CN118005476A - Synthesis of 1-methyl-4-(phenylethynyl)benzene by using a palladium-catalyzed tetrafluorothianthrene salt - Google Patents

Abstract

The invention discloses a novel method for synthesizing 1-methyl-4- (phenylethynyl) benzene by using palladium to catalyze 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 Sonogashira coupling reaction. The invention uses Pd/AntPhos as a catalyst to efficiently synthesize the 1-methyl-4- (phenylethynyl) benzene. Compared with the traditional method, the method has the advantages of mild reaction conditions, high reaction activity, high yield, simple and convenient process and good application and popularization values.

Description

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

Technical Field

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 technique

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 palladium-catalyzed C-C bond formation reaction between terminal alkynes and aromatic or vinyl halides. It was first published in 1975 by three Japanese chemists, Sonogashira, Kenkichi, Yasuo Nimuda, and Nobue Hagiwara, at Osaka University. 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.

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.

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 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

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.

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

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, and 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.

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

The reaction results are as follows:

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.

Description of the drawings:

Figure 1: ¹ H NMR of tetrafluorothianthrene salt 1a

Figure 2: ¹³ C NMR of tetrafluorothianthrene salt 1a

Figure 3: ¹ H NMR of 1-methyl-4-(phenylethynyl)benzene 2a

Detailed ways

Example 1

(1) Tetrafluorothianthrene salt 1a was prepared using toluene as raw material in the presence of (CF ₃ CO) ₂ O and HBF ₄ ·OEt ₂ .

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 (CF ₃ CO) ₂ O (6 mmol, 3.0 equiv) was added dropwise to the reaction bottle, and then 0.4 mL of HBF ₄ ·OEt ₂ (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 was completed, 10 mL of DCM was added to the reaction bottle to dilute the reaction, and then 10 mL of saturated NaHCO ₃ was slowly added dropwise (stirred). After the reaction solution stopped bubbling, a separatory funnel was used to separate the organic phase. The aqueous phase was extracted with 5 mL of dichloromethane each time, and the extraction was repeated three times. The organic phases were combined, and the organic phase was washed with 10 mL of 20% NaBF ₄ to separate the organic phase. The organic phase was dried with anhydrous Na ₂ SO ₄ for 2 hours, filtered, and the solvent was recovered by distillation under reduced pressure. The residue was separated by silica gel column chromatography, with dichloromethane: methanol = 5:1 as the eluent. The eluent of the second band was collected, and the solvent was recovered by distillation under reduced pressure to obtain a crude product, which was recrystallized with dichloromethane: ether = 1:20 to obtain 885.8 mg of a white solid, which was compound 1a, with a yield of 95%.

¹ H NMR (500 MHz, DMSO-d6) δ 8.90-8.85 (m, 2H), 8.40-8.35 (m, 2H), 7.38 (dd, J = 5.5 Hz, 5.5 Hz, 2H), 7.26 (dd, J = 5.5 Hz, 6.0 Hz, 2H), 2.34 (s, 3H).

¹³ C NMR (126 MHz, DMSO-d6) δ 154.17 (d, J = 12.6 Hz), 152.11 (d, J = 12.6 Hz), 150.87 (d, J = 13.9 Hz), 148.85 (d, J = 13.9 Hz), 144.16, 133.67-133.58 (m), 131.45, 128.79, 125.58 (d, J = 21.8 Hz), 120.90, 120.23 (d, J = 21.8 Hz), 115.92-115.84 (m), 21.16.

(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.

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 was completed, the aqueous phase was extracted with 5 mL of ethyl acetate each time for 3 times, the organic phases were combined, the organic phases were washed with an equal volume of saturated sodium chloride to separate the organic phase, the organic phase was dried with anhydrous Na ₂ SO ₄ for 2 hours, filtered, and the solvent was recovered by vacuum distillation. The residue was separated by silica gel column chromatography, petroleum ether was used as eluent, the first color band was collected, the solvent was recovered by vacuum distillation to obtain impurities, and then petroleum ether: ethyl acetate = 100: 1 was used as eluent, the eluent of the second band was collected, and the solvent was recovered by vacuum distillation to obtain 20.4 mg of white solid, which was 1-methyl-4-(phenylethynyl)benzene 2a, with a yield of 96%. ¹ H NMR (500MHz, CDCl ₃ )δ7.52(dd, J＝1.9,1.5Hz,2H),7.43(d, J＝8.1Hz,2H),7.33(q, J＝5.8Hz,3H),7.15(d, J＝7.9Hz,2H),2.37(s,3H).

Claims (8)

1. A method for synthesizing 1-methyl-4-(phenylethynyl)benzene from tetrafluorothianthrene salt catalyzed by palladium, characterized in that: Et ₃ N is a base, phosphine ligand AntPhos and Pd(OAc) ₂ are catalysts, catalyzing the Sonogashira coupling reaction of tetrafluorothianthrene salt 1a and phenylacetylene, and the reaction formula is as follows: 2. A palladium-catalyzed synthesis of 1-methyl-4-(phenylethynyl)benzene by tetrafluorothianthrene salt, characterized in that during the reaction as claimed in claim 1, the molar ratio of Pd(OAc) ₂ and the phosphine ligand AntPhos is 1:2. 3. A palladium-catalyzed synthesis of 1-methyl-4-(phenylethynyl)benzene using a tetrafluorothianthrene salt, characterized in that during the reaction as described in claim 1, the molar ratio of the tetrafluorothianthrene salt 1a to the phenylacetylene substance is 1:1.1. 4. A palladium-catalyzed synthesis of 1-methyl-4-(phenylethynyl)benzene by tetrafluorothianthrene salt, characterized in that during the reaction as described in claim 1, the molar ratio of Pd(OAc)2 and tetrafluorothianthrene salt 1a is 1:20. 5. A palladium-catalyzed synthesis of 1-methyl-4-(phenylethynyl)benzene by tetrafluorothianthrene salt, characterized in that during the reaction as claimed in claim 1, the molar ratio of _Et3N to tetrafluorothianthrene salt 1a is 1:3. 6. A palladium-catalyzed synthesis of 1-methyl-4-(phenylethynyl)benzene by tetrafluorothianthrene salt, characterized in that during the reaction as claimed in claim 1, the solvent used in the reaction is tetrahydrofuran, and the amount used is 10 mL/mmol of compound 1a. 7. A palladium-catalyzed synthesis of 1-methyl-4-(phenylethynyl)benzene by tetrafluorothianthrene salt, characterized in that during the reaction as claimed in claim 1, CuI is used as a co-catalyst, and the molar ratio of tetrafluorothianthrene salt 1a to CuI is 1:3.3. 8. A method for synthesizing 1-methyl-4-(phenylethynyl)benzene by using a palladium-catalyzed tetrafluorothianthrene salt, characterized in that the reaction temperature is 100°C and the reaction time is 12 hours during the reaction as described in claim 1.