Method for synthesizing 1, 4-diphenyl-1-butyne derivative through nickel catalytic reduction coupling

Abstract

The invention belongs to the technical field of organic synthesis, and discloses a method for synthesizing 1, 4-diphenyl-1-butyne derivatives through nickel catalytic reduction coupling. The method comprises the following steps: in a protective atmosphere, taking an organic solvent as a reaction medium, and reacting a benzene butyne electrophilic reagent with a halogenated aryl electrophilic reagent under the action of a catalyst, a ligand and a reducing agent to obtain the 1, 4-diphenyl-1-butyne derivative. The structure of the 1, 4-diphenyl-1-butyne derivative is shown in the specification. The catalyst is a nickel catalyst, and the ligand is a nitrogen or phosphine compound. The method disclosed by the invention is simple, low in cost, efficient in reaction, few in byproducts, easy to separate and purify and high in yield. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing 1,4-diphenyl-1-butyne derivatives by nickel-catalyzed reduction coupling. Background Art

[0002] 1,4-Diphenyl-1-butyne has 1,2-alkynyl, 3,4-alkyl and 1,4-diphenyl reactive sites and can be used to synthesize chemicals, agrochemicals, organic materials and natural product molecules with complex and varied structures. Due to its unique structural core, it is considered a promising building block in drug discovery and organic synthesis. At present, the synthesis method of 1,4-diphenyl-1-butyne is the Sonogashira cross-coupling reaction of 4-phenyl-1-butyne with bromobenzene or iodobenzene in the presence of palladium and copper (Warner, AJ; Lawson, JR; Fasano, V.; Ingleson, MJ Angew. Chem., Int. Ed. 2015, 54 (38), 11245-11249; Wang, De.; Song, ZF; Zhang, JY; Xu, T. Org. Chem. Front. 2021, 8 (6), 1125-1131; Shao, YA; Zhang, Z.; Li, PF; Eur. J. Org. Chem. 2021, 2021 (21), 3059-3070). Some 1,4-diphenyl-1-butyne is obtained by substitution reaction of strong base (butyl lithium) / low temperature (-78°C). However, the above method requires expensive catalysts, and the reaction raw material 4-phenyl-1-butyne used is difficult to obtain commercially and requires multi-step synthesis; the strong base / low temperature substitution reaction conditions are harsh, the operation is cumbersome, and the functional group compatibility is poor, which limits the promotion and industrial application of the above method. Summary of the invention

[0003] In view of the problems and shortcomings of the existing synthesis methods of 1,4-diphenyl-1-butyne compounds, such as expensive catalysts, high synthesis costs, limited sources of 4-phenyl-1-butyne, harsh reaction conditions, cumbersome operations, and low raw material yields, the present invention aims to provide a method for synthesizing 1,4-diphenyl-1-butyne derivatives by nickel-catalyzed reduction coupling. The method of the present invention is simple, low in cost, highly efficient in reaction, few by-products, easy to separate and purify, and high in yield.

[0004] The purpose of the present invention is achieved through the following technical solutions:

[0005] A method for synthesizing 1,4-diphenyl-1-butyne derivatives by nickel-catalyzed reduction coupling comprises the following steps: in a protective atmosphere, with an organic solvent as a reaction medium, reacting a phenylbutyne electrophilic reagent with a halogenated aryl electrophilic reagent under the action of a catalyst, a ligand and a reducing agent to obtain a 1,4-diphenyl-1-butyne derivative.

[0006] The structure of the phenylbutyryne electrophilic reagent is

[0007]

[0008] The structure of the halogenated aryl electrophilic reagent is

[0009]

[0010] The structure of 1,4-diphenyl-1-butyne derivatives is

[0011]

[0012] Where R 1 is H, ester group, halogen, substituted or unsubstituted aryl group, heteroaryl group; R 1 In the structure of phenylbutyryne electrophiles, it is monosubstituted, disubstituted, and trisubstituted;

[0013] R 2 is a substituent on the benzene ring or R 2 Form a benzocyclic group with the benzene ring; R 2 When R is a substituent on a benzene ring, 2 is H, CN, acyl, substituted or unsubstituted aryl, heteroaryl; R 2 It forms a benzocyclic group with the benzene ring. In this case, the benzocyclic group is indolyl, quinolyl, benzofuranyl, isobenzofuran-1(3H)-one Benzothiphenyl, 1,2-methylenedioxybenzene

[0014] R 3 and R 4 is independently hydrogen (H), alkyl, or aryl;

[0015] R 1 The aryl group is phenyl, naphthyl, or biphenyl, and the substituent in the substituted aryl group is one, two, or three of alkyl, F, Cl, amino, or amide;

[0016] R 2 The aryl group is phenyl, naphthyl, or biphenyl, and the substituent in the substituted aryl group is one, two, or three of alkyl, F, Cl, amino, or amide;

[0017] R 1The heteroaryl group is pyridyl, indolyl, quinolyl, furyl, or thienyl; R 2 The heteroaryl group is pyridyl, indolyl, quinolyl, furyl, thienyl;

[0018] R 3 The aryl group is phenyl, naphthyl or biphenyl; R 4 The aryl group is phenyl, naphthyl or biphenyl.

[0019] R 1 With R 2 Not H at the same time.

[0020] In the phenylbutyryne electrophiles, X is chlorine (Cl), bromine (Br) or iodine (I).

[0021] X is preferably Br, R 1 Preferably, H, ester group (R'-OC(O)-, R' is alkyl), halogen (such as Cl, Br, etc., R 1 is monosubstituted or disubstituted. When disubstituted, R 1 is 3,5-dichlorosubstituted) or more; R 3 and R 4 Preferably H.

[0022] In the halogenated aryl electrophilic reagent, Y is Br or I, and Y is preferably Br.

[0023] R 2 Preferably, a substituent on the benzene ring or R 2 Form a benzocyclic group with the benzene ring; R 2 When R is a substituent on a benzene ring, 2 is H, CN, acyl; R 2 It forms a benzocyclic group with the benzene ring. In this case, the benzocyclic group is indolyl, quinolyl, benzofuranyl, isobenzofuran-1(3H)-one Benzothiphenyl, 1,2-methylenedioxybenzene

[0024] The catalyst is a nickel catalyst; the nickel catalyst is one or more of nickel iodide, nickel bromide, nickel chloride, nickel acetate tetrahydrate, nickel acetylacetonate, nickel tetrakis(triphenylphosphine), nickel dibromide bis(pyridine) nickel, bis(triphenylphosphine) nickel dichloride, nickel trifluoromethanesulfonate, nickel fluoroborate hexahydrate, ethylene glycol dimethyl ether nickel bromide, and ethylene glycol dimethyl ether nickel chloride; preferably one or more of nickel iodide, nickel bromide, nickel chloride, nickel dibromide bis(pyridine) nickel, ethylene glycol dimethyl ether nickel chloride, nickel trifluoromethanesulfonate, nickel acetate tetrahydrate, and nickel acetylacetonate.

[0025] The ligand is a nitrogen or phosphine compound, specifically one or more of bis(diphenylphosphino)methane (DPPM), bis(diphenylphosphino)ethane (DPPE), bis(diphenylphosphino)propane (DPPB), bis(diphenylphosphino)butane (DPPP), bis(diphenylphosphino)benzene (DPPBz), bis(diphenylphosphino)pyridine (DPPy), triphenylphosphine (PPh3), tributylphosphine (PBu3), tricyclohexylphosphine (PCy3), pyridine (Py), 2,2-bipyridine (bpy), 4,4-di-tert-butyl-2,2-bipyridine (dtbpy), and 1,10-phenanthroline (Phen); preferably one or more of 2,2-bipyridine, 1,10-phenanthroline, 4,4-di-tert-butyl-2,2-bipyridine, bis(diphenylphosphino)pyridine, and bis(diphenylphosphino)butane.

[0026] The reducing agent is a metal reducing agent and an organic reducing agent; the metal reducing agent is zinc (Zn) and manganese (Mn); and the organic reducing agent is tetrakis(dimethylamino)ethylene (TDAE).

[0027] The reducing agent is preferably a metal reducing agent.

[0028] The organic solvent is at least one of tetrahydrofuran, ethylene glycol dimethyl ether, 1,4-dioxane, dichloromethane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide; preferably at least one of acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, and 1,4-dioxane.

[0029] The molar mass ratio of the phenylbutyryne electrophilic reagent to the halogenated aryl electrophilic reagent is 1:1.05-2.5, the reaction temperature is 15-80°C, and the reaction time is 4-24h, preferably room temperature to 60°C.

[0030] The amount of the catalyst used is 1-15% of the molar amount of the phenylbutyryne electrophilic reagent.

[0031] The amount of the ligand used is 1-15% of the molar amount of the phenylbutyryne electrophilic reagent.

[0032] The amount of the reducing agent used is 2 to 2.5 times the molar amount of the phenylbutyryne electrophilic reagent.

[0033] Compared with the prior art, the present invention has the following advantages:

[0034] (1) In the preparation method of 1,4-diphenyl-1-butyne derivatives of the present invention, the nickel catalyst is inexpensive, the two different electrophilic reagents are stable, and the structures are diverse and readily available, so that 1,4-diphenyl-1-butyne derivatives with rich and diverse structures can be synthesized;

[0035] (2) The reaction conditions of the present invention are mild, the operation is simple, the reagents used are safe, and there is no pollution from the three wastes;

[0036] (3) The reaction has the advantages of high efficiency, few by-products, and easy separation and purification. The entire method can synthesize complex 1,4-diphenyl-1-butyne derivatives with low consumption and high efficiency, and has good applicability. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Figure 1 is the hydrogen spectrum of ethyl 4-(4-bromo-1-butyne)benzoate (4a) 1 H NMR: 400MHz, CDCl3) graph;

[0038] Figure 2 is the hydrogen spectrum of 4-bromo-1-phenyl-1-butyne (4b) 1 H NMR: 500MHz, CDCl3) graph;

[0039] Figure 3 is the hydrogen spectrum of ethyl 4-(4-phenyl-1-butyne)benzoate (6a) 1 H NMR: 500MHz, CDCl3) graph;

[0040] Figure 4 The carbon spectrum of ethyl 4-(4-phenyl-1-butyne)benzoate (6a) is 13 C NMR: 1256z, CDCl3) graph;

[0041] Figure 5 The hydrogen spectrum of 4-cyano-1,4-diphenyl-1-butyne (6b) is ( 1 H NMR: 500MHz, CDCl3) graph;

[0042] Figure 6 The carbon spectrum of 4-cyano-1,4-diphenyl-1-butyne (6b) is ( 13 C NMR: 126MHz, CDCl3) graph;

[0043] Figure 7 The hydrogen spectrum of ethyl 4-(4-(4-cyanophenyl)-1-butyne)-1-benzoate (6c) is 1 H NMR: 500MHz, CDCl3) graph;

[0044] Figure 8 The carbon spectrum of ethyl 4-(4-(4-cyanophenyl)-1-butyne)-1-benzoate (6c) is 13 C NMR: 126MHz, CDCl3) graph;

[0045] Fig. 9The hydrogen spectrum of ethyl 4-(4-(4-acetylphenyl)but-1-yn-1-yl)benzoate (6d) is 1 H NMR: 500MHz, CDCl3) graph;

[0046] Fig.10 The carbon spectrum of ethyl 4-(4-(4-acetylphenyl)but-1-yn-1-yl)benzoate (6d) is 13 C NMR: 126MHz, CDCl3) graph;

[0047] Fig.11 The hydrogen spectrum of ethyl 4-(4-(1-oxo-1,3-dihydroisobenzofuran-5-yl)but-1-yn-1-yl)benzoate (6e) is 1 H NMR: 500MHz, CDCl3) graph;

[0048] Fig.12 The carbon spectrum of ethyl 4-(4-(1-oxo-1,3-dihydroisobenzofuran-5-yl)but-1-yn-1-yl)benzoate (6e) is 13 C NMR: 126MHz, CDCl3) graph;

[0049] Fig.13 The hydrogen spectrum of ethyl 4-(4-(1,2-methylenedioxyphenyl)but-1-yn-1-yl)benzoate (6f) is 1 HNMR: 500MHz, CDCl3) graph;

[0050] Fig.14 The carbon spectrum of ethyl 4-(4-(1,2-methylenedioxyphenyl)but-1-yn-1-yl)benzoate (6f) is 13 CNMR: 126MHz, CDCl3) image;

[0051] Fig.15 The hydrogen spectrum of 4-(4-(3,5-dichlorophenyl)but-3-yn-1-yl)benzonitrile (6 g) is ( 1 H NMR: 500MHz, CDCl3) graph;

[0052] Fig.16 The carbon spectrum of 4-(4-(3,5-dichlorophenyl)but-3-yn-1-yl)benzonitrile (6 g) is ( 13 C NMR: 126 MHz, CDCl3) chart. DETAILED DESCRIPTION

[0053] In order to better understand the present invention, the following examples are provided for illustration. The following examples and corresponding data are only used to further describe the technical solution of the present invention in detail, and cannot be understood as limiting the scope of protection of the present invention. The raw materials, reagents and solvents used in the present invention are all commercially available bulk products.

[0054] The phenylbutyryne electrophilic reagent of the present invention can be prepared by the following method: using an organic solvent as a reaction medium, reacting a compound containing an alcoholic hydroxyl group with a halogenating reagent to obtain a phenylbutyryne electrophilic reagent.

[0055] The structure of the compound containing alcoholic hydroxyl group:

[0056] R 1 , R 3 , R 4 Same as the previous phenylbutyryne electrophilic reagent.

[0057] The halogenating agent is dichlorohydantoin, carbon tetrabromide, bromine, and iodine. The organic solvent is one or more of tetrahydrofuran, toluene, dichloromethane, and acetonitrile. The reaction uses a catalyst, which is triphenylphosphine. The amount of the catalyst used is 1.2 to 2.5 times the molar amount of the compound containing alcoholic hydroxyl groups.

[0058] The molar ratio of the compound containing alcoholic hydroxyl group to the halogenating agent is 1:1.1-2, and the reaction temperature is room temperature.

[0059] The preparation method of the compound containing alcoholic hydroxyl group comprises: using an organic solvent as a reaction medium, reacting compound 1 with compound 2 under the action of a catalyst to obtain a compound containing alcoholic hydroxyl group. The catalyst is bis(triphenylphosphine)palladium dichloride (the amount used is 0.5-1.5% of the molar amount of compound 2) and cuprous iodide (the amount used is 0.5-1.5% of the molar amount of compound 2).

[0060] Compound 1: Compound 2:

[0061] The molar ratio of compound 1 to compound 2 is 1:1.05-1.5, the reaction temperature is 15-30° C., the organic solvent is one or more of tetrahydrofuran, triethylamine, N,N-dimethylformamide, and N,N-dimethylacetamide, and the reaction time is 4-12 hours.

[0062] The reaction equation of phenylbutyryne electrophilic reagents:

[0063]

[0064] Preparation of phenylbutyryne electrophilic reagents:

[0065] (1) Synthesis of ethyl 4-(4-bromo-1-butyne)benzoate (4a), reaction equation:

[0066]

[0067] (1-1) Under nitrogen conditions, 10 mmol of 4-hydroxy-1-alkyne (2a), 1.3 equivalents of ethyl 4-iodobenzoate (1a) (the molar ratio of compound 2a: compound 1a is 1:1.3), 1% (1% of the molar amount of compound 2a) of bis(triphenylphosphine)palladium dichloride, and 1% (1% of the molar amount of compound 2a) of cuprous iodide were added to a reaction flask, and finally triethylamine and tetrahydrofuran (Et3N / THF=1 / 1, volume ratio) were added as reaction solvents (20 mL). The reaction was carried out at room temperature for 12 h. After the reaction was completed, the reaction was filtered, and the filtrate was removed by vacuum distillation before continuing to the next step of the reaction.

[0068] (1-2) Under air conditions, 1.5 equivalents of carbon tetrabromide (CBr4) and 2 equivalents of triphenylphosphine (PPh3) (the molar ratio of compound 2a:triphenylphosphine is 1:2) were added to the crude product of the previous step, and finally dichloromethane (DCM) was added as the reaction solvent (20 mL). The reaction was carried out at room temperature for 3 h. After the reaction was completed, dichloromethane was removed by vacuum distillation to obtain a crude product, which was separated by column chromatography on silica gel to obtain 2.72 g of ethyl 4-(4-bromo-1-butyne)benzoate (4a) with an isolation yield of 97%.

[0069] Characterization data of ethyl 4-(4-bromo-1-butyne)benzoate (4a): 1 H NMR (400MHz, Chloroform-d) δ7.96 (d, J = 8.3Hz, 2H), 7.46 (d, J = 8.4Hz, 2H), 4.36 (q, J = 7.1Hz, 2H), 3.52 (t, J = 7.2Hz, 2H), 2.99 (t, J = 7.2Hz, 2H), 1.38 (t, J = 7.1Hz, 3H). Hydrogen spectrum is shown in Figure 1 shown.

[0070] (2) Synthesis of 4-bromo-1-phenyl-1-butyne (4b), reaction equation:

[0071]

[0072] (2-1) Under nitrogen conditions, 10 mmol of 4-hydroxy-1-yne (2a), 1.2 equivalents of iodobenzene (1b) (the molar ratio of compound 2a: iodobenzene is 1:1.2), 1% (1% of the molar amount of compound 2a) of bis(triphenylphosphine)palladium dichloride, and 1% (1% of the molar amount of compound 2a) of cuprous iodide were added to a reaction flask. Finally, triethylamine and tetrahydrofuran (Et3N / THF=1 / 1) were added as reaction solvents (20 mL). The reaction was carried out at room temperature for 12 h. After the reaction was completed, the mixture was filtered, the filtrate was removed by vacuum distillation, and the next step of the reaction was continued.

[0073] (2-2) Under air conditions, 1.5 equivalents of carbon tetrabromide (CBr4) and 2 equivalents of triphenylphosphine (PPh3) (the molar ratio of compound 2a:triphenylphosphine is 1:2) were added to the crude product of the previous step, and finally dichloromethane (DCM) was added as a reaction solvent (20 mL), and the reaction was carried out at room temperature for 3 h. After the reaction was completed, dichloromethane was removed by vacuum distillation to obtain a crude product, which was separated by column chromatography on silica gel to obtain 2.04 g of 4-bromo-1-phenyl-1-butyne (4a), with an isolated yield of 98%.

[0074] Characterization data of 4-bromo-1-phenyl-1-butyne (4b): 1 H NMR (500MHz, Chloroform-d) δ7.42 (dd, J = 6.7, 3.0 Hz, 2H), 7.31-7.28 (m, 3H), 3.53 (t, J = 7.4 Hz, 2H), 2.98 (t, J = 7.4 Hz, 2H). The hydrogen spectrum is shown in Figure 2 shown.

[0075] Example 1: Synthesis of ethyl 4-(4-phenyl-1-butyne)benzoate (6a)

[0076] Reaction equation:

[0077]

[0078] Under nitrogen conditions, 84.0 mg (0.30 mmol) of ethyl 4-(4-bromo-1-butyne)benzoate (4a), 2.5 equivalents of bromobenzene (bromobenzene is 2.5 times the molar amount of compound 4a), 10% (10% of the molar amount of compound 4a) of nickel bromide as a catalyst, 10% (10% of the molar amount of compound 4a) of 2,2-bipyridine (bpy) as a ligand, 2.2 equivalents of Zn as a reducing agent, and 1 mL of N,N-dimethylacetamide as a solvent were added to a reaction flask in sequence. The reaction was carried out at room temperature (25°C) for 12 h. After the reaction was completed, the mixture was cooled to room temperature, quenched with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, ethyl acetate was removed by rotary evaporation, and separated by column chromatography on silica gel to obtain 74 mg of ethyl 4-(4-phenyl-1-butyne)benzoate (6a) with an isolation yield of 89%.

[0079] Characterization data of ethyl 4-(4-phenyl-1-butyne)benzoate (6a): 1 H NMR(500MHz,Chloroform-d)δ7.95(d,J=8.4Hz,2H),7.41(d,J=8.4Hz,2H),7.35-7.20(m,7H) ,4.36(q,J=7.1Hz,3H),2.93(t,J=7.5Hz,3H),2.72(t,J=7.5Hz,3H),1.38(d,J=14.3Hz,2H). 13 C NMR (126MHz, CDCl3)δ166.2,140.5,131.4,129.39,129.35,128.5,128.4,126.4,92.9,80.9,61.1,35.0,21.8,14.3. Hydrogen and carbon spectra are shown in Figure 3 and 4 shown.

[0080] Example 2: Synthesis of 4-cyano-1,4-diphenyl-1-butyne (6b)

[0081] Reaction equation:

[0082]

[0083] Under nitrogen conditions (the amounts added below are based on the molar mass of 4b), 62.4 mg (0.30 mmol) of 4-bromo-1-phenyl-1-butyne (4b), 1.5 equivalents of 4-cyanobenzene, 10% (10% of the molar amount of compound 4b) of nickel chloride as a catalyst, 10% (10% of the molar amount of compound 4a) of 1,10-phenanthroline (Phen) as a ligand, 2.2 equivalents of Mn as a reducing agent, and 1 mL of N,N-dimethylacetamide as a solvent were added to the reaction flask in sequence. The reaction was carried out at room temperature (25°C) for 12 h. After the reaction was completed, the mixture was cooled to room temperature, quenched with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, ethyl acetate was removed by rotary evaporation, and 4-cyano-1,4-diphenyl-1-butyne (6b) 62 mg was obtained by column chromatography on silica gel with an isolation yield of 90%.

[0084] Characterization data of 4-cyano-1,4-diphenyl-1-butyne (6b): 1 H NMR(500MHz,Chloroform-d)δ7.60(d,J=8.2Hz,2H),7.38(d,J=8.2Hz,2H),7.3 6-7.32(m,2H),7.29-7.27(m,3H),2.97(t,J=7.2Hz,2H),2.72(t,J=7.2Hz,2H). 13 C NMR (126MHz, CDCl3)δ146.1,132.2,131.5,129.5,128.3,127.9,123.5,119.1,110.3,88.3,82.1,35.1,21.1. Hydrogen and carbon spectra are shown in Figure 5 and 6 shown.

[0085] Example 3: Synthesis of ethyl 4-(4-(4-cyanophenyl)-1-butyne)-1-benzoate (6c)

[0086] Reaction equation:

[0087]

[0088] Under nitrogen conditions, 84.0 mg (0.30 mmol) of ethyl 4-(4-bromo-1-butyne)benzoate (4a), 1.5 equivalents of 4-cyanobenzene, 10% (10% of the molar amount of compound 4a) of ethylene glycol dimethyl ether nickel chloride as a catalyst, 10% (10% of the molar amount of compound 4a) of 4,4-di-tert-butyl-2,2-bipyridine (dtbpy) as a ligand, and 2.2 equivalents of 4-bromo-1-butyne (4a) were added to the reaction flask in sequence. The reaction mixture was stirred for 12 h at room temperature (25 °C) and cooled to room temperature. The mixture was quenched with water and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The ethyl acetate was removed by rotary evaporation and separated by column chromatography on silica gel to obtain 4-(4-(4-cyanophenyl)-1-butyne)-1-benzoic acid ethyl ester (6c) 78 mg in an isolation yield of 86%.

[0089] Characterization data of ethyl 4-(4-(4-cyanophenyl)-1-butyne)-1-benzoate (6c): 1 H NMR(500MHz,Chloroform-d)δ7.95(d,J=8.2Hz,2H),7.61(d,J=8.2Hz,2H),7.38(dd,J=8.3,2.2H z, 4H), 4.36 (q, J = 7.2Hz, 2H), 2.98 (t, J = 7.2Hz, 2H), 2.74 (t, J = 7.2Hz, 2H), 1.38 (t, J = 7.2Hz, 3H). 13 C NMR (126MHz, CDCl3)δ166.1,145.9,132.2,131.4,129.6,129.4,129.4,128.1,119.0,110.4,91.5,81.6,61.2,34.9,21.1,14.3. Hydrogen and carbon spectra are shown in Figure 7 and 8 shown.

[0090] Example 4: Synthesis of ethyl 4-(4-(4-acetylphenyl)but-1-yn-1-yl)benzoate (6d)

[0091] Reaction equation:

[0092]

[0093] Under nitrogen, 84.0 mg (0.30 mmol) of ethyl 4-(4-bromo-1-butyne)benzoate (4a), 2.0 equivalents of 4-acetyl bromobenzene, 10% (10% of the molar amount of compound 4a) of dibromobis(pyridine)nickel as a catalyst, 10% (10% of the molar amount of compound 4a) of bis(diphenylphosphine)pyridine (DPPy) as a ligand, 2-2.5 equivalents of Mn as a reducing agent, 1 mL of dimethyl sulfoxide as a solvent were added to the reaction bottle in sequence, and the reaction was carried out at 45°C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, quenched with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, ethyl acetate was removed by rotary evaporation, and 88 mg of ethyl 4-(4-(4-acetylphenyl)but-1-yn-1-yl)benzoate (6d) was obtained by column chromatography on silica gel, with an isolated yield of 92%.

[0094] Characterization data of ethyl 4-(4-(4-acetylphenyl)but-1-yn-1-yl)benzoate (6d): 1 H NMR(500MHz,Chloroform-d)δ7.92(dd,J=18.0,8.4Hz,4H),7.36(dd,J=15.8,8.4Hz,4H),4.35(q ,J=7.1Hz,2H),2.96(t,J=7.3Hz,2H),2.73(t,J=7.3Hz,2H),2.57(s,3H),1.37(t,J=7.1Hz,3H). 13 C NMR (126MHz, CDCl3)δ197.8,166.1,146.0,135.6,131.4,129.5,129.4,128.8,128.6,128.3,92.1,81.3,61.1,34.8,26.6,21.3,14.3. Hydrogen and carbon spectra are shown in Fig. 9 and 10 shown.

[0095] Example 5: Synthesis of ethyl 4-(4-(1-oxo-1,3-dihydroisobenzofuran-5-yl)but-1-yn-1-yl)benzoate (6e)

[0096] Reaction equation:

[0097]

[0098] Under nitrogen conditions, 84.0 mg (0.30 mmol) of ethyl 4-(4-bromo-1-butyne)benzoate (4a), 1.8 equivalents of 5-bromoisobenzofuran-1(3H)-one, 10% (10% of the molar amount of compound 4a) of nickel trifluoromethanesulfonate as a catalyst, 10% (10% of the molar amount of compound 4a) of bis(diphenylphosphino)butane (DPPP) as a ligand, and 2 equivalents of M n as a reducing agent, 1 mL of acetonitrile as a solvent, and reacted at 50°C for 12 h. After the reaction was completed, the mixture was cooled to room temperature and quenched with water. The mixture was extracted with ethyl acetate, and the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and ethyl acetate was removed by rotary evaporation. 94 mg of ethyl 4-(4-(1-oxo-1,3-dihydroisobenzofuran-5-yl)but-1-yn-1-yl)benzoate (6e) was obtained by column chromatography on silica gel. The yield was 94%.

[0099] Characterization data of ethyl 4-(4-(1-oxo-1,3-dihydroisobenzofuran-5-yl)but-1-yn-1-yl)benzoate (6e): 1 H NMR(500MHz,Chloroform-d)δ7.95(d,J=8.4Hz,2H),7.87(d,J=7.9Hz,1H),7.44(d,J=7.3Hz,1H),7.41-7.33( m,3H),5.29(s,2H),4.36(q,J=7.2Hz,2H),3.06(t,J=7.3Hz,2H),2.78(t,J=7.3Hz,2H),1.38(t,J=7.1Hz,3H). 13 C NMR (126MHz, CDCl3)δ170.96,166.05,147.45,147.13,131.36,129.84,129.64,129.44,128.03,125.77,124.21,122.06,91.53,81.62,77.30,77.05,76.79,69.49,61.13,35.12,21.42,14.31. Hydrogen and carbon spectra are shown in Fig.11 and 12 shown.

[0100] Example 6: Synthesis reaction equation of ethyl 4-(4-(1,2-methylenedioxyphenyl)but-1-yn-1-yl)benzoate (6f):

[0101]

[0102] Under nitrogen conditions, 84.0 mg (0.30 mmol) of ethyl 4-(4-bromo-1-butyne)benzoate (4a), 2.5 equivalents of 4-bromo-1,2-methylenedioxybenzene, 10% (10% of the molar amount of compound 4a) of nickel acetate tetrahydrate as a catalyst, 10% (10% of the molar amount of compound 4a) of 4,4-di-tert-butyl-2,2-bipyridine (dtbpy) as a ligand, 2.5 equivalents of Zn as a reducing agent, and 1 mL of 1,4-dioxane as a solvent were added to a reaction flask in sequence, and the reaction was carried out at room temperature (25°C) for 12 h. After the reaction, the mixture was cooled to room temperature, quenched with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and ethyl acetate was removed by rotary evaporation. The mixture was separated by column chromatography on silica gel to obtain 91 mg of ethyl 4-(4-(1,2-methylenedioxyphenyl)but-1-yn-1-yl)benzoate (6f) with an isolation yield of 94%.

[0103] Characterization data of ethyl 4-(4-(1,2-methylenedioxyphenyl)but-1-yn-1-yl)benzoate (6f): 1 H NMR(500MHz,Chloroform-d)δ7.96(d,J=8.3Hz,2H),7.42(d,J=8.3Hz,2H),6.76(d,J=7.7Hz,2H),6.71(d,J=7.6 Hz,1H),5.93(s,2H),4.37(q,J=7.1Hz,2H),2.84(t,J=7.4Hz,2H),2.67(t,J=7.4Hz,2H),1.39(t,J=7.2Hz,3H). 13 C NMR (126MHz, CDCl3)δ166.2,147.6,146.1,134.3,131.4,129.4,129.4,128.5,121.4,109.0,108.2,100.9,92.8,81.0,61.1,34.7,22.1,14.3. Hydrogen and carbon spectra are shown in Fig.13 and 14 shown.

[0104] Example 7: Synthesis of 4-(4-(3,5-dichlorophenyl)but-3-yn-1-yl)benzonitrile (6 g)

[0105] Reaction equation:

[0106]

[0107] Under nitrogen conditions, 82.8 mg (0.30 mmol) of 1-(4-bromobut-1-yn-1-yl)-3,5-dichlorobenzene (4c), 1.5 equivalents of 4-cyanobenzene (the amount is 1.5 times the molar amount of compound 4c), 10% (the amount is 10% of the molar amount of compound 4c) of nickel acetylacetonate as a catalyst, 10% (the amount is 10% of the molar amount of compound 4c) of 2,2-bipyridine (dtbpy) as a ligand, 2 equivalents of Zn as a reducing agent, and 1 mL of N,N-dimethylacetamide as a solvent were added sequentially into a reaction flask, and the reaction was carried out at room temperature (25°C) for 20 h. After the reaction, the mixture was cooled to room temperature, quenched with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and ethyl acetate was removed by rotary evaporation. The mixture was separated by column chromatography on silica gel to obtain 87 mg of 4-(4-(3,5-dichlorophenyl)but-3-yn-1-yl)benzonitrile (6 g), with an isolation yield of 97%.

[0108] Characterization data of 4-(4-(3,5-dichlorophenyl)but-3-yn-1-yl)benzonitrile (6 g): 1 H NMR (500MHz, Chloroform-d) δ7.61(d,J=8.0Hz,2H),7.36(d,J=8.0Hz,2H),7.23(s,1H),7.19(s,2H),2.96(t,J=7.3Hz,2H),2.72(t,J=7.3Hz,2H). 13 C NMR (126MHz, CDCl3)δ145.7,134.8,132.3,129.8,129.4,128.2,126.3,118.9,110.5,91.2,79.6,34.7,21.0. Hydrogen and carbon spectra are shown in Fig.15 and 16 shown.

[0109] Comparative Example 1

[0110] Reaction equation:

[0111]

[0112] Under nitrogen conditions, with triethylamine and tetrahydrofuran (Et3N / THF=1 / 1) as reaction solvents, p-bromotoluene and 4-phenylbutyne (the molar ratio of the two substances is 1:1.1) were heated under reflux for 12 hours in the presence of Pd(PPh3)4 (2% of the molar amount of phenylbutyne) and CuBr (4% of the molar amount of phenylbutyne), and the product was obtained with a yield of 35%.

[0113] Comparative Example 2

[0114] Reaction equation:

[0115]

[0116] Under nitrogen conditions, with tetrahydrofuran as the reaction solvent, phenylacetylene and 1-(2-bromoethyl)-3-methoxybenzene (the molar ratio of the two substances is 1:1.1) were first reacted at -78°C for 0.5h in the presence of BuLi (1.2 molar amount of phenylacetylene) and NaI (5% molar amount of phenylacetylene) at room temperature for 12h to obtain a product with a yield of 29%.

[0117] Comparative Example 3

[0118] Reaction equation:

[0119]

[0120] Under nitrogen conditions, with 1,4-dioxane as the reaction solvent, triethylamine (the amount is 1.0 of the molar amount of phenylbutyne), 3-chloro-4-bromonitrobenzene and 4-phenylbutyne (the molar ratio of the two substances is 1:1.1) were reacted at 100°C for 10 hours in the presence of Pd(PPh3)4 (the amount is 2% of the molar amount of phenylbutyne) and CuBr (the amount is 2% of the molar amount of phenylbutyne) to obtain a product with a yield of 42%.

[0121] Comparative Example 4

[0122] Reaction equation:

[0123]

[0124] Under nitrogen conditions, with 1,4-dioxane as the reaction solvent, triethylamine (the amount is 1.0 of the molar amount of phenylbutyne), 2-bromopyrazine and 4-phenylbutyne (the molar ratio of the two substances is 1:1.1) were reacted at 100°C for 12 hours in the presence of Pd(PPh3)4 (the amount is 2% of the molar amount of phenylbutyne) and CuBr (the amount is 2% of the molar amount of phenylbutyne) to obtain a product with a yield of 47%.

[0125] Comparative Example 5

[0126]

[0127] Under nitrogen conditions, with triethylamine and tetrahydrofuran (Et3N / THF=1 / 1) as reaction solvents, o-bromotoluene and 4-phenylbutyne (the molar ratio of the two substances is 1:1.1) were heated under reflux for 12 hours in the presence of Pd(PPh3)4 (2% of the molar amount of phenylbutyne) and CuBr (4% of the molar amount of phenylbutyne) to obtain a product with a yield of 50%.

[0128] From the above comparative examples, it can be seen that the current Pd / Cu catalyzed coupling reaction or the strong base / low temperature substitution reaction does not obtain a good yield, while the implementation examples of the present invention obtain very good results, with a yield of more than 86%, indicating that the method of the present invention can efficiently synthesize 1,4-diphenyl-1-butyne compounds.

Claims

1. A method for synthesizing 1,4-diphenyl-1-butyne derivatives by nickel-catalyzed reduction coupling, characterized in that: The following steps are involved: In a protective atmosphere, an organic solvent is used as a reaction medium, and a phenylbutyne electrophilic reagent and a halogenated aryl electrophilic reagent are reacted under the action of a catalyst, a ligand and a reducing agent to obtain a 1,4-diphenyl-1-butyne derivative; The structure of the phenylbutyryne electrophilic reagent is The structure of the halogenated aryl electrophilic reagent is The structure of 1,4-diphenyl-1-butyne derivatives is Where R 1 is H, ester group, halogen, substituted or unsubstituted aryl group, heteroaryl group; R 1 In the structure of phenylbutyryne electrophiles, it is monosubstituted, disubstituted, and trisubstituted; R 2 is H or a substituent on the benzene ring or R 2 Form a benzocyclic group with the benzene ring; R 2 When R is a substituent on a benzene ring, 2 is CN, acyl, substituted or unsubstituted aryl, or heteroaryl; R 2 With the benzene ring to form a benzocyclic group, in this case the benzocyclic group is indolyl, quinolyl, benzofuranyl, Benzothiphenyl, R 3 and R 4 is H, alkyl, or aryl alone; R 1 With R 2 Not at the same time H; In the phenylbutyryne electrophilic reagent, X is Cl, Br or I; In halogenated aryl electrophiles, Y is Br or I; The catalyst is a nickel catalyst; the nickel catalyst is one or more of nickel iodide, nickel bromide, nickel chloride, nickel acetate tetrahydrate, nickel acetylacetonate, nickel tetrakis(triphenylphosphine), nickel dibromide(pyridine), bis(triphenylphosphine) nickel dichloride, nickel trifluoromethanesulfonate, nickel fluoroborate hexahydrate, ethylene glycol dimethyl ether nickel bromide, and ethylene glycol dimethyl ether nickel chloride; The ligand is one or more of bis(diphenylphosphino)methane, bis(diphenylphosphino)ethane, bis(diphenylphosphino)propane, bis(diphenylphosphino)butane, bis(diphenylphosphino)benzene, bis(diphenylphosphino)pyridine, triphenylphosphine, tributylphosphine, tricyclohexylphosphine, pyridine, 2,2-bipyridine, 4,4-di-tert-butyl-2,2-bipyridine, and 1,10-phenanthroline.

2. The method for synthesizing 1,4-diphenyl-1-butyne derivatives by nickel-catalyzed reduction coupling according to claim 1, characterized in that: R 1 The aryl group is phenyl, naphthyl, or biphenyl, and the substituent in the substituted aryl group is one, two, or three of alkyl, F, Cl, amino, or amide; R 2 The aryl group is phenyl, naphthyl, or biphenyl, and the substituent in the substituted aryl group is one, two, or three of alkyl, F, Cl, amino, or amide; R 1 The heteroaryl group is pyridyl, indolyl, quinolyl, furyl, or thienyl; R 2 The heteroaryl group is pyridyl, indolyl, quinolyl, furyl, thienyl; R 3 The aryl group is phenyl, naphthyl or biphenyl; R 4 The aryl group is phenyl, naphthyl or biphenyl.

3. The method for synthesizing 1,4-diphenyl-1-butyne derivatives by nickel-catalyzed reduction coupling according to claim 1, characterized in that: In the phenylbutyryne electrophilic reagent, X is Br, R 1 is one or more of H, ester group, and halogen; R 3 and R 4 is H; ester group: R'-OC(O)-, R' is an alkyl group.

4. The method for synthesizing 1,4-diphenyl-1-butyne derivatives by nickel-catalyzed reduction coupling according to claim 1, characterized in that: Among halogenated aromatic electrophiles, R 2 is H or a substituent on the benzene ring or R 2 It forms a benzocyclic group with the benzene ring; R 2 When R is a substituent on a benzene ring, 2 is CN, acyl, acyl: R″-C(O)-, R″ is alkyl; R 2 With the benzene ring to form a benzocyclic group, in this case the benzocyclic group is indolyl, quinolyl, benzofuranyl, Benzothiphenyl, In the case of halogenated aryl electrophiles, Y is Br.

5. The method for synthesizing 1,4-diphenyl-1-butyne derivatives by nickel-catalyzed reduction coupling according to claim 1, characterized in that: The nickel catalyst is one or more of nickel iodide, nickel bromide, nickel chloride, dibromobis(pyridine)nickel, ethylene glycol dimethyl ether nickel chloride, nickel trifluoromethanesulfonate, nickel acetate tetrahydrate, and nickel acetylacetonate; The ligand is one or more of 2,2-bipyridine, 1,10-phenanthroline, 4,4-di-tert-butyl-2,2-bipyridine, bis(diphenylphosphine)pyridine and bis(diphenylphosphine)butane.

6. The method for synthesizing 1,4-diphenyl-1-butyne derivatives by nickel-catalyzed reduction coupling according to claim 1, characterized in that: The reducing agent is a metal reducing agent or an organic reducing agent; the metal reducing agent is Zn or Mn; the organic reducing agent is tetratris(dimethylamino)ethylene; The organic solvent is at least one of tetrahydrofuran, ethylene glycol dimethyl ether, 1,4-dioxane, dichloromethane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone and dimethyl sulfoxide.

7. The method for synthesizing 1,4-diphenyl-1-butyne derivatives by nickel-catalyzed reduction coupling according to claim 6, characterized in that: The reducing agent is Zn or Mn; The organic solvent is one or more of acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, and 1,4-dioxane.

8. The method for synthesizing 1,4-diphenyl-1-butyne derivatives by nickel-catalyzed reduction coupling according to claim 1, characterized in that: The molar ratio of the phenylbutyryne electrophilic reagent to the halogenated aryl electrophilic reagent is 1:1.05-2.5, the reaction temperature is 15-80°C, and the reaction time is 4-24h.

9. The method for synthesizing 1,4-diphenyl-1-butyne derivatives by nickel-catalyzed reduction coupling according to claim 1, characterized in that: The dosage of the catalyst is 1-15% of the molar amount of the phenylbutyryne electrophilic reagent; the dosage of the ligand is 1-15% of the molar amount of the phenylbutyryne electrophilic reagent; the dosage of the reducing agent is 2-2.5 times of the molar amount of the phenylbutyryne electrophilic reagent.

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