Method for synthesizing polysubstituted thiophene compound

Abstract

The invention discloses a method for synthesizing a polysubstituted thiophene compound. According to the method, trans-beta-styrene sulfonyl chloride or trans-beta-styrene sulfinic acid sodium salt, or trans-beta-styrene sulfonyl chloride and phenylacetylene, or trans-beta-styrene sulfonyl chloride and ethyl 2-fluoro-3-oxo-3-phenylpropionate are used as raw materials, and are fully reacted under the action of triphenylphosphine and a transition metal catalyst to obtain the 2-fluoro-3-oxo-3-phenylpropionate. The polysubstituted thiophene compound is obtained. The method is simple and convenient to operate, and thiophene compounds with different structures can be obtained by changing different substrates and reaction conditions.

Description

Technical Field

[0001] The present invention belongs to the field of organic synthesis and relates to a method for synthesizing polysubstituted thiophene compounds. Background Art

[0002] Polysubstituted thiophenes are a very important class of heterocyclic compounds. They can not only serve as building blocks for synthesizing natural products but also be key structural units of many bioactive compounds. In addition, polysubstituted thiophene structures also have extensive applications in the field of materials chemistry. Among them, especially polysubstituted thiophene compounds have certain pharmacological applications, and related compounds can be used as anti-inflammatory drugs. However, the synthesis of polysubstituted thiophene compounds is somewhat difficult because it is not easy to selectively substitute one or more β-positions of the thiophene heterocycle, and most reaction systems tend to undergo aromatic substitution reactions at the more favorable α-position. Therefore, the development of effective methods for synthesizing polysubstituted thiophene compounds has received particular attention in the fields of organic synthesis and medicinal chemistry. Currently, such compounds are mainly synthesized by using phenylboronic acid and 3,4-dibromothiophene via Suzuki coupling reaction, which requires the use of an excessive amount of arylboronic acid substrate and expensive metal catalysts and the reaction conditions are relatively harsh. In addition, α-bromoacetophenone can also be used to synthesize such compounds, but it requires three-step reactions, and the reaction also faces problems such as difficult separation, low yield, long reaction time, and polluting gas by-products. The following introduces some specific examples of synthesizing polysubstituted thiophene compounds:

[0003] Literature 1 (Henckens, A.; Colladet, K.; Fourier, S.; et al. Synthesis of 3,4-Diphenyl-Substituted Poly(Thienylene Vinylene), Low-Band-Gap Polymers via the Dithiocarbamate Route [J]. Macromolecules, 38, 19 - 26; 2005) obtained 3,4-diphenylthiophene products by reacting 3,4-dibromothiophene with arylboronic acid under palladium-catalyzed conditions. Relatively speaking, there are more types of arylboronic acids, but this method requires the use of nearly 5 times the substrate amount of arylboronic acid and relatively expensive metal catalysts, which brings certain difficulties to the separation of products. The reaction formula is as follows:

[0004]

[0005] Reference 2 (Agarwal, Neeraj; Mishra, Sarada P.; Kumar, A.; Ravikanth, M. Synthesis of β-thiophene-substituted 21,23-dithiaporphyrins [J]. Chemistry Letters, 32, 744-745; 2003) obtained 3,4-diphenylthiophene products using 3,4-dibromothiophene and phenylmagnesium bromide under nickel catalysis. The disadvantages of this method are the need to use Grignard reagents and metal catalysts, high reaction conditions, general yields, few types of Grignard reagents, and limited substrate scope. The reaction formula is as follows:

[0006]

[0007] Reference 3 (Dang, Yizhe; Chen, Yi. Oxidation of 3,4-diaryl-2,5-dihydrothiophenes to 3,4-diarylthiophenes using CuBr 2 : simple and efficient preparation of 3,4-diarylthiophenes [J]. European Journal of Organic Chemistry, 34, 5661-5664; 2007) synthesized diphenylthiophene products through three steps using α-bromoacetophenone. This method has cumbersome steps, requires separation and purification for each step, and uses a large amount of metal reagents. The reaction formula is as follows:

[0008]

[0009] The above-mentioned several methods all have certain drawbacks, such as the general use of excessive reaction reagents, as well as the problems of cumbersome reaction steps and complex post-treatment. Therefore, developing a method for synthesizing polysubstituted thiophene compounds with simple reaction conditions, without the need for metal catalysts, and simple post-treatment has good practical value. Summary of the Invention

[0010] The object of the present invention is to provide a method for synthesizing polysubstituted thiophene compounds. This method uses trans-β-styrenesulfonyl chloride or sodium trans-β-styrenesulfinate, or trans-β-styrenesulfonyl chloride and phenylacetylene, or trans-β-styrenesulfonyl chloride and ethyl 2-fluoro-3-oxo-3-phenylpropionate as raw materials to synthesize polysubstituted thiophenes, and the reaction conditions are simple and mild.

[0011] The technical solution for achieving the object of the present invention is as follows:

[0012] A method for synthesizing polysubstituted thiophene compounds, and the reaction formula is as follows:

[0013]

[0014] wherein R is tert-butyl, chloro, fluoro, or methyl,

[0015] The specific steps are as follows:

[0016] Using anti-β-styrenesulfonyl chloride compound (B) or anti-β-styrenesulfinate sodium compound (C) as raw materials, triphenylphosphine (PPh 3 ) as a reducing agent, toluene as a solvent, under the protection of an inert gas, reacting fully at 100 ± 5 °C, and obtaining symmetric 3,4-disubstituted thiophene compound (A) through separation and purification;

[0017] Or using anti-β-styrenesulfonyl chloride compound (B) and phenylacetylene (D) as raw materials, triphenylphosphine as a reducing agent, tetrakis(triphenylphosphine)palladium (Pd(PPh 3 ) 4 ) as a catalyst, N,N-dimethylformamide (DMF) as a solvent, under the protection of an inert gas, reacting fully at 100 ± 5 °C, and obtaining asymmetric 3,4-disubstituted thiophene compound (A) through separation and purification;

[0018] Or using anti-β-styrenesulfonyl chloride compound (B) and ethyl 2-fluoro-3-oxo-3-phenylpropionate (E) as raw materials, triphenylphosphine as a reducing agent, bis(1,5-cyclooctadiene)nickel as a catalyst, 2,6-bis(diphenylphosphino)pyridine as a ligand, tetrahydrofuran (THF) as a solvent, under the protection of an inert gas, reacting fully at 50 ± 5 °C, and obtaining trisubstituted thiophene compound (A) through separation and purification.

[0019] Further, the anti-β-styrenesulfonyl chloride compounds are anti-β-p-tert-butylstyrenesulfonyl chloride, anti-β-p-fluorostyrenesulfonyl chloride, anti-β-styrenesulfonyl chloride, anti-β-p-methylstyrenesulfonyl chloride, anti-β-p-chlorostyrenesulfonyl chloride or anti-β-m-chlorostyrenesulfonyl chloride; the anti-β-sodium styrenesulfinate compounds are anti-β-p-tert-butylsodium styrenesulfinate, anti-β-p-fluorosodium styrenesulfinate, anti-β-sodium styrenesulfinate, anti-β-p-methylsodium styrenesulfinate, anti-β-p-chlorosodium styrenesulfinate or anti-β-m-chlorosodium styrenesulfinate; the symmetric 3,4-disubstituted thiophene compounds are 3,4-bis(4-(tert-butyl)phenyl)thiophene, 3,4-bis(4-fluorophenyl)thiophene, 3,4-bis(phenyl)thiophene, 3,4-bis(4-methylphenyl)thiophene, 3,4-bis(4-chlorophenyl)thiophene or 3,4-bis(3-chlorophenyl)thiophene; the asymmetric 3,4-disubstituted thiophene compounds are 3-phenyl-4-(p-tolyl)thiophene; the trisubstituted thiophene compound is ethyl 2,4-diphenylthiophene-3-carboxylate.

[0020] Further, in the synthesis of the symmetric 3,4-disubstituted thiophene compound, the molar ratio of anti-β-styrenesulfonyl chloride to triphenylphosphine is 1:1.5 - 1:2, preferably 1:2.

[0021] Further, in the synthesis of the symmetric 3,4-disubstituted thiophene compound, the molar ratio of anti-β-sodium styrenesulfinate to triphenylphosphine is 1:1.5 - 1:2, preferably 1:2.

[0022] Further, in the synthesis of the asymmetric 3,4-disubstituted thiophene compound, the molar amount of tetrakis(triphenylphosphine)palladium is 10 ± 5% of the molar amount of anti-β-styrenesulfonyl chloride.

[0023] Further, in the synthesis of the trisubstituted thiophene compound, the molar amount of bis(1,5-cyclooctadiene)nickel is 10 ± 5% of the molar amount of anti-β-styrenesulfonyl chloride.

[0024] Further, in the synthesis of the trisubstituted thiophene compound, the molar amount of 2,6-bis(diphenylphosphino)pyridine is 15 ± 5% of the molar amount of anti-β-styrenesulfonyl chloride.

[0025] Further, the reaction time is 10 - 16 h.

[0026] Further, the separation and purification method is as follows: after the reaction is completed, the reaction solution is cooled to room temperature, the solvent is removed by vacuum distillation, and a mixed solution of ethyl acetate and petroleum ether with a volume ratio of 1:50 - 1:10 is used as the eluent, and the crude product is separated by column chromatography to obtain the polysubstituted thiophene compound.

[0027] Compared with the prior art, the remarkable advantages of the present invention are:

[0028] (1) The reaction conditions of the present invention are simple and mild, the steps are simple and the conversion rate is high, and high-purity products can be conveniently obtained, which is suitable for large-scale industrial production.

[0029] (2) The raw materials used in the present invention, such as trans-β-styrenesulfonyl chloride, trans-β-styrenesulfinic acid sodium salt, phenylacetylene, ethyl 2-fluoro-3-oxo-3-phenylpropionate, etc., are easily obtained, with low commercial prices and stable properties, making them easy to use.

[0030] (3) Different structural types of thiophene compounds can be obtained by the present invention through different substrates and conditions. Description of the Drawings

[0031] Figure 1 is the 1 H NMR spectrum of 3,4-bis(4-(tert-butyl)phenyl)thiophene;

[0032] Figure 2 is the 13 C NMR spectrum of 3,4-bis(4-(tert-butyl)phenyl)thiophene;

[0033] Figure 3 is the 1 H NMR spectrum of 3,4-bis(4-fluorophenyl)thiophene;

[0034] Figure 4 is the 13 C NMR spectrum of 3,4-bis(4-fluorophenyl)thiophene;

[0035] Figure 5 is the 19 F NMR spectrum of 3,4-bis(4-fluorophenyl)thiophene;

[0036] Figure 6 is the 1 H NMR spectrum of 3,4-diphenylthiophene;

[0037] Figure 7 is the 13 C NMR spectrum of 3,4-diphenylthiophene;

[0038] Figure 8 is the 1 H NMR spectrum of 3,4-bis(4-methylphenyl)thiophene;

[0039] Figure 9 is the 13 C NMR spectrum of 3,4-bis(4-methylphenyl)thiophene;

[0040] Figure 10 is the 1 H NMR spectrum of 3,4-bis(4-chlorophenyl)thiophene;

[0041] Figure 11 is the 13 C NMR spectrum of 3,4-bis(4-chlorophenyl)thiophene;

[0042] Figure 12 is the 1 H NMR spectrum of 3,4-bis(3-chlorophenyl)thiophene;

[0043] Figure 13 is the 13 C NMR spectrum of 3,4-bis(3-chlorophenyl)thiophene;

[0044] Figure 14 is the 1 H NMR spectrum of 3-phenyl-4-(p-tolyl)thiophene;

[0045] Figure 15 is the 13 C NMR spectrum of 3-phenyl-4-(p-tolyl)thiophene;

[0046] Figure 16 is the 1 H NMR spectrum of ethyl 2,4-diphenylthiophene-3-carboxylate;

[0047] Figure 17 is the 13 C NMR spectrum of ethyl 2,4-diphenylthiophene-3-carboxylate. Detailed implementation mode

[0048] To better understand the present invention, the technical solutions of the present invention will be further described below through specific examples and drawings.

[0049] Example 1

[0050] Add 258 mg (1 mmol) of trans-β-p-tert-butylstyrenesulfonyl chloride, 524 mg (2 mmol) of triphenylphosphine and 3 ml of toluene into a reactor, and stir at 100 °C under argon protection for 10 h. After the reaction is completed, the reaction solution is distilled under reduced pressure to remove the solvent. The crude product is separated by column chromatography (the eluent is a mixed solution of ethyl acetate and petroleum ether, and the volume ratio of the two is 1:50) to obtain 160 mg of 3,4-bis(4-(tert-butyl)phenyl)thiophene, and the yield is 46%.

[0051] Example 2

[0052] 246 mg (1 mmol) of sodium trans-β-p-tert-butylstyrenesulfinate, 524 mg (2 mmol) of triphenylphosphine and 3 ml of toluene were added to a reactor, and the mixture was stirred at 100 °C under argon protection for 10 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent. The crude product was separated by column chromatography (the eluent was a mixture of ethyl acetate and petroleum ether with a volume ratio of 1:50) to obtain 143 mg of 3,4-bis(4-(tert-butyl)phenyl)thiophene, with a yield of 44%.

[0053] For 3,4-bis(4-(tert-butyl)phenyl)thiophene 1 The 1H NMR spectrum is shown in Figure 1 , 13 The 13C NMR spectrum is shown in Figure 2 .

[0054] 1 1H NMR (500 MHz, Chloroform-d) δ 7.29 - 7.27 (m, 6H), 7.16 (d, J = 8.4 Hz, 4H), 1.33 (s, 18H).

[0055] 13 13C NMR (126 MHz, Chloroform-d) δ 148.67, 140.61, 132.69, 127.53, 123.96, 122.61, 33.47, 30.34.

[0056] Example 3

[0057] 220 mg (1 mmol) of trans-β-p-fluorostyrenesulfonyl chloride, 524 mg (2 mmol) of triphenylphosphine and 3 ml of toluene were added to a reactor, and the mixture was stirred at 100 °C under argon protection for 10 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent. The crude product was separated by column chromatography (the eluent was a mixture of ethyl acetate and petroleum ether with a volume ratio of 1:50) to obtain 117 mg of 3,4-bis(4-fluorophenyl)thiophene, with a yield of 43%.

[0058] Example 4

[0059] 208 mg (1 mmol) of sodium trans-β-p-fluorostyrenesulfinate, 524 mg (2 mmol) of triphenylphosphine and 3 ml of toluene were added to a reactor, and the mixture was stirred at 100 °C under argon protection for 10 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent. The crude product was separated by column chromatography (the eluent was a mixture of ethyl acetate and petroleum ether with a volume ratio of 1:50) to obtain 122 mg of 3,4-bis(4-fluorophenyl)thiophene, with a yield of 45%.

[0060] For 3,4-bis(4-fluorophenyl)thiophene 1The \(^1H\) NMR spectrum is shown in Figure 3 , 13 The \(^{13}C\) NMR spectrum is shown in Figure 4 , 19 The \(^{19}F\) NMR spectrum is shown in Figure 5 .

[0061] 1 \(^1H\) NMR (500 MHz, Chloroform-d) δ 7.28 (s, 2H), 7.15 - 7.10 (m, 4H), 6.99 - 6.93 (m, 4H). 13 \(^{13}C\) NMR (126 MHz, Chloroform-d) δ 161.02 (d, J=246.6 Hz), 139.59, 131.38, 129.53 (d, J=8.1 Hz), 123.02, 114.16 (d, J=21.4 Hz).

[0062] 19 \(^{19}F\) NMR (470 MHz, Chloroform-d) δ -114.15.

[0063] Example 5

[0064] 202 mg (1 mmol) of trans-β-styrenesulfonyl chloride, 524 mg (2 mmol) of triphenylphosphine and 3 ml of toluene were added to a reactor, and the mixture was stirred at 100 °C under argon protection for 10 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent. The crude product was separated by column chromatography (the eluent was a mixture of ethyl acetate and petroleum ether, and the volume ratio of the two was 1:50) to obtain 113 mg of 3,4-diphenylthiophene, with a yield of 48%.

[0065] Example 6

[0066] 190 mg (1 mmol) of sodium trans-β-styrenesulfinate, 524 mg (2 mmol) of triphenylphosphine and 3 ml of toluene were added to a reactor, and the mixture was stirred at 100 °C under argon protection for 10 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent. The crude product was separated by column chromatography (the eluent was a mixture of ethyl acetate and petroleum ether, and the volume ratio of the two was 1:50) to obtain 116 mg of 3,4-diphenylthiophene, with a yield of 49%.

[0067] For 3,4-diphenylthiophene, 1 the \(^1H\) NMR spectrum is shown in Figure 6 , 13 the \(^{13}C\) NMR spectrum is shown in Figure 7 .

[0068] 1H NMR (500 MHz, Chloroform-d) δ 7.33 (s, 2H), 7.27 (dd, J = 5.2, 2.1 Hz, 6H), 7.23 - 7.19 (m, 4H).

[0069] 13C NMR (126 MHz, Chloroform-d) δ 140.77, 135.56, 128.02, 127.13, 125.87, 123.01.

[0070] Example 7

[0071] 216 mg (1 mmol) of trans-β-p-methylstyrenesulfonyl chloride, 524 mg (2 mmol) of triphenylphosphine and 3 ml of toluene were added to a reactor, and stirred at 100 °C under argon protection for 10 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent. The crude product was separated by column chromatography (the eluent was a mixture of ethyl acetate and petroleum ether with a volume ratio of 1:50) to obtain 118 mg of 3,4-bis(4-methylphenyl)thiophene, with a yield of 45%.

[0072] Example 8

[0073] 204 mg (1 mmol) of sodium trans-β-p-methylstyrenesulfinate, 524 mg (2 mmol) of triphenylphosphine and 3 ml of toluene were added to a reactor, and stirred at 100 °C under argon protection for 10 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent. The crude product was separated by column chromatography (the eluent was a mixture of ethyl acetate and petroleum ether with a volume ratio of 1:50) to obtain 115 mg of 3,4-bis(4-methylphenyl)thiophene, with a yield of 44%.

[0074] For 3,4-bis(4-methylphenyl)thiophene 1 The 1H NMR spectrum is shown in Figure 8 , 13 and the 13C NMR spectrum is shown in Figure 9 .

[0075] 1 1H NMR (500 MHz, Chloroform-d) δ 7.29 (s, 2H), 7.11 (q, J = 8.2 Hz, 8H), 2.36 (s, 6H).

[0076] 13 13C NMR (126 MHz, Chloroform-d) δ 140.72, 135.48, 132.79, 127.86, 122.56, 20.17.

[0077] Example 9

[0078] Add 236 mg (1 mmol) of trans-β-p-chlorostyrenesulfonyl chloride, 524 mg (2 mmol) of triphenylphosphine, and 3 ml of toluene to a reactor, and stir for 10 h under argon protection at 100 °C. After the reaction is completed, the reaction solution is distilled under reduced pressure to remove the solvent. The crude product is separated by column chromatography (the eluent is a mixed solution of ethyl acetate and petroleum ether, and the volume ratio of the two is 1:50) to obtain 130 mg of 3,4-bis(4-chlorophenyl)thiophene, with a yield of 43%.

[0079] Example 10

[0080] Add 224 mg (1 mmol) of sodium trans-β-p-chlorostyrenesulfinate, 524 mg (2 mmol) of triphenylphosphine, and 3 ml of toluene to a reactor, and stir for 10 h under argon protection at 100 °C. After the reaction is completed, the reaction solution is distilled under reduced pressure to remove the solvent. The crude product is separated by column chromatography (the eluent is a mixed solution of ethyl acetate and petroleum ether, and the volume ratio of the two is 1:50) to obtain 137 mg of 3,4-bis(4-chlorophenyl)thiophene, with a yield of 45%.

[0081] For 3,4-bis(4-chlorophenyl)thiophene 1 The 1H NMR spectrum is shown in Figure 10 , 13 The 13C NMR spectrum is shown in Figure 11 .

[0082] 1 1H NMR (500 MHz, Chloroform-d) δ 7.31 (s, 2H), 7.27 - 7.24 (m, 4H), 7.13 - 7.08 (m, 4H). 13 13C NMR (126 MHz, Chloroform-d) δ 139.33, 133.68, 132.10, 129.22, 127.51, 123.53.

[0083] Example 11

[0084] Add 236 mg (1 mmol) of trans-β-m-chlorostyrenesulfonyl chloride, 524 mg (2 mmol) of triphenylphosphine, and 3 ml of toluene to a reactor, and stir for 10 h under argon protection at 100 °C. After the reaction is completed, the reaction solution is distilled under reduced pressure to remove the solvent. The crude product is separated by column chromatography (the eluent is a mixed solution of ethyl acetate and petroleum ether, and the volume ratio of the two is 1:50) to obtain 121 mg of 3,4-bis(3-chlorophenyl)thiophene, with a yield of 40%.

[0085] Example 12

[0086] 224 mg (1 mmol) of sodium trans-β-m-chlorostyrenesulfonate, 524 mg (2 mmol) of triphenylphosphine and 3 ml of toluene were added to a reactor, and the mixture was stirred at 100 °C under argon protection for 10 h. After the reaction was completed, the reaction solution was distilled under reduced pressure to remove the solvent. The crude product was separated by column chromatography (the eluent was a mixed solution of ethyl acetate and petroleum ether, and the volume ratio of the two was 1:50) to obtain 129 mg of 3,4-bis(3-chlorophenyl)thiophene, with a yield of 43%.

[0087] For 3,4-bis(3-chlorophenyl)thiophene 1 The 1H NMR spectrum is shown in Figure 12 , 13 The 13C NMR spectrum is shown in Figure 13 .

[0088] 1 1H NMR (500 MHz, Chloroform-d) δ 7.35 (s, 2H), 7.28 - 7.23 (m, 4H), 7.18 (td, J = 7.5, 1.3 Hz, 2H), 6.99 (dt, J = 7.6, 1.4 Hz, 2H).

[0089] 13 13C NMR (126 MHz, Chloroform-d) δ 139.11, 136.89, 133.14, 128.41, 127.89, 126.21, 123.94.

[0090] Example 13

[0091] 108 mg (0.5 mmol) of trans-β-p-methylstyrenesulfonyl chloride, 262 mg (1 mmol) of triphenylphosphine, 102 mg (1 mmol) of phenylacetylene, 58 mg (0.05 mmol) of tetrakis(triphenylphosphine)palladium and 3 ml of N,N-dimethylformamide were added to a reactor, and the mixture was stirred at 100 °C under argon protection for 10 h. After the reaction was completed, the reaction solution was extracted and distilled under reduced pressure to remove the solvent. The crude product was separated by column chromatography (the eluent was a mixed solution of ethyl acetate and petroleum ether, and the volume ratio of the two was 1:50) to obtain 66 mg of 3-phenyl-4-(p-tolyl)thiophene, with a yield of 53%.

[0092] For 3-phenyl-4-(p-tolyl)thiophene 1 The 1H NMR spectrum is shown in Figure 14 , 13 The 13C NMR spectrum is shown in Figure 15 .

[0093] 11H NMR (500 MHz, Chloroform-d) δ 7.41 - 7.27 (m, 7H), 7.19 - 7.13 (m, 4H), 2.42 (s, 2H).

[0094] 13 13C NMR (126 MHz, Chloroform-d) δ 140.82, 135.70, 135.55, 132.34, 127.84, 127.76, 126.98, 125.74, 122.86, 122.61, 20.05.

[0095] Example 14

[0096] 101 mg (0.5 mmol) of trans-β-styrenesulfonyl chloride, 262 mg (1 mmol) of triphenylphosphine, 210 mg (1 mmol) of ethyl 2-fluoro-3-oxo-3-phenylpropionate, 27.5 mg (0.05 mmol) of bis-(1,5-cyclooctadiene)nickel, 33.5 mg (0.075 mmol) of 2,6-bis(diphenylphosphino)pyridine and 4 ml of tetrahydrofuran were added to a reactor, and stirred at 50 °C under argon protection for 16 h. After the reaction was completed, the reaction solution was extracted and the solvent was removed by distillation under reduced pressure. The crude product was separated by column chromatography (the eluent was a mixed solution of ethyl acetate and petroleum ether, and the volume ratio of the two was 1:10) to obtain 63 mg of ethyl 2,4-diphenylthiophene-3-carboxylate, and the yield was 41%.

[0097] For ethyl 2,4-diphenylthiophene-3-carboxylate 1 The 1H NMR spectrum is shown in Figure 16 , 13 The 13C NMR spectrum is shown in Figure 17 .

[0098] 1 1H NMR (500 MHz, Chloroform-d) δ 7.75 - 7.62 (m, 2H), 7.59 - 7.39 (m, 8H), 7.25 (s, 1H), 4.23 (q, J = 6.9 Hz, 2H), 1.10 (t, J = 7.2 Hz, 3H).

[0099] 13 13C NMR (126 MHz, Chloroform-d) δ 164.81, 145.69, 142.26, 135.18, 132.46, 128.68, 127.90, 127.40, 127.39, 127.20, 127.19, 126.46, 121.29, 60.36, 12.53.

[0100] Comparative Example 1

[0101] In this comparative example, ethanol was used as the reaction solvent. Specifically:

[0102] 202 mg (1 mmol) of trans-β-styrenesulfonyl chloride, 524 mg (2 mmol) of triphenylphosphine, and 3 ml of ethanol were added to a reactor, and the mixture was stirred at 100 °C under argon protection for 10 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent. The crude product was separated by column chromatography (the eluent was a mixture of ethyl acetate and petroleum ether with a volume ratio of 1:50) to obtain 31 mg of 3,4-diphenylthiophene, with a yield of 13%.

[0103] Comparative Example 2

[0104] In this comparative example, the catalyst tetrakis(triphenylphosphine)palladium was not added. Specifically:

[0105] 108 mg (0.5 mmol) of trans-β-p-methylstyrenesulfonyl chloride, 262 mg (1 mmol) of triphenylphosphine, 102 mg (1 mmol) of phenylacetylene, and 3 ml of N,N-dimethylformamide were added to a reactor, and the mixture was stirred at 100 °C under argon protection for 10 h. After the reaction was completed, the reaction solution was extracted and concentrated under reduced pressure to remove the solvent. The corresponding 3-phenyl-4-(p-tolyl)thiophene product was not obtained by column chromatography (the eluent was a mixture of ethyl acetate and petroleum ether with a volume ratio of 1:50).

[0106] Comparative Example 3

[0107] In this comparative example, the ligand 2,6-bis(diphenylphosphino)pyridine was not added. Specifically:

[0108] 101 mg (0.5 mmol) of trans-β-styrenesulfonyl chloride, 262 mg (1 mmol) of triphenylphosphine, 210 mg (1 mmol) of ethyl 2-fluoro-3-oxo-3-phenylpropionate, 27.5 mg (0.05 mmol) of bis(1,5-cyclooctadiene)nickel, and 4 ml of tetrahydrofuran were added to a reactor, and the mixture was stirred at 50 °C under argon protection for 16 h. After the reaction was completed, the reaction solution was extracted and concentrated under reduced pressure to remove the solvent. The corresponding ethyl 2,4-diphenylthiophene-3-carboxylate product was not obtained by column chromatography (the eluent was a mixture of ethyl acetate and petroleum ether with a volume ratio of 1:10).

[0109] The above embodiments do not limit the present invention in any way. Any technical solutions obtained by means of equivalent substitution or equivalent transformation fall within the protection scope of the present invention.

Claims

1. A method for synthesizing polysubstituted thiophene compounds, characterized in that, the specific steps are as follows: Using anti-β-styrenesulfonyl chloride compounds or anti-β-styrenesulfinate sodium compounds as raw materials, triphenylphosphine as a reducing agent, toluene as a solvent, under the protection of an inert gas, reacting fully at 100 ± 5 °C, and obtaining symmetric 3,4-disubstituted thiophene compounds through separation and purification; Or using anti-β-styrenesulfonyl chloride compounds and phenylacetylene as raw materials, triphenylphosphine as a reducing agent, tetrakis(triphenylphosphine)palladium as a catalyst, N,N-dimethylformamide as a solvent, under the protection of an inert gas, reacting fully at 100 ± 5 °C, and obtaining asymmetric 3,4-disubstituted thiophene compounds through separation and purification; Or using anti-β-styrenesulfonyl chloride compounds and ethyl 2-fluoro-3-oxo-3-phenylpropionate as raw materials, triphenylphosphine as a reducing agent, bis(1,5-cyclooctadiene)nickel as a catalyst, 2,6-bis(diphenylphosphino)pyridine as a ligand, tetrahydrofuran as a solvent, under the protection of an inert gas, reacting fully at 50 ± 5 °C, and obtaining trisubstituted thiophene compounds through separation and purification.

2. The method according to claim 1, characterized in that, The anti-β-styrenesulfonyl chloride compounds are anti-β-p-tert-butylstyrenesulfonyl chloride, anti-β-p-fluorostyrenesulfonyl chloride, anti-β-styrenesulfonyl chloride, anti-β-p-methylstyrenesulfonyl chloride, anti-β-p-chlorostyrenesulfonyl chloride or anti-β-m-chlorostyrenesulfonyl chloride; the anti-β-styrenesulfinate sodium compounds are anti-β-p-tert-butylstyrenesulfinate sodium, anti-β-p-fluorostyrenesulfinate sodium, anti-β-styrenesulfinate sodium, anti-β-p-methylstyrenesulfinate sodium, anti-β-p-chlorostyrenesulfinate sodium or anti-β-m-chlorostyrenesulfinate sodium; the symmetric 3,4-disubstituted thiophene compounds are 3,4-bis(4-(tert-butyl)phenyl)thiophene, 3,4-bis(4-fluorophenyl)thiophene, 3,4-bis(phenyl)thiophene, 3,4-bis(4-methylphenyl)thiophene, 3,4-bis(4-chlorophenyl)thiophene or 3,4-bis(3-chlorophenyl)thiophene; the asymmetric 3,4-disubstituted thiophene compounds are 3-phenyl-4-(p-tolyl)thiophene; the trisubstituted thiophene compounds are ethyl 2,4-diphenylthiophene-3-carboxylate.

3. The method according to claim 1, characterized in that, In the synthesis of symmetric 3,4-disubstituted thiophene compounds, the molar ratio of anti-β-styrenesulfonyl chloride to triphenylphosphine is 1:1.5 – 1:

2.

4. The method according to claim 1, characterized in that, In the synthesis of symmetric 3,4-disubstituted thiophene compounds, the molar ratio of anti-β-styrenesulfinate sodium to triphenylphosphine is 1:1.5 – 1:

2.

5. The method according to claim 1, characterized in that, In the synthesis of asymmetric 3,4-disubstituted thiophene compounds, the molar amount of tetrakis(triphenylphosphine)palladium is 10 ± 5% of the molar amount of anti-β-styrenesulfonyl chloride.

6. The method according to claim 1, characterized in that, In the synthesis of trisubstituted thiophene compounds, the molar amount of bis-(1,5-cyclooctadiene) nickel is 10 ± 5% of the molar amount of trans-β-styrenesulfonyl chloride.

7. According to the method described in claim 1, it is characterized in that in the synthesis of trisubstituted thiophene compounds, the molar amount of 2,6-bis(diphenylphosphino)pyridine is 15 ± 5% of the molar amount of trans-β-styrenesulfonyl chloride.

8. According to the method described in claim 1, it is characterized in that the reaction time is 10 - 16 h.

9. According to the method described in claim 1, it is characterized in that the separation and purification method is: after the reaction is completed, the reaction solution is cooled to room temperature, the solvent is removed by vacuum distillation, and a mixed solution of ethyl acetate and petroleum ether with a volume ratio of 1:50 - 1:10 is used as the eluent, and the crude product is separated by column chromatography to obtain polysubstituted thiophene compounds.

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