process for the synthesis of acylindane derivatives according to claim 1, wherein: the base is cesium carbonate.
5. The process for the synthesis of acylindane derivatives according to claim 1, wherein: the solvent is ultra-dry toluene.
6. The method for synthesizing acylindane derivatives according to claim 1, wherein: the reaction temperature is 120 deg.C o C。
7. The process for the synthesis of acylindane derivatives according to claim 1, wherein: and filtering after the reaction is finished, washing the filtrate by using a saturated sodium chloride solution, extracting by using ethyl acetate, drying by using anhydrous sodium sulfate, carrying out rotary evaporation on the combined organic layers by using a rotary evaporator to remove the solvent to obtain a residue, carrying out column layer separation on the residue through a silica gel column, carrying out elution by using an eluent, collecting an effluent containing the target product, combining the effluent, and removing the solvent by vacuum concentration to obtain the target product.
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CN103351290A (en) * 2013-08-01 2013-10-16 扬州大学 Extraction purification method for two allelopathy activity secondary substances of ageratina adenophora sprengel
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