Synthesis of 1-methyl-4-(phenylethynyl)benzene by using a palladium-catalyzed tetrafluorothianthrene salt

Abstract

The invention discloses a novel method for synthesizing 1-methyl-4-(phenylethynyl)benzene by using palladium-catalyzed tetrafluorothianthrene salt. Under the action of AntPhos phosphine ligand and metal Pd(OAc)2, tetrafluorothianthrene salt is used as a novel coupling reagent to participate in the Sonogashira coupling reaction. The present invention uses Pd / AntPhos as a catalyst to efficiently synthesize 1-methyl-4-(phenylethynyl)benzene. Compared with the traditional method, the method has mild reaction conditions, high reaction activity, high yield, simple process, and good application and promotion value.

Description

Technical Field

[0001] The invention relates to a new method for synthesizing 1-methyl-4-(phenylethynyl)benzene by using palladium-catalyzed tetrafluorothianthrene salt, and belongs to the technical field of organic chemistry. Background Art

[0002] Transition metal-catalyzed cross-coupling reactions are one of the most effective methods for constructing carbon-carbon bonds in the field of modern organic synthesis and are widely used in the fields of medicinal chemistry, materials science, chemical raw materials, and biological sciences. The Sonogashira reaction is an important reaction for constructing carbon-carbon bonds. Substituted alkynes and conjugated alkynes are synthesized by constructing carbon-carbon bonds between terminal alkynes and aromatic or vinyl halides. It is a reaction of C-C bond formation between terminal alkynes and aromatic or vinyl halides using a palladium catalyst. It was first published in 1975 by three Japanese chemists at Osaka University, Sonogashira, Kenkichi, Yasuo Nimuda, and Nobue Hagiwara. The reaction can be carried out under mild conditions and has high reactivity and yield, which has attracted widespread attention. It has wide applications in the fields of total synthesis of natural products and drug synthesis. It has synthesized tazarotene, a drug for treating psoriasis and acne, and altinicline, a drug for treating Parkinson's disease by regulating dopamine and acetylcholine in the brain. It also includes the synthesis of Altinicline, a potential substance that can treat Parkinson's disease, Alzheimer's disease, Tourette's syndrome, schizophrenia and attention deficit disorder.

[0003] 1-Methyl-4-(phenylethynyl)benzene is an important organic compound with wide application value in the fields of material science, medicinal chemistry, luminescent materials and liquid crystal display. At present, the synthesis of this compound has several major defects: serious environmental pollution, waste of resources, low yield, complex process, etc.

[0004] Since thianthrene salts and tetrafluorothianthrene salts have the advantages of simple preparation, good stability in air, easy storage, better reaction activity and site selectivity, wide application range, etc., the present invention aims at the problems and defects existing in the prior art, and studies a new method for synthesizing biphenyl by using tetrafluorothianthrene salts catalyzed by phosphine ligands and palladium metal. The purpose of the present invention is to use thianthrene salts and tetrafluorothianthrene salts for Sonogashira coupling reaction, so as to provide a more convenient path for the construction of carbon-carbon bonds, and its mild reaction conditions and high yield make it have a good prospect for promotion and application. Summary of the invention

[0005] In view of the above problems and defects in the prior art, the present invention selects a highly efficient phosphine ligand to develop a catalyst with strong practicability, which is used in a new method for coupling a tetrafluorothianthrene salt with a reagent in the Sonogashira reaction.

[0006] In order to achieve the above-mentioned invention object, the technical solution adopted by the present invention is as follows:

[0007] Under the protection of N2, a certain amount of Pd(OAc)2, AntPhos and tetrahydrofuran are added to the reaction bottle, and stirred for a certain time. A certain amount of phenylacetylene is added to the reaction bottle and stirred thoroughly, and then a certain amount of tetrafluorothianthrene salt 1a is added, and then a certain amount of CuI and Et3N are added, the reaction bottle is sealed, and stirred for a certain time at 100°C. After the reaction is completed, ethyl acetate is extracted, the organic phase is washed with saturated sodium chloride, dried with anhydrous sodium sulfate for a certain time, filtered, and the solvent is recovered by vacuum distillation, separated and purified by silica gel column chromatography, and the eluent of the product color band is collected, and the solvent is recovered by vacuum distillation to obtain the target compound.

[0008] The structure of the novel coupling reagent tetrafluorothianthrene salt 1a used is as follows:

[0009] ;

[0010] The reaction results are as follows:

[0011] ;

[0012] The invention has the advantages of using phosphine ligand AntPhos and Pd(OAc)2 to catalyze the Sonogashira coupling reaction involving tetrafluorothianthrene salt, and the method has mild reaction conditions and high yield. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] Figure 1 :Tetrafluorothianthrene salt 1a 1 H NMR

[0014] Figure 2 :Tetrafluorothianthrene salt 1a 13 C NMR

[0015] Figure 3 :1-methyl-4-(phenylethynyl)benzene 2a 1 H NMR DETAILED DESCRIPTION

[0016] Example 1

[0017] (1) Tetrafluorothianthrene salt 1a was prepared using toluene as raw material in the presence of (CF3CO)2O and HBF4·OEt2.

[0018] ;

[0019] 0.63 mL of toluene (6 mmol, 3.0 equiv), 608 mg of 2,3,7,8-tetrafluorothianthrene-5-oxide (2 mmol, 1.0 equiv) and 8 mL of MeCN were placed in a 20 mL reaction bottle. The reaction bottle was placed in an ice-water bath and cooled to 0°C. 0.83 mL of (CF3CO)2O (6 mmol, 3.0 equiv) was added dropwise to the reaction bottle, and then 0.4 mL of HBF4·OEt2 (3 mmol, 1.5 equiv) was added dropwise. The mixture was stirred at 0°C for 1 hour, and then heated to 25°C and stirred for 3 hours. After the reaction is completed, 10 mL of DCM is added to the reaction bottle to dilute the reaction, and then 10 mL of saturated NaHCO3 is slowly added dropwise (stirred). After the reaction solution stops bubbling, a separatory funnel is used to separate the organic phase. The aqueous phase is extracted with 5 mL of dichloromethane each time, extracted three times, and the organic phases are combined. The organic phase is washed with 10 mL of 20% NaBF4 to separate the organic phase. The organic phase is dried with anhydrous Na2SO4 for 2 hours, filtered, and the solvent is recovered by distillation under reduced pressure. The residue is separated by silica gel column chromatography, dichloromethane: methanol = 5:1 as the eluent, and the eluent of the second band is collected. The solvent is recovered by distillation under reduced pressure to obtain a crude product, which is recrystallized with dichloromethane: ether = 1:20 to obtain 885.8 mg of a white solid, which is compound 1a, with a yield of 95%.

[0020] 1 H NMR (500MHz, DMSO-d6) δ8.90-8.85(m,2H),8.40-8.35(m,2H),7.38(dd,J=5.5Hz,5.5Hz,2H),7.26(dd,J=5.5Hz,6.0Hz,2H),2.34(s,3H).

[0021] 13 C NMR (126MHz, DMSO-d6) δ154.17(d,J=12.6Hz), 152.11(d,J=12.6Hz), 150.87(d,J=13.9Hz), 148.85(d,J=13.9Hz), 144.1 6,133.67-133.58(m),131.45,128.79,125.58(d,J=21.8Hz),120.90,120.23(d,J=21.8Hz),115.92-115.84(m),21.16.

[0022] (2) 1-Methyl-4-(phenylethynyl)benzene 2a was prepared using tetrafluorothianthrene salt 1a as raw material and a complex of Pd(OAc)2 and AntPhos as catalyst.

[0023] ;

[0024] Under N2 protection, 1.2 mg Pd(OAc)2 (5.0 mol%), 4 mg AntPhos (10.0 mol%) and 1 mL of tetrahydrofuran were added to a 4 mL reaction bottle and stirred for 5 minutes to allow the catalyst to be fully complexed. Then, 12.4 mg phenylacetylene (0.1217 mmol, 1.1 equiv) was added to the reaction bottle and stirred sufficiently. Then, 51.6 mg (0.1106 mmol, 1.0 equiv) of tetrafluorothianthrenium salt of toluene was added thereto. Finally, 6.32 mg of CuI (30 mol%) was added to the reaction bottle and 33.5 mg of triethylamine (0.3318 mmol, 3.0 equiv) was added dropwise. The vial was sealed and placed in an oil bath at 100°C for reaction for 12 hours. After the reaction is completed, the aqueous phase is extracted with 5 mL of ethyl acetate each time, extracted 3 times, the organic phases are combined, the organic phase is washed with an equal volume of saturated sodium chloride to separate the organic phase, the organic phase is dried with anhydrous Na2SO4 for two hours, filtered, and the solvent is recovered by distillation under reduced pressure. The residue is separated by silica gel column chromatography, petroleum ether is used as eluent, the first color band is collected, the solvent is recovered under reduced pressure to obtain impurities, and then petroleum ether: ethyl acetate = 100:1 is used as eluent, the eluent of the second band is collected, and the solvent is recovered by distillation under reduced pressure to obtain 20.4 mg of white solid, which is 1-methyl-4-(phenylethynyl)benzene 2a, with a yield of 96%. 1 H NMR (500MHz, CDCl3) δ7.52 (dd, J = 1.9, 1.5 Hz, 2H), 7.43 (d, J = 8.1 Hz, 2H), 7.33 (q, J = 5.8 Hz, 3H), 7.15 (d, J = 7.9 Hz, 2H), 2.37 (s, 3H).

Claims

1. A method for synthesizing 1-methyl-4-(phenylethynyl)benzene using a palladium-catalyzed tetrafluorothianthrene salt, characterized in that: Et3N is used as a base, and the phosphine ligand AntPhos and Pd(OAc)2 are used as catalysts to catalyze the Sonogashira coupling reaction of tetrafluorothianthrene salt 1a with phenylacetylene. The reaction formula is as follows: ； The specific process is as follows: under the protection of N2, a certain amount of Pd(OAc)2, AntPhos and tetrahydrofuran are added to a reaction bottle, and stirred for a certain time; a certain amount of phenylacetylene is added to the reaction bottle and stirred thoroughly, and then a certain amount of tetrafluorothianthrene salt 1a is added, and then a certain amount of CuI and Et3N are added, the reaction bottle is sealed, and stirred for a certain time at 100°C; after the reaction is completed, ethyl acetate is extracted, the organic phase is washed with saturated sodium chloride, dried with anhydrous sodium sulfate for a certain time, filtered, and the solvent is recovered by vacuum distillation, separated and purified by silica gel column chromatography, and the eluate of the product color band is collected, and the solvent is recovered by vacuum distillation to obtain the target compound; Among them, the molar ratio of Pd(0Ac)2 and phosphine ligand AntPhos is 1:2; The molar ratio of tetrafluorothiothianthrene salt 1a to phenylacetylene is 1:1.1; The molar ratio of Pd(0Ac)2 and tetrafluorothianthrene salt 1a is: 1:20; The molar ratio of Et3N and tetrafluorothianthrene salt 1a is: 1:3; CuI was used as a co-catalyst, and the molar ratio of tetrafluorothianthrene salt 1a to CuI was 1:3.

3.

2. A method for synthesizing 1-methyl-4-(phenylethynyl)benzene by palladium-catalyzed tetrafluorothianthrene salt as claimed in claim 1, characterized in that The solvent used in the reaction was tetrahydrofuran, and the dosage was 10 mL / mmol of compound 1a.

3. A method for synthesizing 1-methyl-4-(phenylethynyl)benzene by palladium-catalyzed tetrafluorothianthrene salt as claimed in claim 1, characterized in that , the reaction temperature is 100°C and the reaction time is 12 hours.

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