Compounds based on diphenylamine derivatives and quinoxaline skeletons, preparation methods and applications as photocatalysts

Abstract

The invention relates to a compound based on a diphenylamine derivative and a quinoxaline skeleton, a preparation method and an application as a photocatalyst, and belongs to the technical field of photocatalysis. The compound exhibits excellent photocatalytic efficiency and selectivity in an amination dehydrogenation aromatization reaction synergistically catalyzed by organic photoredox catalysis and cobalt oxime complexes, and can efficiently promote the synthesis of aromatic amine / heterocyclic amine compounds under mild visible light conditions. Compared with the prior art, the photocatalyst of the invention has higher catalytic activity and wider substrate applicability, has significant practical application value, can be effectively applied to the field of green organic synthesis, and is particularly suitable for the green synthesis process of aromatic amine compounds and drugs such as local anesthetic tetracaine.

Description

Technical Field

[0001] The invention relates to the technical field of photocatalysts, and in particular to compounds based on diphenylamine derivatives and quinoxaline skeletons, preparation methods and applications thereof as photocatalysts. Background Art

[0002] In recent years, photoredox catalysts based on ruthenium (Ru) and iridium (Ir) have attracted widespread attention. Since the complexes of Ru and Ir cover a wide range of photoredox potentials to drive the intermolecular single electron transfer (SET) process, many complex organic transformations, including dual catalytic reactions, have been achieved. However, due to the high price of Ru and Ir complexes, their application is limited. Technologists have studied photocatalysts based on copper (Cu), chromium (Cr), and iron (Fe), which are abundant resources on the earth. They have overcome the problems of narrow light response range and low quantum efficiency of traditional photocatalysts (such as TiO), but there are also problems such as difficulty in light absorption and band gap regulation, serious recombination of photogenerated carriers, poor chemical stability, complex reaction mechanism, and difficulty in catalyst recovery and reuse.

[0003] Based on the above technical problems, the research group of the inventor obtained an organic photocatalyst based on quinoxaline skeleton (CN114907328B) in the previous research. The above organic photocatalyst showed excellent photocatalytic efficiency in the visible light catalytic organic reaction of dehydrogenation / (3+2) cycloaddition reaction catalyzed by organic photoredox catalysis and Lewis acid synergistic catalysis. However, the inventor found in the subsequent research process that the above organic photocatalyst has a poor catalytic effect on the synthesis of aromatic amine compounds and cannot be used for the synthesis of aromatic amine compounds.

[0004] In order to better synthesize aromatic amine compounds and to meet the demand for green, practical and sustainable processes, the inventor's research group conducted continuous research and obtained compounds based on diphenylamine derivatives and quinoxaline skeletons. This compound has a significant catalytic effect on the synthesis of aromatic amine compounds and has broad application prospects. Summary of the invention

[0005] In view of the above-mentioned shortcomings, the present invention provides a compound based on a diphenylamine derivative and a quinoxaline skeleton, wherein the chemical formula of the compound is shown in formula (I):

[0006]

[0007] (I);

[0008] Among them, R 1 is hydrogen, substituted or unsubstituted C1-C 60 Alkyl, substituted or unsubstituted C2-C60 Alkenyl, substituted or unsubstituted C2-C 60 Alkynyl, substituted or unsubstituted C1-C 60 Alkoxy, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C1-C 10 Heterocycloalkyl, substituted or unsubstituted C3-C 10 Cycloalkenyl, substituted or unsubstituted C1-C 10 Heterocycloalkenyl, substituted or unsubstituted C6-C 60 Aryl, substituted or unsubstituted C1-C 60 a heteroaryl group, a hydroxyl group, a carboxyl group, an ester group, a cyano group, an amide group or a halogen atom;

[0009] R 2 is hydrogen, substituted or unsubstituted C1-C 60 Alkyl, substituted or unsubstituted C1-C 60 an alkoxy group, a hydroxy group, a carboxyl group, an ester group, a cyano group, an amide group or a halogen atom.

[0010] Preferably, R 1 is hydrogen, substituted or unsubstituted C1-C 60 Alkyl, hydroxyl, carboxyl or halogen atom; R 2 is substituted or unsubstituted C1-C 60 Alkyl, substituted or unsubstituted C1-C 60 an alkoxy group, a hydroxy group, a carboxyl group, an ester group, a cyano group, an amide group or a halogen atom.

[0011] Preferably, R 2 is substituted or unsubstituted C1-C 60 an alkoxy group or a halogen atom.

[0012] Preferably, the structural formula of the compound is as follows:

[0013]

[0014] The second object of the present invention is to provide a method for preparing the compound based on diphenylamine derivatives and quinoxaline skeleton, comprising the following steps:

[0015]

[0016] (1) Compound 1 and NaBH4 ethanol solution were stirred at 0°C for 1 h, and then at room temperature until the reaction system changed color. After the reaction was completed by TLC monitoring, water was poured into the system to quench the reaction, and then extracted with ethyl acetate. The organic phase was evaporated to dryness to obtain o-phenylenediamine compound 2;

[0017] (2) o-phenylenediamine compound 2 was placed in a round-bottom flask, 4N HCl aqueous solution was added, the first portion of oxalic acid was added and the reaction mixture was refluxed for 6 h, then the second portion of oxalic acid was added and the mixture was refluxed overnight for 12 h, the solution mixture was cooled to room temperature and vacuum filtered, the filtrate was washed several times with a large amount of deionized water and dried in air to obtain a brown solid compound 3;

[0018] (3) Compound 3 was dissolved in dichlorothione in a flask, stirred at room temperature for 5 min, and then a small amount of dimethylformamide was added dropwise. The reaction mixture was refluxed for 5 h and cooled to room temperature. The reaction mixture was dried under vacuum, and the solid was washed several times with a large amount of deionized water and MeOH, dried in air, and the pure product yellow solid compound 4 was obtained by silica gel column using pure DCM.

[0019] (4) subjecting the compound 4 obtained in step (3) to a nucleophilic substitution reaction with a diphenylamine compound 5, and separating and purifying the reaction system to obtain the target product 6.

[0020] Preferably, the molar ratio of the compound 1 in step (1) to sodium borohydride is 1:4-10, and the molar ratio of the o-phenylenediamine compound 2 in step (2) to the total amount of oxalic acid added is 1:1-1.5.

[0021] Preferably, the addition ratio of the compound 3, thionyl chloride and N,N-dimethylformamide in step (3) is 1-20:20-70:1; the molar ratio of the compound 4 and the diphenylamine compound 5 in step (4) is 1-2:1-8.

[0022] The third object of the present invention is to provide use of the compound as an organic photocatalyst.

[0023] The fourth object of the present invention is to provide the use of the compound in catalyzing the synthesis of aromatic amine compounds.

[0024] The fifth object of the present invention is to provide the use of the compound in catalyzing the synthesis of heteroaromatic amine compounds.

[0025] The beneficial effects of the present invention are as follows: the present invention provides compounds based on diphenylamine derivatives and quinoxaline skeletons, which exhibit excellent catalytic efficiency and selectivity in aspects such as the preparation of aromatic amine compounds and the preparation of aniline drug molecules by amination dehydrogenation aromatization catalyzed by organic photoredox catalysis and cobalt oxime complex synergistic catalysis, and can efficiently promote the synthesis of aromatic amine / heteroaromatic amine compounds under mild visible light conditions. Compared with the prior art, the photocatalyst of the present invention has higher catalytic activity and wider substrate applicability, has significant practical application value, can be effectively applied to the field of green organic synthesis, and is particularly suitable for the green synthesis process of aromatic amine compounds and local anesthetic drugs such as tetracaine, and has broad application prospects. DETAILED DESCRIPTION

[0026] In order to make the purpose, technical scheme and advantages of the present invention clearer, the technical scheme of the present invention is described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention, that is, the embodiments described are only part of the embodiments of the present invention, rather than all the embodiments. Therefore, the following detailed description of the embodiments of the present invention provided is not intended to limit the scope of the claimed invention, but merely represents the selected embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without making creative work belong to the scope of protection of the present invention.

[0027] It should be noted that, in the following examples, unless otherwise specified, the methods described are conventional methods that can be obtained from the literature, and the reagents described can be purchased from the market.

[0028] In the following embodiments, the Cz-NI refers to 4-((9-phenylcarbazole-3-yl)ethynyl)-N-dodecyl-1,8-naphthaleneimide, which is a D-II-A type ethynyl-bridged carbazole naphthaleneimide organic semiconductor, has certain application potential in the field of photocatalytic hydrogen production, and is used as a photocatalyst in the present invention;

[0029] In the following examples, Eosin Y, also known as eosin and tetrabromofluorescent yellow, is a widely used water-soluble dye, used as an indicator or color developer in some chemical analyses and detections, and can also be used in the research of photocatalysis, photoelectric materials and other fields. It is used as a photocatalyst in the present invention;

[0030] In the following examples, the 4CzIPN, whose Chinese name is 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile, is an organic compound with unique properties and wide applications, and is widely used in the field of photocatalyst technology;

[0031] In the following examples, the Acr-Mes-ClO4 is methyl-9-mesityl acridine perchlorate, which is a common organic photocatalyst;

[0032] In the following examples, Ir(ppy)2(dtbbpy)PF6, whose Chinese name is (4,4'-di-tert-butyl-2,2'-bipyridine)bis((2-pyridyl)phenyl)iridium(III) hexafluorophosphate, is used as a metal catalyst to synthesize β-aminovinylsulfones and can also be used to drive various photochemical reactions, such as atom transfer radical addition (ATRA) reaction, aryl-alkyl CC reductive coupling reaction, etc.

[0033] In the following embodiments, the Ru(bpy)3(PF6)2 described herein is tri(2,2'-bipyridine)ruthenium di(hexafluorophosphate) salt, which can be used as a catalyst or a catalyst precursor, participate in a variety of catalytic reaction processes, and can also serve as an active center of a photocatalyst, participate in photocatalytic reactions, and realize the conversion of light energy into chemical energy.

[0034] In the following examples, Ir(ppy)3 is an important organometallic complex, the full name of which is Tris(2-phenylpyridinato)iridium(III). Due to its excellent photophysical properties, Ir(ppy)3 is also used in photocatalytic reactions.

[0035] In the following examples, the DCQ is an organic photocatalyst based on a quinoxaline skeleton previously applied for by the inventor's research group (see CN114907328B).

[0036] In the following examples, the trace amount refers to an extremely small amount, which is usually used to describe substances with very low content in a sample.

[0037] Example 1: A method for preparing an organic photocatalyst based on a quinoxaline skeleton

[0038] The structure of the synthesized compound is shown in 6b, and the preparation method thereof is specifically carried out according to the following steps:

[0039]

[0040] (1) Synthesis of o-phenylenediamine 2a

[0041] Sodium borohydride (90 mmol) was added to a dry four-necked round-bottom flask containing benzothiadiazole 1a (10 mmol), and stirred in anhydrous ethanol (100 mL) at 0°C under nitrogen atmosphere for 1 h, and at room temperature for 12 h. After confirming that the reactants were consumed by TLC analysis, the solvent was removed. Water was added to the residue and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, and spin-dried to obtain a white solid 2a (no purification was required, and the next step was directly carried out).

[0042] (2) Quinoxaline-2,3-diol 3a

[0043] Add 37.6mmol 2a to a 500mL round-bottom flask and add 150mL 4N HCI aqueous solution. Add the first portion of oxalic acid (27.8mmol) and reflux for 6h. Then add the second portion of oxalic acid (27.8mmol) and reflux the mixture overnight (12h). Cool to room temperature and vacuum filter. Wash the filtrate several times with a large amount of deionized water and dry in air to obtain a brown solid 3a. The product does not need further purification and is used in the next experiment.

[0044] (3) Synthesis of 2,3-dichloroquinoxaline 4a

[0045] In a 500mL three-necked flask, 15.6mmol of 3a was placed in 100mL of thionyl chloride. After stirring at room temperature for 5min, 1mL of dimethylformamide (DMF) was added dropwise. The reaction mixture was cooled to room temperature after reflux for 5h. The reaction mixture was dried under vacuum. The solid was washed several times with a large amount of deionized water and 100mL of methanol, and then dried in air. Pure product 4a (light yellow solid) was obtained by silica gel column using pure dichloromethane (DCM).

[0046] (4) Synthesis of 2,3-bis(bis(4-bromophenyl)amine)quinoxaline 6b

[0047] In a nitrogen atmosphere, the nucleophilic reactants di(4-bromophenyl)amine 5b (4.0 equivalents) and sodium tert-butoxide (4.0 equivalents) were dissolved in 7 mL of DMF, stirred at room temperature for 30 min, and then 2,3-dichloroquinoxaline 4a (1 mmol) was added. The reaction system was then heated to 90 ° C and reacted overnight. After the reaction was completed, it was cooled to room temperature, treated with saturated brine, and filtered to obtain a yellow solid. Finally, the product was purified by flash column chromatography to obtain 2,3-di(di(4-bromophenyl)amine)quinoxaline 6b with a yield of 16%.

[0048] The characterization data of 2,3-bis(bis(4-bromophenyl)amine)quinoxaline 6b are: 1 H NMR (600MHz, CDCl3): δ7.68 (dd, J=6.3, 3.5Hz, 2H), 7.54 (dt, J=6.3, 3.3Hz, 2H), 7.38–7.31 (m, 8H), 6.65–6.59 (m, 8H).; 13 C NMR (151MHz, CDCl3): δ148.34, 144.36, 139.36, 132.09, 128.73, 127.51, 125.87, 119.64, 117.91.

[0049] The synthesis method of compound 2,3-bis(bis(4-bromophenyl)amine)quinoxaline 6b is as described above. It should be noted that the raw materials in the above method are replaced, for example, 5b Replace with Compound 6a can be obtained.

[0050] Add 1a in the raw material Replace with Compound 8b can be obtained;

[0051] Add 1a in the raw material Replace with 5b Replace with Compound 8a can be obtained;

[0052] 1a in the raw material Replace with Compound 7b can be obtained;

[0053] Add 1a in the raw material Replace with 5b Replace with Compound 7a can be obtained;

[0054] 1a in the raw material Replace with Compound 9c can be obtained;

[0055] 1a in the raw material Replace with 5b Replace with Compound 9b can be obtained.

[0056] The following is an explanation of the specific application of the photoredox catalyst in organic synthesis.

[0057] Example 2: Preparation of aniline compounds by amination dehydrogenation aromatization catalyzed by organic photoredox catalysis and cobalt oxime complex

[0058] 1. Reaction conditions

[0059] Add a stirrer to the reaction tube, then add Co(dmgH)2(DMAP)Cl (4 mol%), 6b (1.5 mol%), Base (1.5 equiv.), Lewis Acid (10 mol%); add 4-methylcyclohexanone 11 (1.0 equiv.) and morpholine 10 (1.2 equiv.) The reaction tube is evacuated and filled with N2 (x 3), then add solvent CH3CN (0.3M), turn on the blue LED, and react for 24 hours. Open the reaction tube, dilute the mixture with H2O and EtOAc, extract the aqueous layer with EtOAc (x 2), combine the organic layers, wash with brine, dry (MgSO4), filter, and evaporate to dryness. Purify by silica gel flash column chromatography to obtain the corresponding product.

[0060]

[0061] 2. Grouping

[0062] Replace 6b in the above formula with other catalysts, such as Cz-NI, Eosin Y, 4CzIPN, Acr-Mes-CIO4, DCQ, Ir(ppy)2(dtbbpy)PF6, Ru(bpy)3(PF6)2, and the specific reaction conditions are as described in 1 to obtain aniline compounds prepared by other catalysts.

[0063] 3. Results

[0064] The reaction results of different catalysts are shown in Table 1. It can be seen that catalyst 6b can catalyze the reaction very well, and the yield of the target product 4-(p-tolyl)morpholine 12 is as high as 82.1%, and the catalytic effect is significantly higher than that of traditional organic photocatalysts.

[0065] Target product 12 1 H NMR (600MHz, CDCl3): δ7.10(d,J=8.4Hz,2H), 6.84(d,J=8.4Hz,2H), 3.87(dd,J=5.7,3.7Hz,4H), 3.11(dd,J=5.8,3.7Hz,4H), 2.28(s,3H). 13 C NMR (151MHz, CDCl3): δ149.29,129.82,129.68,116.14,67.09,50.03,20.53.

[0066] Table 1 Reaction results of different catalysts

[0067] Entry Photocatalyst Yield (%) 1 Cz-NI 6.6 2 Eosin Y Trace 3 4CzIPN 11.1 4 <![CDATA[Acr-Mes-CIO 4]]> 3.7 5 DCQ 6.4 6 <![CDATA[Ir(ppy)2(dtbbpy)PF 6]]> 36.0 7 <![CDATA[Ru(bpy)3(PF 6)2]]> Trace 8 6b 82.1

[0068] Example 3 Preparation of heteroaromatic amine compounds by amination dehydrogenation aromatization catalyzed by organic photoredox catalysis and cobalt oxime complex

[0069] 1. Reaction conditions

[0070] Add a stirrer to the reaction tube, then add Co(dmgH)2(DMAP)Cl (4 mol%), 6b (1.5 mol%), Base (3.0 equiv.), Lewis Acid (10 mol%); add N-tert-butyloxycarbonyl-4-piperidone 13 (1.0 equiv.) and morpholine 10 (3.0 equiv.) The reaction tube is evacuated and filled with N2 (x 3), and then the solvent CH3CN (0.1 M) is added; after pre-stirring at 80°C for 15 min, turn on the blue LED and react for 12 h. Open the reaction tube, dilute the mixture with H2O and EtOAc, extract the aqueous layer with EtOAc (x 2), combine the organic layers, wash with brine, dry (MgSO4), filter, and evaporate to dryness. Purify by silica gel flash column chromatography to obtain the corresponding product.

[0071]

[0072] 2. Grouping

[0073] Replacing 6b in the above formula with other catalysts, such as Eosin Y, 4CzIPN, DCQ, Ir(ppy)3, Ir(ppy)2(dtbbpy)PF6, Ru(bpy)3(PF6)2, and the specific reaction conditions are as described in 1, can obtain heteroaromatic amine compounds prepared by other catalysts.

[0074] 3. Results

[0075] The reaction results of different catalysts are shown in Table 2. It can be seen that the catalyst 6b prepared by the present invention can catalyze the reaction well, and the yield of the target product 4-morpholinopyridine 14 is as high as 91%. Characterization of the target product 14: 1 H NMR (600MHz, CDCl3): δ8.30 (dd, J=5.0, 1.7Hz, 2H), 6.66 (dd, J=5.0, 1.6Hz, 2H), 3.86–3.82 (m, 4H), 3.31–3.26 (m, 4H). 13 C NMR (151MHz, CDCl3): δ155.28, 150.44, 108.34, 66.51, 46.20.

[0076] Table 2 Reaction results of different catalysts

[0077]

[0078]

[0079] Through Example 2 and Example 3, those skilled in the art can undoubtedly conclude that the catalyst described in the present invention can synthesize aniline compounds and heteroaromatic amine compounds, mainly synthesizing benzene rings or heterocyclic structures. As long as it is a drug containing the above structure, it can be catalyzed and synthesized by the catalyst described in the present invention, for example, the synthesis of tetracaine, etc.

[0080] Example 4: Synthesis of local anesthetic tetracaine

[0081]

[0082] Reaction conditions:

[0083] Add a stirrer to the reaction tube, then add Co(dmgH)2(DMAP)Cl (4 mol%), 6b (1.5 mol%), Base (1.5 equiv.), Lewis Acid (10 mol%); add ethyl formate, cyclohexanone (1.0 equiv.) and n-butylamine (1.2 equiv.). After the reaction tube is evacuated and filled with N2 (x 3), add solvent CH3CN (0.3 M). Turn on the blue LED and react for 24 hours. Open the reaction tube, dilute the mixture with H2O and EtOAc, extract the aqueous layer with EtOAc (x2), combine the organic layers, wash with brine, dry (MgSO4), filter, and evaporate to dryness. Purify by silica gel flash column chromatography to obtain the corresponding white solid product T-1 with a yield of 51%.

[0084] Characterization of white solid product T-1: 1 H NMR (600MHz, CDCl3): δ7.86 (d, J = 8.9 Hz, 2H), 6.53 (d, J = 8.6 Hz, 2H), 4.31 (q, J = 7.2 Hz, 2H), 4.10 (s, 1H), 3.1 6(t,J=7.2Hz,2H),1.61(dq,J=8.8,6.8Hz,2H),1.48–1.40(m,2H),1.41–1.33(m,3H),0.96(t,J=7.4Hz,3H). 13 C NMR (151MHz, CDCl3): δ167.02,152.15,131.60,118.47,111.39,60.25,43.18,31.50,20.32,14.58,13.97.

[0085] The white solid product T-1 (0.2 mmol) was dissolved in 0.5 mL of 2-(dimethylamino)ethanol solution, NaOMe (0.025 mmol) was added, heated to 130-140°C, and stirred for 16 h. The mixture was cooled to room temperature, diluted with H2O (10 mL) and CH2Cl2 (10 mL). The aqueous layer was extracted with CH2Cl2 (2×10 mL). The combined organic layers were washed with brine, dried (MgSO4) and evaporated. The crude compound was purified by column chromatography (hexane / ethyl acetate 10:1) to obtain tetracaine, a white solid local anesthetic, in a yield of 98%.

[0086] Tetracaine Characteristics: 1 H NMR (600MHz, CDCl3): δ7.86(d,J=8.7Hz,2H),6.53(d,J=8.7Hz,2H),4.37(t,J=5.9Hz,2H),4.08(s,1H),3.16(td,J =7.2,5.5Hz,2H),2.69(t,J=5.9Hz,2H),2.33(s,6H),1.65–1.57(m,2H),1.48–1.38(m,2H),0.96(t,J=7.4Hz,3H). 13 CNMR (151MHz, CDCl3): δ166.93,152.27,131.76,118.11,111.37,62.48,58.10,46.01,43.16,31.50,20.32,13.97.

[0087] In summary, the present invention provides compounds based on diphenylamine derivatives and quinoxaline skeletons, which exhibit excellent catalytic efficiency and selectivity in the preparation of aromatic amine compounds and the preparation of aniline drug molecules by amination dehydrogenation aromatization catalyzed by organic photoredox catalysis and cobalt oxime complex synergistic catalysis, and can efficiently promote the synthesis of aromatic amines / heterocyclic amine compounds under mild visible light conditions. Compared with the prior art, the photocatalyst of the present invention has higher catalytic activity and wider substrate applicability, has significant practical application value, can be effectively applied to the field of green organic synthesis, and is particularly suitable for the green synthesis process of aromatic amine compounds and local anesthetic drugs such as tetracaine, and has broad application prospects.

[0088] The above contents are merely examples and explanations of the present invention. Any modification or supplement made to the described specific embodiments or replacement by similar methods by technicians in the field without creative work still falls within the scope of protection of this patent.

Claims

1. A compound based on a diphenylamine derivative and a quinoxaline skeleton, characterized in that: The general chemical formula of the compound is shown in formula (I): Among them, R 1 is H, methyl or a halogen atom; R 2 is a halogen atom or a methoxy group.

2. The compound based on a diphenylamine derivative and a quinoxaline skeleton according to claim 1, characterized in that: The structural formula of the compound is shown below:

3. Use of the compound as claimed in claim 1 or 2 as an organic photocatalyst.

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