A near-infrared emitting lactam-fused aza-BODIPY fluorescent molecule and its preparation method

Abstract

The present invention discloses a near-infrared emitting amide-fused aza-BODIPY compound and its preparation method. The synthesis method is as follows: 5-aldehyde-2-thiopheneboronic acid and 1-bromo-1-aryl-2,2-diphenylethylene undergo a Suzuki reaction to obtain intermediate 1, which is then oxidized to obtain intermediate 2. This intermediate is further cyclized with diisopropyl succinate to obtain intermediate 3, which is then cyclized and complexed with 5-(pyridine-3-alkynyl)pyridine-2-amine to obtain a near-infrared emitting amide-fused aza-BODIPY compound. The amide-fused aza-BODIPY fluorescent dye prepared by the present invention has a Stokes shift of 72 nm and a maximum fluorescence emission peak of 755 nm.

Description

Technical Field

[0001] The invention belongs to the field of organic small molecule fluorescent materials and relates to a near-infrared emitting lactam-fused aza-BODIPY compound and a preparation method thereof. Background Art

[0002] Boron-azadipyrromethene (aza-BODIPY) is a novel near-infrared fluorescent dye that has garnered widespread attention in recent years. Its core structure consists of a six-membered boron-nitrogen heterocyclic ring surrounded by two pyrrole rings, all coplanar, with two fluorine atoms flanking the core plane. It exhibits near-infrared absorption and emission wavelengths, excellent photostability, a narrow half-width (FWHM), high quantum yield, and a large molar extinction coefficient. It holds broad application prospects in bioanalysis, fluorescence sensors, bioimaging, photodynamic therapy, in vivo fluorescence imaging, and organic electroluminescent devices.

[0003] There are three main synthetic pathways for aza-BODIPY: (a) from 1,3-diaryl-4-nitrobutan-1-one or 3-methyl-4-nitro-1-arylbutan-1-one; (b) via the reaction of o-phthalonitrile with arylmagnesium bromide; and (c) using 2,4-diarylpyrrole or aryl-fused 2,4-diarylpyrrole as starting materials. To further broaden the practical applications of aza-BODIPY, researchers have derivatized aza-BODIPY dyes to shift their absorption and emission wavelengths toward longer wavelengths. Common modification methods include introducing strong electron-donating groups, increasing the rigidity of the molecule, and increasing the conjugated system. Studies have found that the introduction of electron-donating groups at positions 3 and 5 can more effectively modulate their photophysical properties than at positions 1, 7 or 2, 6. However, these methods suffer from small Stokes shifts (<50 nm), multiple synthetic steps, low overall yields, and the inability to further functionalize them.

[0004] To address this issue, the present invention provides a novel strategy for synthesizing near-infrared-emitting lactam-fused aza-BODIPY fluorescent dyes. By introducing an alkynyl pyridine to extend the molecular conjugation, and by incorporating a propeller-shaped electron-donating unit, the photophysical properties of the fluorescent molecule can be easily adjusted and its solubility increased. The electron push-pull system within the fluorescent molecule facilitates the red shift of the fluorescence emission. The NH bond and pyridine group in the molecular structure facilitate subsequent functionalization. Currently, there are no literature or patent reports on the near-infrared-emitting lactam-fused aza-BODIPY compound of the present invention and its preparation method. Summary of the Invention

[0005] The present invention aims to address the shortcomings of existing aza-BODIPY compounds, which have multiple synthesis steps and cannot be further functionalized, and to provide a near-infrared emitting lactam-fused aza-BODIPY compound and a preparation method thereof.

[0006] The purpose of the present invention is achieved through the following technical solutions:

[0007] A near-infrared emitting lactam-fused aza-BODIPY compound has the structural formula:

[0008]

[0009] Wherein, Ar is the following aromatic ring or heteroaromatic ring:

[0010]

[0011] The preparation principle of the near-infrared emitting lactam-fused aza-BODIPY compound is as follows: 5-formyl-2-thiopheneboronic acid undergoes a Suzuki reaction with 1-bromo-1-aryl-2,2-diphenylethylene to obtain intermediate 1, which is then oxidized to obtain intermediate 2. This is further cyclized with diisopropyl succinate to obtain intermediate 3, which is then cyclized and complexed with 5-(pyridin-3-ynyl)pyridin-2-amine to obtain the near-infrared emitting amide-fused aza-BODIPY compound. The reaction formula is:

[0012]

[0013] The steps include:

[0014] (1) Under the protection of inert gas, equimolar amounts of 5-formyl-2-thiopheneboronic acid and 1-bromo-1-aryl-2,2-diphenylethylene are dissolved in an isopropanol-water mixed solvent and the inert gas is passed through for 10 to 20 minutes. A 1 to 15 mol% palladium catalyst containing 5-formyl-2-thiopheneboronic acid and a 0.1 to 5 mol / L alkaline aqueous solution are added and the inert gas is continued to be passed through for 10 to 20 minutes. The mixture is heated to 50 to 80°C, stirred and refluxed for 6 to 24 hours, and then cooled to room temperature. The mixture is washed with water, extracted with CH2Cl2, dried over anhydrous Na2SO4, and subjected to column chromatography to obtain intermediate 1. Among them, the preferred palladium catalyst is Pd(PPh3)4 or Pd(dppf)Cl2.

[0015] (2) Add intermediate 1 and 2 times the equivalent of iodine reagent to an alkaline aqueous solution and mix them. The mixture is reacted at room temperature in the dark for 5 to 20 hours. Then, 2 to 5 times the molar amount of sodium thiosulfate is added and stirred for 0.5 to 5 hours. After extraction with chloroform, the mixture is dried to remove water and solvent. The intermediate 2 is separated by column chromatography. Among them, the preferred base is K2CO3, Na2CO3, NaOH or ammonia water.

[0016] (3) Under the protection of inert gas, intermediate 2 and 1 to 4 equivalents of potassium tert-butoxide are added to tert-amyl alcohol, the temperature is raised to 80 to 110°C, and after stirring for 0.5 to 1.0 h, 3 to 8 equivalents of diisopropyl succinate are slowly added dropwise. Stirring is continued for 12 to 36 h, the reaction is terminated, and the mixture is cooled. The mixture is washed with water, extracted with CH2Cl2, and after removing the solvent, the mixture is washed with methanol several times and dried to obtain intermediate 3.

[0017] (4) Under inert gas protection, intermediate 3 and 0.5-4 times of 5-(pyridin-3-ynyl)pyridin-2-amine are added to toluene, followed by 12-20 times of titanium tetrachloride. The temperature is raised to 70-110°C and stirred continuously. After reacting for 2-4 hours, a base is added, and the reaction is continued for 3-6 hours. 20-40 times of boron trifluoride etherate is added, and the reaction is continued for 3-6 hours to stop the reaction. After cooling, the mixture is washed with water and extracted with CH2Cl2. The organic solvent is removed by rotary evaporation, and the amide-fused aza-BODIPY compound is separated by column chromatography. Among them, the preferred base is triethylamine, diethylamine, K2CO3, and NaOH.

[0018] Compared with the prior art, the present invention has the following advantages:

[0019] (1) A near-infrared emitting amide-fused aza-BODIPY compound fluorescent dye prepared in the present invention has a Stokes shift of up to 72 nm.

[0020] (2) Different electron-donating groups can be used to conveniently adjust the properties of fluorescent dyes such as Stokes shift, fluorescence emission, and absolute fluorescence quantum yield.

[0021] (3) A near-infrared emitting amide-fused aza-BODIPY fluorescent dye prepared in the present invention contains an NH bond and a pyridine group in its structure, which facilitates subsequent functionalization and further expansion of its application.

[0022] (4) The synthetic route of the near-infrared emitting amide-fused aza-BODIPY compound fluorescent dye synthesized in the present invention is simple. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 This is the hydrogen spectrum (DMSO-d6) of PAB-1 prepared in Example 1.

[0024] Figure 2 This is the mass spectrum of PAB-1 prepared in Example 1.

[0025] Figure 3 The normalized absorption and emission spectra of PAB-1 prepared in Example 1 in dimethyl sulfoxide are shown.

[0026] Figure 4 The UV absorption diagram of PAB-1 prepared in Example 1 in different solvents.

[0027] Figure 5 The fluorescence emission diagrams of PAB-1 prepared in Example 1 in different solvents. DETAILED DESCRIPTION

[0028] The specific implementation of the present invention is further described below with reference to the embodiments, but the scope of protection claimed by the present invention is not limited to the scope described in the embodiments.

[0029] Example 1: Preparation of near-infrared emitting amide-fused aza-BODIPY compound PAB-1

[0030] (1) 5-(Pyridin-3-ynyl)pyridin-2-amine was prepared according to the method disclosed in the literature (Dalton Trans, 2006, 1627-1635).

[0031] (2) 30 mmol of 5-formyl-2-thiopheneboronic acid and 30 mmol of (2-bromo-1,1,2-triphenyl)ethylene were added to a mixture of 160 mmol of K2CO3, 80 mL of isopropanol, and 80 mL of water. The mixture was passed through an inert gas for 20 minutes. 10 mol% of Pd(dppf)Cl2 based on 5-formyl-2-thiopheneboronic acid was added. The mixture was heated to reflux for 15 hours and monitored by TLC. After the reaction was stopped, the mixture was cooled to room temperature and the solvent was removed by rotary evaporation. The mixture was separated by column chromatography to obtain 5-(1,2,2-triphenylethylene)-thiophene-2-carboxaldehyde in a yield of 85%.

[0032] (3) 34 mmol of 5-(1,2,2-triphenylethylene)-thiophene-2-carboxaldehyde and 68 mmol of elemental iodine were added to 500 mL of 5 mol / L ammonia water, mixed, and reacted at room temperature in the dark for 20 h. Sodium thiosulfate in an amount 5 times the equivalent of 5-(1,2,2-triphenylethylene)-thiophene-2-carboxaldehyde was added and stirred for 2 h. The mixture was extracted with CH2Cl2 and dried over anhydrous NaSO4. The mixture was separated by column chromatography to obtain 5-(1,2,2-triphenylethylene)-thiophene-2-carbonitrile in a yield of 86%.

[0033] (4) 20 mmol of 5-(1,2,2-triphenylethylene)-thiophene-2-carbonitrile and 30 mmol of potassium tert-butoxide were added to 60 mL of tert-amyl alcohol and passed through an inert gas for 20 minutes. The temperature was raised to 110°C and stirred for 1.0 hour. After that, 80 mmol of diisopropyl succinate was slowly added dropwise and the stirring was continued for 36 hours. The reaction was terminated, and after cooling, the mixture was washed with water and extracted with CH2Cl2. The solvent was removed by rotary evaporation to obtain a solid. The solid was washed with methanol several times to obtain 3,6-bis[(1,2,2-triphenylethylene)-thiophene]-pyrrolopyrroledione with a yield of 37%.

[0034] (5) 0.1 mmol of 3,6-bis((1,2,2-triphenylethylene)-thiophene)-pyrrolopyrroledione and 0.1 mmol of 5-(pyridin-3-ynyl)pyridin-2-amine were added to 20 mL of toluene and an inert gas was passed through for 20 minutes. 1.2 mmol of titanium tetrachloride was added and the temperature was raised to 110°C with continuous stirring. After reacting for 4 hours, 3.2 mmol of triethylamine was added and the reaction was continued for another 4 hours. 2.8 mmol of boron trifluoride etherate was added and the reaction was continued for another 4 hours before stopping the reaction. After cooling, the mixture was washed with water, extracted with CH2Cl2, and dried over anhydrous Na2SO4. The organic phase solvent was removed and the near-infrared emitting amide-fused aza-BODIPY (PAB-1) was isolated by column chromatography with a yield of 22%.

[0035] The proton spectrum of PAB-1 is as follows Figure 1 .

[0036] The mass spectrum of PAB-1 is as follows Figure 2 .

[0037] Performance test case

[0038] The normalized absorption and emission spectra of PAB-1 in dimethyl sulfoxide are shown in Figure 2. Figure 3 .

[0039] UV absorption of PAB-1 in different solvents Figure 4 .

[0040] Fluorescence emission patterns of PAB-1 in different solvents are shown in Figure 2. Figure 5 .

[0041] The photophysical properties of PAB-1 in different solvents are shown in Table 1.

[0042] Table 1 Photophysical properties of PAB-1 in different solvents

[0043]

[0044]

[0045] Example 2: Preparation of near-infrared emitting amide-fused aza-BODIPY compound PAB-2

[0046] (1) 5-(Pyridin-3-ynyl)pyridin-2-amine was prepared according to the method disclosed in the literature (Dalton Trans, 2006, 1627-1635).

[0047] (2) 30 mmol of 5-formyl-2-thiopheneboronic acid and 30 mmol of (2-bromo-2-thiophene-1,1-diphenyl)ethylene were added to a mixture of 160 mmol of Na2CO3, 80 mL of isopropanol, and 80 mL of water. The mixture was passed through an inert gas for 15 minutes. Pd(PPh3)4 was added in a catalytic amount of 8 mol% based on 5-formyl-2-thiopheneboronic acid. The reaction was heated under reflux for 8 hours and monitored by TLC. After stopping, the mixture was cooled to room temperature, the solvent was removed, and the mixture was separated by column chromatography to obtain 5-(2-thiophene-1,1-diphenylethylene)-thiophene-2-carboxaldehyde in a yield of 88%.

[0048] (3) 34 mmol of 5-(2-thiophene-1,1-diphenylethylene)-thiophene-2-carboxaldehyde and 102 mmol of elemental iodine were added to 500 mL of 2 mol / L ammonia water, mixed, and reacted at room temperature in the dark for 15 h. Three equivalents of sodium thiosulfate based on 5-(2-thiophene-1,1-diphenylethylene)-thiophene-2-carboxaldehyde were added and stirred for 3 h. The mixture was extracted with CH2Cl2 and dried over anhydrous Na2SO4. The mixture was separated by column chromatography to obtain 5-(2-thiophene-1,1-diphenylethylene)-thiophene-2-carbonitrile in a yield of 89%.

[0049] (4) 20 mmol of 5-(2-thiophene-1,1-diphenylethylene)-thiophene-2-carbonitrile and 60 mmol of potassium tert-butoxide were added to 60 mL of tert-amyl alcohol. The mixture was passed through an inert gas for 20 minutes. The temperature was raised to 90°C and stirred for 0.5 hours. After that, 60 mmol of diisopropyl succinate was slowly added dropwise. The mixture was stirred for 24 hours. The reaction was terminated and the mixture was cooled. The mixture was washed with water and extracted with CH2Cl2. The solvent was removed to obtain a solid. The solid was washed with methanol several times to obtain 3,6-bis((2-thiophene-1,1-diphenylethylene)-thiophene)-pyrrolopyrroledione with a yield of 41%.

[0050] (5) 0.1 mmol of 3,6-bis((2-thiophene-1,1-diphenylethylene)-thiophene)-pyrrolopyrroledione and 0.2 mmol of 5-(pyridin-3-ynyl)pyridin-2-amine were added to 20 mL of toluene and inert gas was passed through for 20 minutes. 2.0 mmol of titanium tetrachloride was added and the temperature was raised to 100°C with continuous stirring. After reacting for 3 hours, 3.2 mmol of triethylamine was added and the reaction was continued for another 4 hours. 4.0 mmol of boron trifluoride etherate was added and the reaction was continued for another 3 hours before stopping the reaction. After cooling, the mixture was washed with water, extracted with CH2Cl2, and dried over anhydrous Na2SO4. The organic phase solvent was removed and the near-infrared emitting amide-fused aza-BODIPY (PAB-2) was isolated by column chromatography with a yield of 27%.

[0051] Example 3: Preparation of near-infrared emitting amide-fused aza-BODIPY compound PAB-3

[0052] (1) 5-(Pyridin-3-ynyl)pyridin-2-amine was prepared according to the method disclosed in the literature (Dalton Trans, 2006, 1627-1635).

[0053] (2) 30 mmol of 5-formyl-2-thiopheneboronic acid and 30 mmol of (2-bromo-2-furan-1,1-diphenyl)ethylene were added to a mixture of 160 mmol of K2CO3, 80 mL of isopropanol, and 80 mL of water. The mixture was passed through an inert gas for 15 minutes. Pd(dppf)Cl2 was added in a catalytic amount of 5 mol% based on 5-formyl-2-thiopheneboronic acid. The reaction was heated under reflux for 20 hours and monitored by TLC. After stopping, the mixture was cooled to room temperature, the solvent was removed, and the mixture was separated by column chromatography to obtain 5-(2-furan-1,1-diphenylethylene)-thiophene-2-carboxaldehyde in a yield of 80%.

[0054] (3) 34 mmol of 5-(2-furan-1,1-diphenylethylene)-thiophene-2-carboxaldehyde and 136 mmol of elemental iodine were added to 500 mL of 5 mol / L ammonia water, mixed, and reacted at room temperature in the dark for 15 h. Sodium thiosulfate, twice the equivalent of 5-(1,2,2-triphenylethylene)-thiophene-2-carboxaldehyde, was added and stirred for 4 h. The mixture was extracted with CH2Cl2 and dried over anhydrous NaSO4. The mixture was separated by column chromatography to obtain 5-(2-furan-1,1-diphenylethylene)-thiophene-2-carbonitrile in a yield of 82%.

[0055] (4) 20 mmol of 5-(2-furan-1,1-diphenylethylene)-thiophene-2-carbonitrile and 30 mmol of potassium tert-butoxide were added to 60 mL of tert-amyl alcohol, and an inert gas was introduced for 20 minutes. The temperature was raised to 100°C, and after stirring for 0.5 hours, 40 mmol of diisopropyl succinate was slowly added dropwise, and the stirring was continued for 24 hours. The reaction was terminated and cooled, and the mixture was washed with water, extracted with CH2Cl2, and extracted with a water / dichloromethane system. After removing the solvent, a solid was obtained. The solid was washed with methanol several times to obtain 3,6-bis((2-furan-1,1-diphenylethylene)-thiophene)-pyrrolopyrroledione with a yield of 32%.

[0056] (5) 0.1 mmol of 3,6-bis((2-furan-1,1-diphenylethylene)-thiophene)-pyrrolopyrroledione and 0.4 mmol of 5-(pyridin-3-ynyl)pyridin-2-amine were added to 20 mL of toluene and inert gas was passed through for 20 minutes. 1.5 mmol of titanium tetrachloride was added and the temperature was raised to 105°C with continuous stirring. After reacting for 3 hours, 3.2 mmol of triethylamine was added and the reaction was continued for another 3 hours. 4.0 mmol of boron trifluoride etherate was added and the reaction was continued for another 6 hours before stopping the reaction. After cooling, the mixture was washed with water, extracted with CH2Cl2, and dried over anhydrous Na2SO4. The organic phase solvent was removed and the near-infrared emitting amide-fused aza-BODIPY (PAB-3) was isolated by column chromatography with a yield of 25%.

Claims

1. A near-infrared emitting amide-fused aza-BODIPY compound, characterized in that: Its structural formula is: The structure of Ar is:

2. The method for preparing the amide-fused aza-BODIPY compound according to claim 1, comprising the following steps: (1) Under the protection of inert gas, equimolar amounts of 5-formyl-2-thiopheneboronic acid and 1-bromo-1-aryl-2,2-diphenylethylene are dissolved in an isopropanol-water mixed solvent, and the inert gas is passed for 10 to 20 minutes. A 1 to 15 mol% palladium catalyst containing 5-formyl-2-thiopheneboronic acid and a 0.1 to 5 mol / L alkaline aqueous solution are added, and the inert gas is continued for 10 to 20 minutes. The mixture is heated to 50 to 80°C, stirred and refluxed for 6 to 24 hours, and then cooled to room temperature. The mixture is washed with water, extracted with CH2Cl2, dried over anhydrous Na2SO4, and separated by column chromatography to obtain intermediate 1; (2) Intermediate 1 and 2 times the equivalent of elemental iodine are added to an aqueous ammonia solution and mixed. The mixture is reacted at room temperature in the dark for 5 to 20 hours. Then, 2 to 5 times the molar amount of sodium thiosulfate is added and stirred for 0.5 to 5 hours. After extraction with chloroform, the mixture is dried to remove water and solvent, and separated by column chromatography to obtain intermediate 2. (3) Under inert gas protection, intermediate 2 and 1 to 4 equivalents of potassium tert-butoxide are added to tert-amyl alcohol, the temperature is raised to 80 to 110°C, and after stirring for 0.5 to 1.0 h, 3 to 8 equivalents of diisopropyl succinate are slowly added dropwise. Stirring is continued for 12 to 36 h, the reaction is terminated, and the mixture is cooled, washed with water, extracted with CH2Cl2, and after removing the solvent, washed with methanol several times, and dried to obtain intermediate 3; (4) Under the protection of inert gas, the intermediate 3 and 0.5-4 times of 5-(pyridin-3-ynyl)pyridin-2-amine are added to toluene, and then 12-20 times of titanium tetrachloride is added. The temperature is raised to 70-110°C and stirred continuously. After reacting for 2-4 hours, a base is added, and the reaction is continued for 3-6 hours. Then, 20-40 times of boron trifluoride etherate is added, and the reaction is continued for 3-6 hours. The reaction is stopped; after cooling, the mixture is washed with water and extracted with CH2Cl2 to remove the organic solvent. The amide-fused aza-BODIPY compound is separated by column chromatography.

3. The preparation method according to claim 2, wherein: The palladium catalyst in step (1) is Pd(PPh3)4 or Pd(dppf)Cl2.

4. The preparation method according to claim 2, wherein: The base in step (4) is triethylamine, diethylamine, K2CO3, or NaOH.

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