Aza-binaphthol compound and preparation method thereof
The one-step synthesis of nitrogen-containing naphthols from 7-hydroxyquinoline compounds using Cu-TMEDA catalyst at room temperature solves the problems of complexity and inefficiency in existing methods, and achieves a simple and efficient synthesis and gram-scale preparation.
Patent Information
- Application Number
- CN202511016915.6
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-07-23
- Publication Date
- 2025-12-12
AI Technical Summary
Existing methods for synthesizing nitrogen-modified naphthols are cumbersome, have low yields, require low-temperature conditions, and use precious metals, resulting in poor practicality and failing to meet the requirements of green chemistry.
A one-step synthesis of nitrogen-containing naphthols from 7-hydroxyquinoline compounds was achieved using a copper dihydroxy-bis(tetramethylethylenediamine)-copper chloride (Cu-TMEDA) catalyst at room temperature. The synthesis was carried out by screening for suitable solvents and catalyst equivalences, followed by purification by silica gel column chromatography.
A simple and efficient synthesis of nitrogen-based heteronaphthol compounds was achieved, improving synthesis efficiency, reducing costs, and making it suitable for gram-scale preparation.
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Figure CN121108044A_ABST
Abstract
Description
TECHNICAL FIELD
[0001] The application belongs to the technical field of organic chemistry, and particularly relates to a kind of azanaphthol compound and a preparation method thereof. BACKGROUND
[0002] Developing new efficient chiral ligands is still the core research direction in the field of organic chemistry, which is not only due to the new structure type ligand can expand the application space of synthesis, but also because it provides a key entry point for exploring basic chemical processes and new application scenarios. Among the many classic chiral ligands, 1,1'-binaphthyl (BINOL) has become one of the most efficient ligand skeletons in the field of asymmetric catalysis (Chem. Rev. 2003, 103, 3155-3212). At the same time, the chiral assembly based on BINOL derivatives shows significant value in the cross fields of supramolecular recognition, crystal engineering and electronic materials (Org. Lett. 2006, 8, 355-358; Chem. Mater. 2005, 17, 118-121; J. Am. Chem. Soc. 2003, 125, 6014-6015; J. Am. Chem. Soc. 2007, 129, 7712-7713). Therefore, it is of great significance to develop new chiral ligands and expand the application boundary by precisely modifying the BINOL skeleton to regulate its stereo and electronic properties.
[0003] In recent years, based on the research orientation of exploring new chiral ligands, attempts have been made to introduce heteroatoms at the 8,8'-position of BINOL. However, when the 8-carbon is replaced by a hetero nitrogen atom, the resulting bifunctional molecule 7,7'-dihydroxy-8,8'-quinoline (I) exhibits conformational instability at room temperature (J. Org. Chem. 2005, 70, 373-376). In addition, the high polarity, low solubility, difficulty in resolution and difficulty in synthesis of the compound in common organic solvents further limit its potential application in asymmetric catalysis.
[0004] The methods for synthesizing azanaphthol reported so far are as follows:
[0005] When X is carbon:
[0006] Method 1
[0007]
[0008] Specific procedure: Starting from 7-hydroxyquinoline, the hydroxyl group was protected as carbamate using dimethylcarbamoyl chloride at 100 °C for 48 h, then lithiation of 2 was performed using lithium diisopropylamide in THF at -10 °C for 10 min, then the resulting mixture was added to a solution of iodine in THF at -78 °C for half an hour to give the iodo product. The iodo 4 was able to couple with 8-lithioquinoline 3 in copper, DMF system at 140 °C for 2 days to give the coupling product 5 in 60% yield. In addition to this, the coupling product 5 can also be prepared directly from 2 by in situ oxidation dimerization of 8-lithioquinoline 3 with anhydrous iron chloride, in 71% yield, which improved the synthesis of 6. Finally, the dimethylcarbamoyl group was removed quantitatively using KOH, MeOH under heating conditions to give the target product. J. Org. Chem. 2005, 70, 373-376
[0009] Method 2:
[0010]
[0011] Specific procedure: Starting from 8-chloroquinoline, the coupling was performed using NiCl2, PPh3, Zn in DMF at 80 °C to give the coupling product, then acetoxy groups were introduced at 7 and 7' positions using Pd(OAc)2, PhI(OAc)2 (PIDA), ACOH-CHCl3; 60-80 °C for 20 h, finally the acetyl group was removed using hydrazine hydrate to give the target product. Org. Lett. 2011, 13, 4024-4027
[0012] When X is nitrogen:
[0013] Method 1:
[0014]
[0015] Specific procedure: Starting from 8-iodoquinoline derivative, Suzuki coupling with 1-naphthaleneboronic acid was performed using toluene reflux for 46 h to give the coupling product, then acetoxy groups were introduced at quinoline 2 position using Pd(OAc)2, PhI(OAc)2, ACOH-CHCl3; 60-80 °C for 36 h, finally the protecting group was removed quantitatively using KOH, MeOH under heating conditions for 18 h to give the target product. Synthesis 2015, 47, 4008-4016
[0016]
[0017] Specific steps: quinoline N-oxide is coupled with 1-diazo-2-naphthalenone under the catalysis of metal rhodium to obtain product 2, then sodium hydride and methyl iodide can reduce the N-oxide to quinoline coupling product, and finally the target product can be obtained by removing the methyl group under the action of boron tribromide. Chem. Asian J. 2018, 13, 2388
[0018] The above method has the following defects: 1) the steps are complicated, the synthesis path is as long as 3-6 steps, which increases the complexity and time cost of the synthesis process, and the multi-step yield is not high, the synthesis efficiency is low, and the requirements of green chemistry cannot be met. 2) Some steps need low temperature (minus 78℃), which cannot complete the preparation of kilogram scale. 3) The use of noble metals palladium and rhodium greatly reduces the practicability of the method. SUMMARY
[0019] In view of the problems existing in the prior art, the purpose of the present application is to provide a kind of azanaphthol compound and preparation method thereof. The present application realizes one-step synthesis of azanaphthol compound by reasonable catalyst equivalent and solvent screening, under the action of chlorinated dihydroxy-bis-tetramethyl ethylene diamine copper (Cu-TMEDA) catalyst, with 7-hydroxyquinoline compound as raw material.
[0020] The first aspect of the present application provides an azanaphthol compound represented by formula (I):
[0021]
[0022] In formula (I), X is carbon or nitrogen, R 1 , R 2 is any one of hydrogen, methyl, chlorine, bromine, methoxy, aryl; each aryl is any one of the structures shown in the following figure:
[0023]
[0024] Further, the azanaphthol compound represented by formula (I) is any one of compounds 1-25:
[0025]
[0026] The two aspects of the present application provide a preparation method of the azanaphthol compound shown in formula (I), which comprises the following steps: dissolving a chlorinated dihydroxy-bistetramethyl ethylene diamine copper (Cu-TMEDA) catalyst in an organic solvent under an air atmosphere, then adding a 7-hydroxy quinoline derivative shown in formula (II) and a compound shown in formula (III), stirring at room temperature, and monitoring the reaction progress by TLC. After the reaction is completed, the reaction solution is concentrated under reduced pressure, and silica gel column chromatography is performed with petroleum ether and ethyl acetate as eluents (or with dichloromethane and methanol as eluents) in a volume ratio of 10:1-4:1, R f The effluent with a value of 0.2-0.4 is concentrated under reduced pressure to dryness to obtain the azanaphthol compound shown in formula (I).
[0027] The organic solvent is selected from any one of dichloromethane, tetrahydrofuran, methanol, ethyl acetate, toluene, acetonitrile, 1,2-dichloroethane, chloroform, chloroform / tetrahydrofuran=4:1, chloroform / methanol=4:1, preferably chloroform when X is carbon, and preferably methanol when X is nitrogen;
[0028] The amount of the catalyst is any one of 1-20 mol%, preferably 10 mol% when X is carbon, and preferably 20 mol% when X is nitrogen;
[0029] The reaction formula is as follows:
[0030]
[0031] R in formula (I) is the same as R in formula (III) 1 R in formula (I) is the same as R in formula (III) 1 R in formula (I) is the same as R in formula (II) 2 R in formula (I) is the same as R in formula (II) 2 .
[0032] Further, the catalyst is selected from Cu-TMEAD, and the structure is shown as follows:
[0033]
[0034] Further, preferably, when X is nitrogen, formula (II) and formula (III) are the same compound, the molar ratio of the compound shown in formula (II) to the catalyst feed is 1:0.01-0.1, preferably 1:0.1; the solvent volume is 10-20 mL / mmol based on the amount of the compound shown in formula (II), preferably 10 mL / mmol; when X is carbon, the molar ratio of the compound shown in formula (II) to the compound shown in formula (III) is 1:2-4, preferably 1:4, the molar ratio of the compound shown in formula (II) to the catalyst feed is 1:0.1-0.2, preferably 1:0.2; the solvent volume is 10-20 mL / mmol based on the amount of the compound shown in formula (II), preferably 10 mL / mmol.
[0035] This invention, through rational reaction design, appropriate catalyst selection, and catalyst stoichiometry, enables the efficient one-step synthesis of two classes of nitrogen-modified naphthol compounds via self-coupling of 7-hydroxyquinoline and cross-coupling of 7-hydroxyquinoline with naphthol under an air atmosphere. A concise, efficient, and rapid synthetic strategy has been developed, providing a synthetic foundation for the subsequent development and application of nitrogen-modified naphthol compounds. Attached Figure Description
[0036] Figure 1 For compound I-1 1 H NMR spectrum;
[0037] Figure 2 For compound I-1 13 C NMR spectrum;
[0038] Figure 3 For compound I-19 1 H NMR spectrum;
[0039] Figure 4 For compound I-19 13 C NMR spectrum. Detailed Implementation
[0040] The present invention will be further described below with reference to specific embodiments in order to better understand the technical solution.
[0041] Example 1: Preparation of compound 1-1
[0042] Preparation of [8,8'-biquinoline]-7,7'-diol I-1:
[0043]
[0044] At room temperature, copper dihydroxy-bis(tetramethylethylenediamine)diamine (Cu-TMEDA) catalyst (0.02 mmol, 0.1 eq.) and chloroform (2 mL) were added to the reaction tube, followed by 7-hydroxyquinoline II (0.2 mmol, 1.0 eq.). The mixture was stirred at room temperature, and the reaction progress was monitored by TLC. After the reaction was complete, the reaction solution was eluted with dichloromethane and methanol at a volume ratio of 50:1–10:1 and subjected to silica gel column chromatography. R was collected. f The eluent with a pH of 0.2-0.4 was rotary evaporated under reduced pressure to dryness to give a pale yellow solid product I-1 (84% yield). The 1H NMR spectrum is shown below. Figure 1 As shown, 13 The C NMR spectrum is shown below. Figure 2 As shown.
[0045] Examples 2-18: Preparation of compounds 1-2 to 1-18
[0046] At room temperature, copper dihydroxy-bis(tetramethylethylenediamine)diamine (Cu-TMEDA) catalyst (0.02 mmol, 0.1 eq.) and chloroform (2 mL) were added to the reaction tube, followed by the addition of a 7-hydroxyquinoline derivative (0.2 mmol, 1.0 eq.). The mixture was stirred at room temperature, and the reaction progress was monitored by TLC. After the reaction was completed, the reaction solution was concentrated under reduced pressure and subjected to silica gel column chromatography using petroleum ether and ethyl acetate (v / v) at a ratio of 10:1 to 4:1 (or dichloromethane and methanol (v / v) at a ratio of 50:1 to 10:1). R was collected. f The effluent with a value of 0.2-0.4 was evaporated to dryness under reduced pressure to obtain the corresponding product.
[0047]
[0048] Example 19: Preparation of compounds 1-19
[0049] 8-(2-hydroxy-1-naphthyl)-7-hydroxyquinoline
[0050]
[0051] At room temperature, copper dihydroxy-bis(tetramethylethylenediamine)diamine (Cu-TMEDA) catalyst (0.04 mmol, 0.2 eq.) and methanol (2 mL) were added to a reaction tube, followed by 7-hydroxyquinoline II (0.2 mmol, 1.0 eq.) and naphthol III (0.2 mmol, 4.0 eq.). The mixture was stirred at room temperature, and the reaction progress was monitored by TLC. After the reaction was complete, the reaction solution was subjected to silica gel column chromatography with dichloromethane and methanol as the eluent at a volume ratio of 50:1–10:1. R was collected. fThe eluent with a pH of 0.2-0.4 was rotary evaporated under reduced pressure to dryness to give a pale yellow solid product I-1 (84% yield). The 1H NMR spectrum is shown below. Figure 3 As shown, 13 The C NMR spectrum is shown below. Figure 4 As shown.
[0052] Examples 20-22: Preparation of compounds 1-20 to 1-22
[0053] At room temperature, copper dihydroxy-bis(tetramethylethylenediamine)diamine (Cu-TMEDA) catalyst (0.04 mmol, 0.2 eq.) and methanol (2 mL) were added to the reaction tube, followed by 7-hydroxyquinoline II (0.2 mmol, 1.0 eq.) and naphthol derivative III (0.2 mmol, 4.0 eq.). The mixture was stirred at room temperature, and the reaction progress was monitored by TLC. After the reaction was completed, the reaction solution was concentrated under reduced pressure and subjected to silica gel column chromatography using petroleum ether and ethyl acetate in a volume ratio of 10:1–4:1 as eluents. R was collected. f The effluent with a pH of 0.2-0.4 was evaporated to dryness under reduced pressure to obtain the product.
[0054]
[0055] Examples 23-25: Preparation of compounds 1-23 to 1-25
[0056] At room temperature, copper dihydroxy-bis(tetramethylethylenediamine)diamine (Cu-TMEDA) catalyst (0.02 mmol, 0.1 eq.) and chloroform (2 mL) were added to the reaction tube, followed by the addition of a 7-hydroxyquinoline derivative (0.2 mmol, 1.0 eq.) and β-naphthol III (0.2 mmol, 4.0 eq.). The mixture was stirred at room temperature, and the reaction progress was monitored by TLC. After the reaction was completed, the reaction solution was concentrated under reduced pressure and subjected to silica gel column chromatography using petroleum ether and ethyl acetate (v / v) at a ratio of 10:1 to 4:1 (or dichloromethane and methanol (v / v) at a ratio of 50:1 to 10:1). R was collected. f The effluent with a value of 0.2-0.4 was evaporated to dryness under reduced pressure to obtain the corresponding product.
[0057]
[0058] The high-resolution mass spectrometry data of the proton NMR spectra of each compound are shown in Table 1.
[0059] Table 1
[0060]
[0061]
[0062]
[0063]
[0064]
[0065]
Claims
1. A nitrogen-modified naphthol compound, characterized in that, The structural formula of the compound is shown in formula (Ⅰ): In formula (Ⅰ), X is carbon or nitrogen, and R 1 R 2 Each of the following groups is independently composed of hydrogen, methyl, chlorine, bromine, methoxy, or aryl; each of the aryl groups is independently composed of any one of the structures shown in the figure below:
2. The nitrogen-modified naphthol compound as described in claim 1, characterized in that, The compound represented by formula (Ⅰ) is any one of the following compounds:
3. The method for preparing the nitrogen-hetero-naphthol compound according to claim 1, characterized in that, The specific preparation method is as follows: In an air atmosphere, the catalyst was dissolved in an organic solvent, followed by the addition of the 7-hydroxyquinoline derivative shown in formula (II) and the compound shown in formula (III). The mixture was stirred at room temperature, and the reaction progress was monitored by TLC. After the reaction was completed, post-treatment was performed to obtain the nitrogen-containing heteronaphthol compound shown in formula (I). The reaction formula is as follows:
4. The method for preparing the nitrogen-hetero-naphthol compound as described in claim 3, characterized in that, The catalyst is copper dihydroxy-bis(tetramethylethylenediamine)amine (Cu-TMEDA), with an amount of 1-20 mol%, and its structural formula is as follows:
5. The method for preparing the nitrogen-hetero-naphthol compound as described in claim 3, characterized in that, The organic solvent is selected from any one of dichloromethane, tetrahydrofuran, methanol, ethyl acetate, toluene, acetonitrile, 1,2-dichloroethane, chloroform, chloroform / tetrahydrofuran = 4:1, and chloroform / methanol = 4:
1.
6. The method for preparing the nitrogen-hetero-naphthol compound as described in claim 3, characterized in that, When X is nitrogen, formula (II) and formula (III) are the same compound, and the molar ratio of the compound shown in formula (II) to the catalyst is 1:0.01-0.1; the solvent volume is 10-20 mL / mmol based on the amount of the compound shown in formula (II); when X is carbon, the molar ratio of the compound shown in formula (II) to the compound shown in formula (III) is 1:2-4, and the molar ratio of the compound shown in formula (II) to the catalyst is 1:0.1-0.2; the solvent volume is 10-20 mL / mmol based on the amount of the compound shown in formula (II).
7. The method for preparing the nitrogen-hetero-naphthol compound as described in claim 3, characterized in that, The post-processing specifically includes: After the reaction was completed, the reaction solution was concentrated under reduced pressure and subjected to silica gel column chromatography using petroleum ether and ethyl acetate (v / v) at a ratio of 10:1 to 4:1 or dichloromethane and methanol (v / v) at a ratio of 50:1 to 10:
1. R was collected. f The effluent with a value of 0.2-0.4 was evaporated under reduced pressure to dryness to obtain the nitrogen-containing heteronaphthol compound shown in formula (Ⅰ).