Method for selective nitration of naphthylamine under catalysis of palladium, 8-nitro-1-naphthylamine and derivatives of 8-nitro-1-naphthylamine
The selective nitration of naphthylamine using palladium catalysis, employing silver nitrite and palladium catalysts under the action of a bidentate directing group in pyridine amide, achieved highly selective synthesis of 8-nitro-1-naphthylamine and its derivatives. This method solves the problems of insufficiently mild synthesis and numerous byproducts in existing technologies, and exhibits high yield and good functional group tolerance.
Patent Information
- Application Number
- CN202511503533.6
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-10-21
- Publication Date
- 2026-02-17
AI Technical Summary
Existing technologies are difficult to synthesize 8-nitro-1-naphthylamine and its derivatives with high selectivity and efficiency, and the reaction conditions are not mild enough, easily generating byproducts.
A palladium-catalyzed selective nitration method for naphthylamine was adopted, using silver nitrite as the nitrating agent and oxidant. Under the action of palladium catalyst and pyridine amide bidentate directing group, 8-nitro-1-naphthylamine and its derivatives were prepared through nitration and hydrolysis reactions.
The highly selective synthesis of 8-nitro-1-naphthylamine and its derivatives was achieved under mild reaction conditions, with excellent yields and good functional group tolerance, reducing the formation of byproducts.
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Figure CN121537342A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of organic synthesis technology, and more specifically, to a method for selectively generating 8-nitro-1-naphthylamine and its derivatives from naphthylamine using palladium catalysis. Background Technology
[0002] Palladium-catalyzed CH bond functionalization has become an important synthetic strategy in organic synthesis, providing new pathways from simple starting materials to complex molecules and improving the overall efficiency of desired transformations, thus fundamentally changing how chemists tackle synthetic challenges. In recent decades, the field of activating CH bonds through metal insertion using palladium catalysis has yielded many groundbreaking discoveries. The position selectivity of palladium-catalyzed directed CH bond functionalization reactions can be controlled by the chelation of CH bonds with the active palladium center, and the coordination of heteroatoms with the palladium catalyst can significantly promote substrate-catalyst interactions.
[0003] Directed CH bond functionalization reactions are generally classified into two categories: monodentate chelate-directed CH bond functionalization reactions and bidentate chelate-directed CH bond functionalization reactions. Among them, the coordination of palladium with the bidentate directing group in the bidentate chelate system is generally considered to be the key step in realizing the CH bond activation process.
[0004] 8-nitro-1-naphthylamine is an important organic intermediate, but electrophilic substitution can only yield 4-nitro-1-naphthylamine. Currently, there is no suitable synthetic method to achieve highly selective and efficient synthesis of 8-nitro-1-naphthylamine.
[0005] Therefore, there is an urgent need to provide a new method for preparing 8-nitro-1-naphthylamine and its derivatives, which has the advantages of simple operation, mild reaction conditions, precise substitution, and low likelihood of generating other by-products. Summary of the Invention
[0006] To address the lack of existing synthetic techniques for 8-nitro-1-naphthylamine, the present invention aims to provide 8-nitro-1-naphthylamine and its derivatives, and a method for selectively generating 8-nitro-1-naphthylamine and its derivatives using palladium catalysis. This method uses naphthylamine derivatives as raw materials, and under the action of palladium catalyst and silver nitrite, the prepared pyridine amides and their derivatives containing various functional groups can undergo nitration and hydrolysis reactions to obtain 8-nitro-1-naphthylamine and its derivatives. Moreover, the reaction conditions are mild, and the yield and regioselectivity are excellent.
[0007] To solve the above problems, the present invention adopts the following technical solution.
[0008] A method for the selective nitration of naphthylamine catalyzed by palladium, the reaction process is shown below: ; Wherein, R1 is H, a halogen, a nitro group, a C1-C4 alkyl group, an acetamino group, an aryl group, an alkoxycarbonyl group, a benzyloxy group, or a C1-C4 alkoxy group; The preparation steps are as follows: S1: Using 2-pyridinecarboxylic acid and the compound shown in formula (IV) as raw materials, a solvent was added and an alkali was added to adjust the pH. The temperature was lowered and then phosphorus oxychloride was slowly added dropwise while magnetic stirring was applied. After the addition was completed, the temperature was raised to room temperature to continue the reaction, and the compound shown in formula (V) was obtained. S2: The compound obtained in step S1, as shown in formula (V), undergoes a nitration reaction with N-(o-tolyl)quinoline-2-carboxamide under the action of silver nitrite and palladium catalysts. After magnetic stirring for a certain period of time, the compound shown in formula (II) is obtained.
[0009] Furthermore, the halogens are Cl, Br, or I.
[0010] Furthermore, in step S1, the molar ratio of 2-pyridinecarboxylic acid, the compound shown in formula (IV), and phosphorus oxychloride is 1-1.1:1-1.1:2-10, preferably 1.1:10:2.34.
[0011] Furthermore, in step S2, the molar ratio of the compound as shown in formula (V), silver nitrite, and palladium catalyst is 1-1.1:1-1.3:0.03-0.1; preferably 1:1.2:0.05.
[0012] Furthermore, the compounds shown in formula (IV) are preferably those shown in formulas (IV-1) to (IV-23): .
[0013] Further, in step S1, the reaction temperature is -15 to 0°C, and the reaction time is 2 to 4 hours; the base is triethylamine, morpholine, or pyridine, preferably triethylamine, and the pH is adjusted to neutral by adding base; in step S2, the reaction temperature is 50 to 120°C, and the reaction time is 2 to 6 hours; in step S1, the solvent is dichloromethane or chloroform; in step S2, the solvent is dioxane, tetrahydrofuran, or methyl tert-butyl ether. Dioxane is preferred.
[0014] Furthermore, in step S2, the palladium catalyst is palladium acetate, palladium chloride, or palladium bromide. Palladium acetate is preferred.
[0015] Furthermore, the preparation method also includes the following steps: ; Wherein, R1 is H, a halogen, a nitro group, a C1-C4 alkyl group, an acetamino group, an aryl group, an alkoxycarbonyl group, a benzyloxy group, or a C1-C4 alkoxy group; The specific preparation steps are as follows: S3: Add alkali to the compound shown in formula (II), then heat, and after a certain reaction time, obtain the compound shown in formula (III).
[0016] Furthermore, the halogens are Cl, Br, or I.
[0017] Furthermore, the molar ratio of the compound and the base shown in formula (II) is 1:2-4, preferably 1:3.
[0018] Furthermore, the reaction temperature of step S3 is 40-80℃, the reaction time is 1-6h, and step S3 is carried out in a solvent, such as dioxane, tetrahydrofuran, or methyl tert-butyl ether; the base is sodium hydroxide, potassium hydroxide, sodium carbonate, or potassium carbonate.
[0019] The present invention also provides an 8-nitro-1-naphthylamine, which is prepared by the palladium-catalyzed selective nitration method of naphthylamine described above.
[0020] The present invention also provides a derivative of 8-nitro-naphthylamine, which is prepared by the palladium-catalyzed selective nitration method of naphthylamine described above.
[0021] Furthermore, the general formula of the derivative is shown in formula (I): ; Wherein, D is independently selected from H and acetylpyridine; R1 is independently selected from H, halogens, nitroso, methyl, nitroacetyl, phenyl, ethoxyformyl, benzyloxy, and methoxy.
[0022] Furthermore, the halogen element is Cl, Br, or I.
[0023] Furthermore, when D is acetylpyridine, the general formula of the derivative is shown in formula (II): ; R1 is independently selected from H, Cl, Br, I, nitroso, methyl, nitroacetyl, phenyl, ethoxyformyl, benzyloxy, or methoxy.
[0024] Furthermore, the compounds shown in formula (II) are preferably shown in formulas (II-1) to (II-23): .
[0025] Furthermore, when D is H, the general formula of the derivative is shown in formula (III): ; R1 is independently selected from H, Cl, Br, I, nitroso, methyl, nitroacetyl, phenyl, ethoxyformyl, benzyloxy, or methoxy.
[0026] Furthermore, the compounds shown in formula (III) are preferably those shown in formulas (III-1) to (III-5): .
[0027] Compared with the prior art, the advantages of this invention are: I. In this scheme, under palladium catalysis, silver nitrite is used as a bifunctional reagent for nitrification and oxidization. The nitration of 1-naphthylamine containing a bidentate directing group of pyridine amide at the C-8 position yields 8-nitro-1-naphthylamine and its derivatives. The preparation method has mild reaction conditions, excellent yield and regioselectivity, and the reaction substrate has good functional group tolerance. Detailed Implementation
[0028] Example 1: Preparation method of 8-nitro-1-naphthylamine: Step 1: Preparation of N-(1-naphthyl)pyridine amide 2-Pyridinecarboxylic acid (11 mmol), 1-naphthylamine (10 mmol), triethylamine (3 mL), and dichloromethane (30 mL) were added sequentially to a 50 mL round-bottom flask. Phosphorus oxychloride (2 mL) was added dropwise under magnetic stirring at 0 °C, and the reaction was allowed to proceed for 30 min, followed by 2 h at room temperature. After the reaction was complete, 50 mL of ice water was added to quench the remaining POCl3, and the mixture was then transferred to a separatory funnel and extracted three times with 50 mL of ethyl acetate. The combined organic phases were then extracted three times with 50 mL of saturated sodium bicarbonate to remove excess 2-pyridinecarboxylic acid. Finally, the mixture was dried over anhydrous sodium sulfate. The solution was concentrated by evaporation and separated by column chromatography using ethyl acetate / petroleum ether (1:5) as the eluent to obtain the desired starting material, N-(1-naphthyl)pyridineamide.
[0029] Step 2: Preparation of N-(8-nitro-1-naphthyl)pyridine amide: N-(1-naphthyl)pyridine amide (0.1 mmol, 1.0 equiv), palladium acetate (5 mol%), silver nitrite (0.12 mmol, 1.2 equiv), and dioxane (0.25 mL) were added to a 4 mL pressure-resistant tube with a PTFE cap. After adding a clean magnetic stir bar, the mixture was heated at 60 °C for 3 h. After the reaction was completed, the reaction mixture was cooled to room temperature, diluted with ethyl acetate (2 mL), spotted by TLC, and then extracted with saturated sodium carbonate solution. The organic phase was retained, dried over anhydrous sodium sulfate, and concentrated. Finally, it was purified by silica gel column chromatography with ethyl acetate / petroleum ether. The obtained substance was detected by NMR, and the results are shown below, confirming that the obtained compound is N-(8-nitro-1-naphthyl)pyridine amide, and its chemical structure is shown below. The yield of N-(8-nitro-1-naphthyl)pyridine amide was 88%.
[0030] .
[0031] White solid; yield: 88%; mp 156 – 157ºC: 1 H NMR (400 MHz, CDCl3) δ10.57 (s, 1H), 8.73 (d, J = 4.2 Hz, 1H), 8.34 (d, J = 7.6 Hz, 1H), 8.12(d, J= 8.2 Hz, 1H), 7.98 (d, J = 7.2 Hz, 2H), 7.93 (t, J = 7.6 Hz, 1H), 7.87 (d, J= 8.2 Hz, 1H), 7.66 (t, J = 7.8 Hz, 1H), 7.53 (dd, J = 14.8, 7.6 Hz, 2H); 13 CNMR (100 MHz, CDCl3) δ 149.4, 148.3, 137.5, 136.4, 134.6, 134.2, 131.9,128.0, 127.9, 127.3, 127.1, 126.7, 125.0, 122.8, 119.5,106.4. Step 3: Add NaOH (3 mmol, 3.0 equiv) and 1,4-dioxane (3 mL) to the N-(8-nitro-1-naphthyl)pyridine amide prepared in Step 2. After stirring evenly, heat to 60℃ and react for 3 h to obtain 8-nitro-1-naphthylamine with a yield of 96%.
[0032] Example 2: Preparation method of 8-nitro-5-chloro-1-naphthylamine: Step 1: N-(5-chloro-1-naphthyl)pyridine amide 2-Pyridinecarboxylic acid (11 mmol), 5-chloro-1-naphthylamine (10 mmol), triethylamine (3 mL), and dichloromethane (30 mL) were added sequentially to a 50 mL round-bottom flask. Phosphorus oxychloride (2 mL) was added dropwise under magnetic stirring at 0 °C. The reaction was allowed to proceed for 30 min, followed by 2 h at room temperature. After the reaction was complete, 50 mL of ice water was added to quench the remaining POCl3. The mixture was then transferred to a separatory funnel and extracted three times with 50 mL of ethyl acetate. The combined organic phases were then extracted three times with 50 mL of saturated sodium bicarbonate to remove excess 2-pyridinecarboxylic acid. Finally, the mixture was dried over anhydrous sodium sulfate. The solution was concentrated by evaporation and separated by column chromatography using ethyl acetate / petroleum ether (1:5) as the eluent to obtain the desired starting material, N-(5-chloro-1-naphthyl)pyridineamide.
[0033] Step 2: Preparation of N-(8-nitro-5-chloro-1-naphthyl)pyridine amide N-(5-chloro-1-naphthyl)pyridine amide (0.1 mmol, 1 equiv), palladium acetate (5 mol%), silver nitrite (0.12 mmol, 1.2 equiv), and dioxane (0.25 mL) were added to a 4 mL pressure-resistant tube with a PTFE cap. After adding a clean magnetic stir bar, the mixture was heated at 60 °C for 3 h. After the reaction was completed, the reaction mixture was cooled to room temperature, diluted with ethyl acetate (2 mL), spotted by TLC, and then extracted with saturated sodium carbonate solution. The organic phase was retained, dried over anhydrous sodium sulfate, and concentrated. Finally, it was purified by silica gel column chromatography with ethyl acetate / petroleum ether. The obtained substance was detected by NMR, and the results are shown below, confirming that the obtained compound is N-(8-nitro-5-chloro-1-naphthyl)pyridine amide, and its chemical structure is shown below. The yield of N-(8-nitro-5-chloro-1-naphthyl)pyridine amide was 78%.
[0034] .
[0035] White solid; yield: 78%; mp 161 – 163ºC: 1H NMR (400 MHz, CDCl3) δ10.58 (s, 1H), 8.72 (d, J = 4.0 Hz, 1H), 8.37 (dd, J = 16.9, 8.2 Hz, 2H), 8.01 (d, J = 7.5 Hz, 1H), 7.95 (td, J = 7.7, 1.4 Hz, 1H), 7.89 (d, J = 7.8Hz, 1H), 7.81 – 7.75 (m, 1H), 7.67 (d, J = 7.8 Hz, 1H), 7.54 (dd, J = 12.9,5.9 Hz, 1H); 13 C NMR (100 MHz, CDCl3) δ 149.1, 148.2, 138.7, 137.6, 137.7,132.3, 132.1, 129.2, 128.4, 128.1, 126.8, 125.8, 124.5, 122.9, 118.9, 105.8. Step 3: Add NaOH (3 mmol, 3 equiv) and 1,4-dioxane (3 mL) to the N-(8-nitro-5-chloro-1-naphthyl)pyridine amide prepared in Step 2. After stirring evenly, heat to 60℃ and react for 3 h to obtain 8-nitro-5-chloro-1-naphthylamine with a yield of 93%.
[0036] Example 3: Preparation method of 8-nitro-5-bromo-1-naphthylamine: Step 1: N-(5-bromo-1-naphthyl)pyridine amide 2-Pyridinecarboxylic acid (11 mmol), 5-bromo-1-naphthylamine (10 mmol), triethylamine (3 mL), and dichloromethane (30 mL) were added sequentially to a 50 mL round-bottom flask. Phosphorus oxychloride (2 mL) was added dropwise under magnetic stirring at 0 °C, and the reaction was allowed to proceed for 30 min, followed by 2 h at room temperature. After the reaction was complete, 50 mL of ice water was added to quench the remaining POCl3, and the mixture was then transferred to a separatory funnel and extracted three times with 50 mL of ethyl acetate. The combined organic phases were then extracted three times with 50 mL of saturated sodium bicarbonate to remove excess 2-pyridinecarboxylic acid. Finally, the mixture was dried over anhydrous sodium sulfate. The solution was concentrated by evaporation and separated by column chromatography using ethyl acetate / petroleum ether (1:5) as the eluent to obtain the desired starting material, N-(5-bromo-1-naphthyl)pyridineamide.
[0037] Step 2: Preparation of N-(8-nitro-5-bromo-1-naphthyl)pyridine amide N-(5-bromo-1-naphthyl)pyridine amide (0.1 mmol, 1 equiv), palladium acetate (5 mol%), silver nitrite (0.12 mmol, 1.2 equiv), and dioxane (0.25 mL) were added to a 4 mL pressure-resistant tube with a PTFE cap. After adding a clean magnetic stir bar, the mixture was heated at 60 °C for 3 h. After the reaction was completed, the reaction mixture was cooled to room temperature, diluted with ethyl acetate (2 mL), spotted by TLC, and then extracted with saturated sodium carbonate solution. The organic phase was retained, dried over anhydrous sodium sulfate, and concentrated. Finally, it was purified by silica gel column chromatography with ethyl acetate / petroleum ether. The obtained substance was detected by NMR, and the results are shown below, confirming that the obtained compound is N-(8-nitro-5-bromo-1-naphthyl)pyridine amide, and its chemical structure is shown below. The yield of N-(8-nitro-5-bromo-1-naphthyl)pyridine amide was 75%.
[0038] .
[0039] White solid; yield: 75%; mp 182 – 184ºC: 1 H NMR (400 MHz, CDCl3) δ10.53 (s, 1H), 8.73 (d, J = 4.4 Hz, 1H), 8.35 (dd, J = 14.6, 8.0 Hz, 2H), 8.00 (d, J = 7.4 Hz, 1H), 7.94 (td, J = 7.6, 1.6 Hz, 1H), 7.89 (d, J = 7.8Hz, 1H), 7.82 – 7.75 (m, 2H), 7.54 (dd, J = 7.2, 5.4 Hz, 1H); 13 C NMR (100MHz, CDCl3)δ164.1, 149.1, 148.3, 137.5, 135.8, 133.2, 132.3, 130.0, 129.6,129.0, 128.6, 128.1, 127.4, 126.8, 122.8, 118.9, 106.5. Step 3: Add NaOH (3 mmol, 3 equiv) and 1,4-dioxane (3 mL) to the N-(8-nitro-5-bromo-1-naphthyl)pyridine amide prepared in Step 2. After stirring evenly, heat to 60℃ and react for 3 h to obtain 8-nitro-5-bromo-1-naphthylamine with a yield of 91%.
[0040] Example 4: Preparation method of 8-nitro-5-iodo-1-naphthylamine: Step 1: N-(5-iodo-1-naphthyl)pyridine amide 2-Pyridinecarboxylic acid (11 mmol), 5-iodo-1-naphthylamine (10 mmol), triethylamine (3 mL), and dichloromethane (30 mL) were added sequentially to a 50 mL round-bottom flask. Phosphorus oxychloride (2 mL) was added dropwise under magnetic stirring at 0 °C, and the reaction was allowed to proceed for 30 min, followed by 2 h at room temperature. After the reaction was complete, 50 mL of ice water was added to quench the remaining POCl3, and the mixture was then transferred to a separatory funnel and extracted three times with 50 mL of ethyl acetate. The combined organic phases were then extracted three times with 50 mL of saturated sodium bicarbonate to remove excess 2-pyridinecarboxylic acid. Finally, the mixture was dried over anhydrous sodium sulfate. The solution was concentrated by evaporation and separated by column chromatography using ethyl acetate / petroleum ether (1:5) as the eluent to obtain the desired starting material, N-(5-iodo-1-naphthyl)pyridineamide.
[0041] Step 2: Preparation of N-(8-nitro-5-iodo-1-naphthyl)pyridine amide N-(5-iodo-1-naphthyl)pyridine amide (0.1 mmol, 1 equiv), palladium acetate (5 mol%), silver nitrite (0.12 mmol, 1.2 equiv), and dioxane (0.25 mL) were added to a 4 mL pressure-resistant tube with a PTFE cap. After adding a clean magnetic stir bar, the mixture was heated at 60 °C for 3 h. After the reaction was completed, the reaction mixture was cooled to room temperature, diluted with ethyl acetate (2 mL), spotted by TLC, and then extracted with saturated sodium carbonate solution. The organic phase was retained, dried over anhydrous sodium sulfate, and concentrated. Finally, it was purified by silica gel column chromatography with ethyl acetate / petroleum ether. The obtained substance was detected by NMR, and the results are shown below, confirming that the obtained compound is N-(8-nitro-5-iodo-1-naphthyl)pyridine amide, and its chemical structure is shown below. The yield of N-(8-nitro-5-iodo-1-naphthyl)pyridine amide was 73%.
[0042] .
[0043] Yellow solid; yield: 73%; mp 217 – 218ºC: 1H NMR (400 MHz, CDCl3) δ10.52 (s, 1H), 8.71 (d, J =4.0 Hz, 1H), 8.34 (dd, J= 15.0, 8.0 Hz, 2H), 8.00(d, J = 6.8 Hz, 1H), 7.94 – 7.89 (m, 2H), 7.64 (t, J = 7.8 Hz, 1H), 7.55 (dd,J = 7.2, 5.4 Hz, 1H), 7.28 (dd, J = 12.4, 5.4 Hz, 1H); 13 C NMR (100 MHz, CDCl3) δ 149.2, 148.4, 141.0, 138.1, 137.5, 133.5, 131.7, 129.7, 129.0,128.7, 127.6, 125.8, 124.5, 122.1, 118.9, 105.9. Step 3: Add NaOH (3 mmol, 3 equiv) and 1,4-dioxane (3 mL) to the N-(8-nitro-5-iodo-1-naphthyl)pyridine amide prepared in Step 2. After stirring evenly, heat to 60℃ and react for 3 h to obtain 8-nitro-5-iodo-1-naphthylamine with a yield of 87%.
[0044] Example 5: Preparation method of 5,8-dinitro-1-naphthylamine: Step 1: N-(5-nitro-1-naphthyl)pyridine amide 2-Pyridinecarboxylic acid (11 mmol), 5-nitro-1-naphthylamine (10 mmol), triethylamine (3 mL), and dichloromethane (30 mL) were added sequentially to a 50 mL round-bottom flask. Phosphorus oxychloride (2 mL) was added dropwise under magnetic stirring at 0 °C, and the reaction was allowed to proceed for 30 min, followed by 2 h at room temperature. After the reaction was complete, 50 mL of ice water was added to quench the remaining POCl3, and the mixture was then transferred to a separatory funnel and extracted three times with 50 mL of ethyl acetate. The combined organic phases were then extracted three times with 50 mL of saturated sodium bicarbonate to remove excess 2-pyridinecarboxylic acid. Finally, the mixture was dried over anhydrous sodium sulfate. The solution was concentrated by evaporation and separated by column chromatography using ethyl acetate / petroleum ether (1:5) as the eluent to obtain the desired starting material, N-(5-nitro-1-naphthyl)pyridine amide.
[0045] Step 2: Preparation of N-(5,8-dinitro-1-naphthyl)pyridine amide N-(5-nitro-1-naphthyl)pyridine amide (0.1 mmol, 1 equiv), palladium acetate (5 mol%), silver nitrite (0.12 mmol, 1.2 equiv), and dioxane (0.25 mL) were added to a 4 mL pressure-resistant tube with a PTFE cap. After adding a clean magnetic stir bar, the mixture was heated at 60 °C for 3 h. After the reaction was completed, the reaction mixture was cooled to room temperature, diluted with ethyl acetate (2 mL), spotted by TLC, and then extracted with saturated sodium carbonate solution. The organic phase was retained, dried over anhydrous sodium sulfate, and concentrated. Finally, it was purified by silica gel column chromatography with ethyl acetate / petroleum ether. The obtained substance was detected by NMR, and the results are shown below, confirming that the obtained compound is N-(5,8-dinitro-1-naphthyl)pyridine amide, and its chemical structure is shown below. The yield of N-(5,8-dinitro-1-naphthyl)pyridine amide was 84%.
[0046] .
[0047] Red solid; yield: 84%; mp 164 – 165ºC: 1 H NMR (400 MHz, DMSO-d6) δ11.15 (s, 1H), 8.68 (dd, J = 20.8, 8.0 Hz, 2H), 8.44 (d, J = 7.6 Hz, 1H), 8.16 (d, J = 7.6 Hz, 1H), 8.06 (d, J = 8.8 Hz, 1H), 7.89 – 7.65 (m, 3H), 7.12(d, J = 7.2 Hz, 1H); 13 C NMR (100 MHz, DMSO-d6) δ 166.9, 158.7, 146.2, 138.7,133.3, 132.4, 130.7, 129.4, 127.4, 127.2, 126.8, 125.4, 123.1, 121.8, 116.3,114.1, 107.6. Step 3: Add NaOH (3 mmol, 3 equiv) and 1,4-dioxane (3 mL) to the N-(5,8-dinitro-1-naphthyl)pyridine amide prepared in Step 2. After stirring evenly, heat to 60℃ and react for 3 h to obtain 8-nitro-5-nitro-1-naphthylamine with a yield of 88%.
[0048] Example 6: Preparation method of 8-nitro-5-acetaminonaphthylamine: Step 1: N-(5-acetamido-1-naphthyl)pyridine amide 2-Pyridinecarboxylic acid (11 mmol), N-acetyl(5-aminonaphthyl)amine (10 mmol), triethylamine (3 mL), and dichloromethane (30 mL) were added sequentially to a 50 mL round-bottom flask. Phosphorus oxychloride (2 mL) was added dropwise under magnetic stirring at 0 °C, and the reaction was allowed to proceed for 30 min, followed by 2 h at room temperature. After the reaction was complete, 50 mL of ice water was added to quench the remaining POCl3, and the mixture was then transferred to a separatory funnel and extracted three times with 50 mL of ethyl acetate. The combined organic phases were then extracted three times with 50 mL of saturated sodium bicarbonate to remove excess 2-pyridinecarboxylic acid. Finally, the mixture was dried over anhydrous sodium sulfate. The solution was concentrated by evaporation and separated by column chromatography using ethyl acetate / petroleum ether (1:5) as the eluent to obtain the desired starting material, N-(5-acetylamino-1-naphthyl)pyridine amide.
[0049] Step 2: Preparation of N-(8-nitro-5-acetamido-1-naphthyl)pyridine amide N-(5-acetamido-1-naphthyl)pyridine amide (0.1 mmol, 1 equiv), palladium acetate (5 mol%), silver nitrite (0.12 mmol, 1.2 equiv), and dioxane (0.25 mL) were added to a 4 mL pressure-resistant tube with a PTFE cap. After adding a clean magnetic stir bar, the mixture was heated at 60 °C for 3 h. After the reaction was completed, the reaction mixture was cooled to room temperature, diluted with ethyl acetate (2 mL), spotted by TLC, and then extracted with saturated sodium carbonate solution. The organic phase was retained, dried over anhydrous sodium sulfate, and concentrated. Finally, it was purified by silica gel column chromatography with ethyl acetate / petroleum ether. The obtained substance was detected by NMR, and the results are shown below, confirming that the obtained compound is N-(8-nitro-5-acetamido-1-naphthyl)pyridine amide, and its chemical structure is shown below. The yield of N-(8-nitro-5-acetamido-1-naphthyl)pyridine amide was 71%.
[0050] .
[0051] White solid; yield: 71%; mp 221 – 223ºC: 1H NMR (400 MHz, DMSO-d6) δ10.73 (s, 1H), 9.81 (s, 1H), 8.79 (d, J =4.4 Hz, 1H), 8.17 (d, J =4.4 Hz, 1H), 8.08 (td, J =7.6, 1.6 Hz, 1H), 7.90 (d, J =7.4 Hz, 1H), 7.81 (d, J =8.4Hz, 1H), 7.74 – 7.67 (m, 2H), 7.55 – 7.49 (m, 2H), 2.21 (s, 3H); 13 C NMR (101MHz, DMSO-d6) δ 171.2, 162.6, 150.2, 148.3, 141.6, 134.9, 135.4, 130.9,129.6, 127.9, 127.7, 126.3, 124.2, 107.9, 25.9. Step 3: Add NaOH (3 mmol, 3 equiv) and 1,4-dioxane (3 mL) to the N-(8-nitro-5-acetamido-1-naphthyl)pyridine amide prepared in Step 2. After stirring evenly, heat to 60℃ and react for 3 h to obtain 8-nitro-5-acetamidonaphthylamine with a yield of 85%.
[0052] Example 7: Preparation method of 8-nitro-4-acetaminonaphthylamine: Step 1: N-(4-acetamido-1-naphthyl)pyridine amide 2-Pyridinecarboxylic acid (11 mmol), N-acetyl(4-aminonaphthyl)amine (10 mmol), triethylamine (3 mL), and dichloromethane (30 mL) were added sequentially to a 50 mL round-bottom flask. Phosphorus oxychloride (2 mL) was added dropwise under magnetic stirring at 0 °C, and the reaction was allowed to proceed for 30 min, followed by 2 h at room temperature. After the reaction was complete, 50 mL of ice water was added to quench the remaining POCl3, and the mixture was then transferred to a separatory funnel and extracted three times with 50 mL of ethyl acetate. The combined organic phases were then extracted three times with 50 mL of saturated sodium bicarbonate to remove excess 2-pyridinecarboxylic acid. Finally, the mixture was dried over anhydrous sodium sulfate. The solution was concentrated by evaporation and separated by column chromatography using ethyl acetate / petroleum ether (1:5) as the eluent to obtain the desired starting material, N-(4-acetylamino-1-naphthyl)pyridine amide.
[0053] Step 2: Preparation of N-(8-nitro-4-acetamido-1-naphthyl)pyridine amide N-(4-acetamido-1-naphthyl)pyridine amide (0.1 mmol, 1 equiv), palladium acetate (5 mol%), silver nitrite (0.12 mmol, 1.2 equiv), and dioxane (0.25 mL) were added to a 4 mL pressure-resistant tube with a PTFE cap. After adding a clean magnetic stir bar, the mixture was heated at 60 °C for 3 h. After the reaction was completed, the reaction mixture was cooled to room temperature, diluted with ethyl acetate (2 mL), spotted by TLC, and then extracted with saturated sodium carbonate solution. The organic phase was retained, dried over anhydrous sodium sulfate, and concentrated. Finally, it was purified by silica gel column chromatography with ethyl acetate / petroleum ether. The obtained substance was detected by NMR, and the results are shown below, confirming that the obtained compound is N-(8-nitro-4-acetamido-1-naphthyl)pyridine amide, and its chemical structure is shown below. The yield of N-(8-nitro-4-acetamido-1-naphthyl)pyridine amide was 74%.
[0054] .
[0055] White solid; yield: 74%; mp 215 – 217ºC: 1H NMR (400 MHz, DMSO-d6)δ 10.69 (s, 1H), 9.79 (s, 1H), 8.78 (d, J =4.4 Hz, 1H), 8.17 (d, J =7.6 Hz,1H), 8.11 13C NMR(101 MHz, DMSO-d6) δ 171.3, 162.8, 150.3, 148.3, 141.5, 132.5, 130.7, 129.4, 128.7, 126.3, 125.8, 125.2, 124.9, 108.0, 25.8. Step 3: Add NaOH (3 mmol, 3 equiv) and 1,4-dioxane (3 mL) to the N-(8-nitro-4-acetamido-1-naphthyl)pyridine amide prepared in Step 2. After stirring evenly, heat to 60℃ and react for 3 h to obtain 8-nitro-4-acetamido-1-naphthylamine with a yield of 77%.
[0056] As can be seen from Examples 1-7, the palladium-catalyzed selective nitration method for naphthylamine to generate 8-nitro-1-naphthylamine and its derivatives provided in this application has good functional group tolerance of the reaction substrate.
[0057] Examples 8-13: Preparation method of 8-nitro-1-naphthylamine: The difference between this embodiment and Example 1 is that the type of catalyst in step two is changed, while the other reaction conditions remain the same as in Example 1. The effects of changing the type of catalyst and the molar ratio of reactants in step two on the product yield are shown in Table 1.
[0058] .
[0059] As can be seen from Examples 1, 8 and 9, when the palladium catalyst is palladium acetate, the yield can be greatly improved, indicating that palladium acetate is the optimal catalyst.
[0060] As can be seen from Examples 1 and 10-13, the yield of N-(8-nitro-1-naphthyl)pyridine amide did not increase significantly with the increase of the amount of silver nitrite and palladium catalyst. Considering the cost, the molar ratio of N-(1-naphthyl)pyridine amide, silver nitrite and palladium catalyst is preferably 1:1.2:0.05.
Claims
1. A method for selective nitration of a naphthylamine catalyzed by palladium, characterized in that: The reaction procedure is shown as follows: ； R1 is H, halogen, nitro, C1-C4 alkyl, acetylamino, aryl, alkoxycarbonyl, benzyloxy or C1-C4 alkoxy; The preparation procedure is shown as follows: S1: 2-pyridinecarboxylic acid and a compound as shown in formula (IV) are used as raw materials, a solvent is added, a base is added to adjust pH, cooling is performed, then phosphorus oxychloride is slowly added dropwise, magnetic stirring is performed during dropwise addition, after dropwise addition is completed, the reaction is continued at room temperature, to obtain a compound as shown in formula (V); S2: the compound as shown in formula (V) obtained in the S1 step is subjected to nitration reaction with N-(o-tolyl)quinoline-2-carboxamide in the presence of silver nitrite and a palladium catalyst, after magnetic stirring for a certain period of time, a compound as shown in formula (II) is obtained.
2. The method of selective nitration of a naphthylamine catalyzed by palladium according to claim 1, characterized by the fact that: In the S1 step, the molar ratio of 2-pyridinecarboxylic acid, the compound as shown in formula (IV) and phosphorus oxychloride is 1-1.1:1-1.1:2-10.
3. The method of selective nitration of naphthylamine catalyzed by palladium according to claim 1, characterized by the fact that: In the S2 step, the molar ratio of the compound as shown in formula (V), silver nitrite and the palladium catalyst is 1-1.1:1-1.3:0.03-0.
1.
4. The method of selective nitration of a naphthylamine catalyzed by palladium according to claim 1, characterized by the fact that: The reaction temperature of the S1 step is -15-0℃, the reaction time is 2-4h; the base is triethylamine, morpholine or pyridine, the base is added to adjust pH to neutral; the reaction temperature of the S2 step is 50-120℃, the reaction time is 2-6h; in the S1 step, the solvent is dichloromethane or chloroform; in the S2 step, the solvent is dioxane, tetrahydrofuran or methyl tert-butyl ether.
5. The method of selective nitration of naphthylamine catalyzed by palladium according to claim 1, characterized by the fact that: In the S2 step, the palladium catalyst is palladium acetate, palladium chloride or palladium bromide.
6. The method of selective nitration of palladium-catalyzed naphthylamine according to claim 1, characterized in that: characterized in that: The preparation method further comprises the following procedure: ； R1 is H, halogen, nitro, C1-C4 alkyl, acetylamino, aryl, alkoxycarbonyl, benzyloxy or C1-C4 alkoxy; The specific preparation procedure is as follows: S3: a base is added to the compound as shown in formula (II), then heating is performed, after reaction for a certain period of time, a compound as shown in formula (III) is obtained.
7. The method of selective nitration of a palladium-catalyzed naphthylamine according to claim 6, characterized by: The molar ratio of the compound as shown in formula (II) and the base is 1:2-4.
8. The method of selective nitration of a palladium-catalyzed naphthylamine according to claim 6, characterized by: The reaction temperature of the S3 step is 40-80℃, the reaction time is 1-6h, the S3 step is performed in a solvent, the solvent is dioxane, tetrahydrofuran or methyl tert-butyl ether; the base is sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate.
9. An 8-nitro-l-naphthylamine characterized by: Prepared by the method of any one of claims 6-8.
10. An 8-nitro-naphthylamine derivative prepared by the method of any one of claims 1-6 or any one of claims 7-8, characterized in that: The derivative general formula is shown as formula (I): ； R1 is independently selected from H, halogen, nitro, C1-C4 alkyl, acetylamino, aryl, alkoxycarbonyl, benzyloxy and C1-C4 alkoxy.