A method for C-N or C-O cross-coupling reaction, a Cu-N3 monatomic catalyst used in the method and a preparation method of the catalyst

Abstract

The application relates to the technical field of organic synthesis and catalytic chemistry, and particularly discloses a C-N or C-O cross-coupling reaction method, a Cu-N3 monatomic catalyst used in the method and a preparation method of the catalyst. x The catalyst is a Cu-N3 monatomic catalyst dispersed on a nitrogen-doped ordered mesoporous carbon carrier to form a Cu-N3 coordination structure. The C-N or C-O bond can be efficiently constructed by using (hetero) aryl halides, (hetero) aryl triflates and amines or alcohols as substrates, under alkaline conditions and at 90-110 DEG C. The method does not need an external organic ligand, has the advantages of simple reaction conditions, wide substrate application range and good functional group tolerance, and is suitable for various substituted aromatic hydrocarbons, heterocyclic substrates and primary and secondary amine and alcohol substrates. The catalytic system still has good activity under air conditions, and can realize 5-100 mmol scale reaction amplification, and the yield can reach 50-96%. The method can be used for late-stage modification of drug molecules and synthesis of functional materials, and has good industrial application prospect.

Description

Technical Field

[0001] This invention relates to the fields of organic synthesis and catalytic chemistry, specifically to a method for CN or CO cross-coupling reaction, the Cu-N3 single-atom catalyst used, and its preparation method. Background Technology

[0002] The construction of C–N and C–O bonds is a fundamental reaction in organic synthesis, widely used in the synthesis of pharmaceutical molecules, agrochemicals, and functional materials. In particular, aryl amine and aryl ether structural units are commonly found in many biologically active compounds; therefore, developing efficient and universal cross-coupling methods is of great significance.

[0003] Currently, transition metal-catalyzed cross-coupling reactions are the main method for constructing the aforementioned chemical bonds. Among them, palladium-catalyzed coupling reaction systems have advantages such as high reaction efficiency and a wide range of applicable substrates. However, due to the high price and scarcity of precious metals such as palladium, as well as the problem of metal residue, their large-scale industrial applications are somewhat limited.

[0004] In contrast, copper catalytic systems have attracted widespread attention due to their low cost and abundant resources; for example, the Ullmann reaction and its improved methods have been used to construct C–N and C–O bonds. However, existing copper catalytic systems typically rely on specific ligands to enhance reaction activity and selectivity. These ligands are often structurally complex, involve cumbersome synthesis steps, and exhibit limited stability during the reaction process, making them difficult to recycle, thus increasing reaction costs and limiting their industrial applications. Furthermore, some copper catalytic systems still suffer from harsh reaction conditions, limited substrate applicability, and sensitivity to steric hindrance.

[0005] In recent years, single-atom catalysts have shown promising applications in various catalytic reactions due to their advantages such as high atomic utilization, uniform active sites, and tunable coordination environments. By anchoring metal active centers to a support in single-atom form, high activity similar to homogeneous catalysis can be achieved without the need for added ligands, while also maintaining the stability and recyclability of heterogeneous catalytic systems. However, research on single-atom copper catalysts in C–N and C–O cross-coupling reactions remains relatively limited. The relationship between their catalytic performance and coordination environment is not yet fully understood, and there are still shortcomings in terms of versatility and large-scale application.

[0006] Therefore, it is necessary to develop a copper-based catalytic system that does not require external ligands, has high activity and stability, and is applicable to a variety of substrates, in order to achieve the efficient construction of C–N and C–O bonds, thereby meeting the application needs in the field of fine chemical and pharmaceutical synthesis. Summary of the Invention

[0007] The purpose of this invention is to address the problems in existing copper-catalyzed cross-coupling reactions, such as reliance on organic ligands, poor stability of the catalytic system, and limited substrate applicability, by providing a method for constructing C–N and C–O bonds that does not require external ligands, exhibits high catalytic activity, and has good applicability.

[0008] To achieve the above objectives, the present invention provides the following technical solution: a method for constructing C–N or C–O cross-coupling reactions, comprising the following steps: in the presence of a base, aryl halides, aryl trifluoromethanesulfonates, or heterocyclic aryl base compounds undergo a coupling reaction with nitrogen- or oxygen-containing nucleophiles under the action of a copper-based single-atom catalyst to obtain the corresponding C–N or C–O coupling products; wherein, in the copper-based single-atom catalyst, copper active centers are anchored on a nitrogen-containing carbon support in an atomically dispersed form and form a coordination structure (Cu–N) with 3-4 nitrogen atoms. x ).

[0009] Preferably, the nitrogen-containing carbon support is a nitrogen-doped porous carbon material, selected from ordered mesoporous carbon, disordered porous carbon, carbon nanomaterials, or combinations thereof.

[0010] Preferably, the copper active center is Cu(I), Cu(II), or a mixture thereof.

[0011] Preferably, the aryl (hetero)electrophilic reagent is selected from aryl bromides, aryl chlorides, aryl trifluoromethanesulfonates, heterocyclic aryl halides, or combinations thereof.

[0012] Preferably, the nitrogen-containing nucleophile is selected from aliphatic amines, aromatic amines, heterocyclic amines, primary amines, secondary amines, ammonia, or combinations thereof.

[0013] Preferably, the oxygen-containing nucleophile is selected from fatty alcohols, aromatic alcohols, benzyl alcohols, cyclic alcohols, or sterically hindered alcohols.

[0014] Preferably, the alkali is selected from alkali metal alkoxides, alkali metal carbonates, hydroxides, or combinations thereof; the reaction temperature is 80–120 °C.

[0015] Preferably, the reaction is carried out in an air atmosphere or an inert atmosphere, and is suitable for late-stage functionalization modification of drug molecules or natural products.

[0016] The present invention also provides a copper-based single-atom catalyst, wherein copper is dispersed in single-atom form and anchored on a nitrogen-containing carbon support to form Cu–N. x Coordination structure.

[0017] The Cu–N x In the catalyst, x is 3 or 4, the catalyst has an ordered mesoporous structure, a specific surface area of ​​200–1500 m² / g, and a copper loading of 0.01–5 wt%.

[0018] This catalyst is used for the C–N or C–O bond coupling reaction of aryl halides, aryl trifluoromethanesulfonates, and amines or alcohols.

[0019] The preparation method of the above catalyst is as follows: a carbon skeleton is constructed using a mesoporous template, a nitrogen-containing precursor and a copper source are introduced, and high-temperature pyrolysis is carried out at 700–1000 °C under an inert atmosphere. After removing the template, a copper single-atom catalyst is obtained.

[0020] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0021] 1. Achieving highly efficient catalysis: This invention anchors copper active centers in single-atom form onto a nitrogen-containing carbon support, forming a stable Cu–N group. x The (X = 3, 4) coordination structure allows the catalyst itself to provide a ligand-like environment, thereby replacing the dependence on organic ligands in traditional copper catalysis systems. This technical approach effectively avoids the problems of increased cost, separation difficulties, and insufficient stability caused by the introduction of ligands, and significantly simplifies the reaction system.

[0022] 2. High catalytic activity and excellent reaction efficiency: The catalytic system described in this invention can achieve efficient coupling reaction of aryl halides with amines or alcohols under relatively mild reaction conditions (such as 80–120 °C), and the yield of the target product can usually reach 50–96%, showing excellent catalytic activity and reaction efficiency.

[0023] 3. Wide substrate applicability and good functional group compatibility: The method of this invention is applicable to aryl bromides, aryl chlorides, aryl trifluoromethanesulfonates, and heterocyclic aromatic substrates, and also exhibits good adaptability to different types of nucleophiles (such as primary amines, secondary amines, aromatic amines, and alcohols). Furthermore, it demonstrates good reactivity with substrates containing electron-donating or electron-withdrawing groups, indicating that the method has good functional group tolerance.

[0024] 4. Good adaptability to sterically hindered substrates: Compared with the problem of low reaction efficiency of traditional copper catalytic systems for substrates with large steric hindrance, the single-atom catalytic system of the present invention has higher accessibility due to the uniform dispersion of active sites, thus effectively promoting the coupling reaction of substrates with large steric hindrance.

[0025] 5. Stable and reusable catalyst structure: In the copper-based single-atom catalyst of this invention, copper atoms exist stably in an atomically dispersed form, making them less prone to aggregation or loss. During multiple cycles of use, the catalytic activity remains essentially unchanged, demonstrating good structural stability and reusability, which helps reduce catalytic costs.

[0026] 6. Operable under air conditions, simple process: The reaction of this invention can be carried out in an air atmosphere without the need for strict inert gas protection, which reduces the difficulty of experimental operation and equipment requirements, and is conducive to practical production application.

[0027] 7. Good potential for scale-up applications: When the reaction scale is expanded to gram level or higher, the method of the present invention can still maintain a high reaction yield and stable reaction performance, showing good potential for industrial scale-up.

[0028] 8. Demonstrates a clear structure-performance correlation advantage: This invention achieves this by regulating the coordination environment between the copper active center and the nitrogen atom (Cu–N). x The single-atom catalytic structure effectively improves catalytic performance, demonstrating its significant advantages in this type of coupling reaction and providing a new technical path for the design of related catalytic systems.

[0029] 9. It is conducive to green chemistry and sustainable development: This invention uses inexpensive and readily available copper as the catalytic center, avoiding the use of precious metals, while reducing the use of organic ligands and the generation of waste, which is in line with the development direction of green chemistry. Attached Figure Description

[0030] Figure 1 To prepare the structural characterization spectrum of the sample;

[0031] Figure 2 Bar chart for catalyst recycling stability test. Detailed Implementation

[0032] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0033] In this embodiment, all nuclear magnetic resonance spectra were measured using a Bruker 400 AVANCE III spectrometer.

[0034] Product separation was performed using a Teledyne Isco RF+UV-VIS fully automated rapid preparative chromatography system.

[0035] Electron impact mass spectrometry (EI) was performed using an Agilent 6224 TOF mass spectrometer.

[0036] The yield of the compound was calculated using the following formula:

[0037] Yield % = (Actual mass of target product obtained / Theoretically expected mass of target product) × 100%

[0038] Example 1

[0039] Catalyst preparation

[0040] Template pretreatment: Weigh 2.0 g of mesoporous silica template material (such as SBA-15) and dry it at 120 ℃ for 6 hours to remove moisture, then set aside.

[0041] Preparation of precursor solution: Dissolve 3.0 g of nitrogen-containing organic precursor (such as o-phenylenediamine) in 30 mL of anhydrous ethanol and stir to form a homogeneous solution; then add 0.10 g of copper salt (such as copper nitrate trihydrate) and continue stirring for 30 minutes to obtain a homogeneous precursor solution.

[0042] Impregnation and composite: The template treated in step (1) is added to the above precursor solution and stirred at room temperature for 12 hours to allow the precursor to fully impregnate into the template pores; then the solvent is slowly evaporated at 60 °C to obtain a solid composite.

[0043] Pyrolysis treatment: The obtained solid was placed in a tube furnace and pyrolyzed under a nitrogen atmosphere: the temperature was increased to 800 ℃ at 5 ℃ / min, held for 2 hours, and then naturally cooled to room temperature to obtain carbonized products.

[0044] Template removal: The above carbonized product was added to a 2 mol / L hydrofluoric acid solution and stirred at room temperature for 12 hours to remove the silica template; then it was repeatedly washed with deionized water until neutral, and washed several times with ethanol.

[0045] Drying: The obtained solid was dried under vacuum at 80 °C for 12 hours to obtain a copper-based single-atom catalyst (denoted as Cu–N3 / OMC).

[0046] ( Figure 1 a) The catalyst exhibits a regular mesoporous layered structure, indicating that the SBA–15 template successfully constructed an ordered mesoporous carbon framework; this porous structure is beneficial for increasing the specific surface area and providing stable anchoring points for copper species.

[0047] ( Figure 1 b) No obvious copper nanoparticles or lattice fringes were observed, indicating that there is no obvious metal agglomeration in the material; the corresponding SAED results only showed diffuse diffraction rings, indicating that the catalyst as a whole presents an amorphous carbon structure.

[0048] ( Figure 1 In c), a large number of uniformly dispersed bright spots can be observed. Since copper atoms have a high atomic number, these bright spots can be attributed to atomically dispersed copper species.

[0049] ( Figure 1 d) Further evidence shows that copper species are uniformly dispersed in the carbon support, and no obvious agglomeration or particle formation was observed, indicating that copper mainly exists stably in the form of single atoms.

[0050] ( Figure 1 e) Indicates the presence of Cu in the catalyst. + With Cu 2+ The species indicates that the copper center has mixed valence state characteristics.

[0051] ( Figure 1 In f), pyridine nitrogen, metal-coordinated nitrogen, pyrrole nitrogen and graphitic nitrogen can be distinguished. The presence of metal-coordinated nitrogen proves that a stable Cu–N coordination structure is formed between copper atoms and nitrogen atoms.

[0052] ( Figure 1 g) indicates that the Cu absorption edge is located between Cu2O and CuO, further illustrating that the average valence state of the copper center is between +1 and +2, and has a local structural environment that is different from that of bulk copper oxide.

[0053] ( Figure 1 A distinct Cu–N / O scattering peak was observed at approximately 1.5 Å in h), while no characteristic peak corresponding to Cu–Cu coordination was observed in the 2.2–2.5 Å range, indicating that there were no obvious copper particles or clusters in the catalyst.

[0054] ( Figure 1 i) This indicates that the average coordination number of Cu–N is about 3, proving that the copper center mainly exists in the form of Cu–N3 coordination.

[0055] Example 2

[0056]

[0057] In a dry, sealed tube, t-BuOK (1.0 mmol), Cu–N3 / OMC (5 mg), DME (1 mL), bromobenzene (0.5 mmol), and morpholine (0.75 mmol) were added sequentially. The reaction mixture was stirred at 100 °C. After the reaction was complete, the mixture was cooled to room temperature and centrifuged to remove the solids. The resulting substance was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to give the target product. The yield was 91%.

[0058] The NMR detection data of the product sample are as follows:

[0059] 1H NMR (400 MHz, CDCl3) δ 7.38 – 7.29 (m, 2H), 7.01 – 6.90 (m, 3H), 4.04 – 3.78 (m, 4H), 3.28 – 3.05 (m, 4H).

[0060] 13 C NMR (100 MHz, CDCl3) δ 151.29, 129.22, 120.09, 115.74, 66.97, 49.39.

[0061] Example 3

[0062]

[0063] In a dry, sealed tube, t-BuOK (1.0 mmol), Cu–N4 / BSC (5 mg), DME (1 mL), bromobenzene (0.5 mmol), and morpholine (0.75 mmol) were added sequentially. The reaction mixture was stirred at 100 °C. After the reaction was complete, the mixture was cooled to room temperature and centrifuged to remove the solids. The resulting substance was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to give the target product. The yield was 61%.

[0064] The NMR detection data of the product sample are as follows:

[0065] 1 H NMR (400 MHz, CDCl3) δ 7.38 – 7.29 (m, 2H), 7.01 – 6.90 (m, 3H), 4.04 – 3.78 (m, 4H), 3.28 – 3.05 (m, 4H).

[0066] 13 C NMR (100 MHz, CDCl3) δ 151.29, 129.22, 120.09, 115.74, 66.97, 49.39.

[0067] Example 4

[0068] In a dry, sealed tube, t-BuOK (1.0 mmol), Cu–N3 / OMC (5 mg), 1,4-dioxane (1 mL), 1-bromo-4-toluene (0.5 mmol), and N-methylaniline (0.75 mmol) were added sequentially. The reaction mixture was stirred at 100 °C. After the reaction was complete, the mixture was cooled to room temperature and centrifuged to remove the solids. The resulting substance was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to give the target product. The yield was 89%.

[0069] The NMR detection data of the product sample are as follows:

[0070] 1 H NMR (400 MHz, CDCl3) δ 7.42 – 7.29 (m, 2H), 7.29 – 7.20 (m, 2H), 7.17 – 7.10 (m, 2H), 7.09 – 7.04 (m, 2H), 7.03 – 6.97 (m, 1H), 3.41 (s, 3H),2.46 (s, 3H).

[0071] 13 C NMR (100 MHz, CDCl3) δ 149.48, 146.72, 132.11, 130.03, 130.01,129.14, 122.67, 119.91, 118.31, 40.42, 20.87.

[0072] Example 5

[0073]

[0074] In a dry, sealed tube, t-BuOK (1.0 mmol), Cu–N3 / OMC (5 mg), DME (1 mL), 1-bromo-4-fluorobenzene (0.5 mmol), and N-methylaniline (0.75 mmol) were added sequentially. The reaction mixture was stirred at 100 °C. After the reaction was complete, the mixture was cooled to room temperature and centrifuged to remove the solids. The resulting substance was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to give the target product. The yield was 82%.

[0075] The NMR detection data of the product sample are as follows:

[0076] 1H NMR (400 MHz, CDCl3) δ 7.36 – 7.28 (m, 2H), 7.10 (m, 4H), 7.00 –6.94 (m, 3H), 3.35 (s, 3H).

[0077] 13 C NMR (100 MHz, CDCl3) δ 157.54, 145.31 (d, J = 2.6 Hz), 129.18,124.27 (d, J = 8.0 Hz), 120.12, 118.12, 116.03 (d, J = 22.4 Hz), 40.56.

[0078] 19 F NMR (376 MHz, CDCl3) δ -120.61.

[0079] Example 6

[0080]

[0081] In a dry, sealed tube, t-BuOK (1.0 mmol), Cu–N3 / OMC (5 mg), DME (1 mL), 1-bromo-3-(trifluoromethyl)benzene (0.5 mmol), and morpholine (0.75 mmol) were added sequentially. The reaction mixture was stirred at 100 °C. After the reaction was complete, the mixture was cooled to room temperature and centrifuged to remove the solids. The resulting substance was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to give the target product. The yield was 89%.

[0082] The NMR detection data of the product sample are as follows:

[0083] 1 H NMR (400 MHz, CDCl3) δ 7.40 (t, J = 8.1 Hz, 1H), 7.18 – 7.13 (m,2H), 7.09 (d, J = 8.5 Hz, 1H), 3.94 – 3.87 (m, 4H), 3.30 – 3.20 (m, 4H).

[0084] 13 C NMR (100 MHz, CDCl3) δ 151.44, 131.50 (q, J = 31.5 Hz), 129.63,124.33 (q, J = 272.5 Hz), 118.45, 116.19 (q, J = 3.5 Hz), 111.84 (q, J = 3.7Hz), 66.71, 48.82.

[0085] 19 F NMR (376 MHz, CDCl3) δ -62.71.

[0086] Example 7

[0087]

[0088] In a dry, sealed tube, t-BuOK (1.0 mmol), Cu–N3 / OMC (5 mg), DME (1 mL), 1-bromo-3-methoxybenzene (0.5 mmol), and morpholine (0.75 mmol) were added sequentially. The reaction mixture was stirred at 100 °C. After the reaction was complete, the mixture was cooled to room temperature and centrifuged to remove the solids. The resulting substance was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to give the target product. The yield was 96%.

[0089] The NMR detection data of the product sample are as follows:

[0090] 1 H NMR (400 MHz, CDCl3) δ 7.27 – 7.19 (m, 1H), 6.63 – 6.54 (m, 1H), 6.52 – 6.45 (m, 2H), 3.96 – 3.86 (m, 4H), 3.84 (s, 3H), 3.22 – 3.12 (m, 4H).

[0091] 13 C NMR (100 MHz, CDCl3) δ 160.65, 152.73, 129.90, 108.49, 104.72,102.23, 66.91, 55.21, 49.30.

[0092] Example 8

[0093]

[0094] In a dry, sealed tube, t-BuOK (1.0 mmol), Cu–N3 / OMC (5 mg), DME (1 mL), 3-bromo-5-chloro-6-ethyl-2-cyanopyrazine (0.5 mmol), and morpholine (0.75 mmol) were added sequentially. The reaction mixture was stirred at 100 °C. After the reaction was complete, the mixture was cooled to room temperature and centrifuged to remove the solids. The resulting substance was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to give the target product. The yield was 71%.

[0095] The NMR detection data of the product sample are as follows:

[0096] 1 H NMR (400 MHz, CDCl3) δ 3.98 – 3.69 (m, 4H), 3.63 – 3.46 (m, 4H), 2.74 (q, J = 7.4 Hz, 2H), 1.31 (t, J = 7.3 Hz, 3H).

[0097] 13 C NMR (100 MHz, CDCl3) δ 155.66, 137.26, 120.35, 116.25, 66.44, 48.94, 27.96, 11.81.

[0098] Example 9

[0099]

[0100] In a dry, sealed tube, t-BuOK (1.0 mmol), Cu–N3 / OMC (5 mg), 1,4-dioxane (1 mL), 2-bromopyrazine (0.5 mmol), and morpholine (0.75 mmol) were added sequentially. The reaction mixture was stirred at 100 °C. After the reaction was complete, the mixture was cooled to room temperature and centrifuged to remove the solids. The resulting substance was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to give the target product. The yield was 72%.

[0101] The NMR detection data of the product sample are as follows:

[0102] 1 H NMR (400 MHz, CDCl3) δ 8.14 – 8.06 (m, 2H), 7.88 (d, J = 2.6 Hz,1H), 4.13 – 3.73 (m, 4H), 3.63 – 3.32 (m, 4H).

[0103] 13C NMR (100 MHz, CDCl3) δ 155.06, 141.74, 133.51, 130.88, 66.48,44.74.

[0104] Example 10

[0105]

[0106] In a dry, sealed tube, t-BuOK (1.0 mmol), Cu–N3 / OMC (5 mg), DME (1 mL), 3-bromo-9-ethyl-9H-carbazole (0.5 mmol), and morpholine (0.75 mmol) were added sequentially. The reaction mixture was stirred at 100 °C. After the reaction was complete, the mixture was cooled to room temperature and centrifuged to remove the solids. The resulting substance was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to give the target product. The yield was 86%.

[0107] The NMR detection data of the product sample are as follows:

[0108] 1 H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 7.7, 1H), 7.76 (d, J = 2.4 Hz,1H), 7.58 – 7.51 (m, 1H), 7.45 (d, J = 8.2 Hz, 1H), 7.40 (d, J = 8.8 Hz, 1H), 7.34 – 7.23 (m, 2H), 4.38 (q, J = 7.2 Hz, 2H), 4.06 – 3.97 (m, 4H), 3.32 –3.25 (m, 4H), 1.48 (t, J = 7.2 Hz, 3H).

[0109] 13 C NMR (100 MHz, CDCl3) δ 145.23, 140.48, 135.60, 125.62, 123.37,120.38, 118.44, 117.82, 109.06, 108.59, 108.20, 67.33, 52.10, 37.59, 13.96.

[0110] Example 11

[0111]

[0112] In a dry, sealed tube, t-BuOK (1.0 mmol), Cu–N3 / OMC (5 mg), DME (1 mL), 4-bromobenzo[b,d]furan (0.5 mmol), and morpholine (0.75 mmol) were added sequentially. The reaction mixture was stirred at 100 °C. After the reaction was complete, the mixture was cooled to room temperature and centrifuged to remove the solids. The resulting substance was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to give the target product. The yield was 90%.

[0113] The NMR detection data of the product sample are as follows:

[0114] 1 H NMR (400 MHz, CDCl3) δ 7.88 (dd, J = 7.6, 1.5 Hz, 1H), 7.84 (d, J =8.6 Hz, 1H), 7.55 (d, J = 8.2 Hz, 1H), 7.45 – 7.36 (m, 1H), 7.36 – 7.29 (m,1H), 7.11 (d, J = 2.2 Hz, 1H), 7.00 (dd, J = 8.5, 2.2 Hz, 1H), 4.03 – 3.89(m, 4H), 3.30 (dd, J = 5.8, 3.9 Hz, 4H).

[0115] 13 C NMR (100 MHz, CDCl3) δ 156.23, 125.60, 124.55, 122.65, 120.90,119.71, 112.01, 111.28, 98.35, 66.88, 49.80.

[0116] Example 12

[0117]

[0118] In a dry, sealed tube, t-BuOK (1.0 mmol), Cu–N3 / OMC (5 mg), DME (1 mL), 5-bromobenzo[b]thiophene (0.5 mmol), and morpholine (0.75 mmol) were added sequentially. The reaction mixture was stirred at 100 °C. After the reaction was complete, the mixture was cooled to room temperature and centrifuged to remove the solids. The resulting substance was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to give the target product. The yield was 87%.

[0119] The NMR detection data of the product sample are as follows:

[0120] 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 8.8 Hz, 1H), 7.47 (d, J = 4.6Hz, 2H), 7.40 – 7.28 (m, 2H), 7.11 (d, J = 8.9 Hz, 1H), 4.01 – 3.90 (m, 4H),3.28 – 3.14 (m, 4H).

[0121] 13 C NMR (100 MHz, CDCl3) δ 149.23, 140.81, 132.11, 127.25, 123.82,122.89, 116.26, 109.52, 67.04, 50.56.

[0122] Example 13

[0123]

[0124] In a dry, sealed tube, t-BuOK (1.0 mmol), Cu–N3 / OMC (5 mg), DME (1 mL), 1-bromo-3-methoxybenzene (0.5 mmol), and 2-fluorobenzylamine (1.0 mmol) were added sequentially. The reaction mixture was stirred at 100 °C. After the reaction was complete, the mixture was cooled to room temperature and centrifuged to remove the solids. The resulting substance was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to give the target product. The yield was 89%.

[0125] The NMR detection data of the product sample are as follows:

[0126] 1 H NMR (400 MHz, CDCl3) δ 7.50 – 7.43 (m, 1H), 7.37 – 7.28 (m, 1H), 7.21 – 7.11 (m, 3H), 6.43 – 6.32 (m, 2H), 6.30 (t, J = 2.3 Hz, 1H), 4.47 (s,2H), 3.83 (s, 3H).

[0127] 13C NMR (100 MHz, CDCl3) δ 162.17, 160.91, 159.73, 149.33, 130.08,129.51 (d, J = 4.5 Hz), 128.85 (d, J = 8.1 Hz), 126.36 (d, J = 14.4 Hz),124.27 (d, J = 3.6 Hz), 115.37 (d, J = 21.4 Hz), 106.09, 102.93, 99.02,55.08, 41.82 (d, J = 4.4 Hz).

[0128] 19 F NMR (376 MHz, CDCl3) δ -118.95.

[0129] Example 14

[0130] In a dry, sealed tube, t-BuOK (1.0 mmol), Cu–N3 / OMC (5 mg), DME (1 mL), 1-bromo-3-methoxybenzene (0.5 mmol), and 4-(aminomethyl)benzonitrile (1.0 mmol) were added sequentially. The reaction mixture was stirred at 100 °C. After the reaction was complete, the mixture was cooled to room temperature and centrifuged to remove the solids. The resulting substance was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to give the target product. The yield was 75%.

[0131] The NMR detection data of the product sample are as follows:

[0132] 1 H NMR (400 MHz, CDCl3) δ 7.69 – 7.61 (m, 2H), 7.55 – 7.47 (m, 2H), 7.16 – 7.08 (m, 1H), 6.37 – 6.32 (m, 1H), 6.27 – 6.22 (m, 1H), 6.16 (t, J =2.3 Hz, 1H), 4.45 (s, 2H), 3.78 (s, 3H).

[0133] 13 C NMR (100 MHz, CDCl3) δ 160.87, 148.86, 145.36, 132.46, 130.17, 127.71, 118.93, 110.91, 106.05, 103.00, 99.17, 55.11, 47.77.

[0134] Example 15

[0135] In a dry, sealed tube, t-BuOK (1.0 mmol), Cu–N3 / OMC (5 mg), DME (1 mL), 1-bromo-3-methoxybenzene (0.5 mmol), and N-([1,1'-biphenyl]-4-ylmethyl)-3-methylbut-2-en-1-amine (0.75 mmol) were added sequentially. The reaction mixture was stirred at 100 °C. After the reaction was complete, the mixture was cooled to room temperature and centrifuged to remove the solids. The resulting substance was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to give the target product. The yield was 90%.

[0136] The NMR detection data of the product sample are as follows:

[0137] 1 H NMR (400 MHz, CDCl3) δ 7.71 (dd, J = 15.4, 7.9 Hz, 4H), 7.56 (t, J= 7.4 Hz, 2H), 7.51 – 7.44 (m, 3H), 7.31 – 7.21 (m, 1H), 6.54 (d, J = 8.1 Hz,1H), 6.48 (s, 1H), 6.44 (d, J = 7.9 Hz, 1H), 5.48 (t, J = 6.3 Hz, 1H), 4.68(s, 2H), 4.14 (d, J = 6.3 Hz, 2H), 3.88 (s, 3H), 1.89 (s, 3H), 1.82 (s, 3H).

[0138] 13 C NMR (100 MHz, CDCl3) δ 160.93, 150.72, 141.08, 139.87, 138.54,134.82, 130.02, 128.88, 127.40, 127.28, 127.14, 121.34, 105.94, 101.41,99.29, 55.15, 54.17, 48.80, 25.88, 18.12.

[0139] Example 16

[0140]

[0141] In a dry, sealed tube, t-BuOK (1.0 mmol), Cu–N3 / OMC (5 mg), 1-4 dioxane (1 mL), bromobenzene (0.5 mmol), and 4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride (1.0 mmol) were added sequentially. The reaction mixture was stirred at 100 °C. After the reaction was complete, the mixture was cooled to room temperature and centrifuged to remove the solids. The resulting substance was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to give the target product. The yield was 80%.

[0142] The NMR detection data of the product sample are as follows:

[0143] 1 H NMR (400 MHz, CDCl3) δ 7.40 – 7.33 (m, 2H), 7.20 (d, J = 5.1 Hz,1H), 7.12 – 7.04 (m, 2H), 6.98 – 6.88 (m, 2H), 4.39 (s, 2H), 3.70 (t, J = 5.7Hz, 2H), 3.06 (t, J = 5.6 Hz, 2H).

[0144] 13 C NMR (100 MHz, CDCl3) δ 150.74, 133.69, 133.33, 129.27, 125.20,122.95, 119.34, 116.09, 49.01, 47.53, 25.39.

[0145] Example 17

[0146]

[0147] In a dry, sealed tube, t-BuOK (1.0 mmol), Cu–N3 / OMC (5 mg), 1,4-dioxane (1 mL), bromobenzene (0.5 mmol), and 1-adamantaneamine (1.0 mmol) were added sequentially. The reaction mixture was stirred at 100 °C. After the reaction was complete, the mixture was cooled to room temperature and centrifuged to remove the solids. The resulting substance was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to give the target product. The yield was 75%.

[0148] The NMR detection data of the product sample are as follows:

[0149] 1H NMR (400 MHz, CDCl3) δ 7.26 – 7.13 (m, 2H), 6.92 – 6.78 (m, 3H), 3.08 (br, 1H), 2.21 – 2.12 (m, 3H), 1.98 – 1.87 (m, 6H), 1.79 – 1.65 (m, 6H).

[0150] 13 C NMR (100 MHz, CDCl3) δ 145.98, 128.76, 119.26, 119.19, 52.30, 43.50, 36.52, 29.77.

[0151] Example 18

[0152]

[0153] In a dry, sealed tube, t-BuOK (1.0 mmol), Cu–N3 / OMC (5 mg), DME (1 mL), 1-bromo-3-methoxybenzene (0.5 mmol), and N-benzyl tert-butylamine (1.0 mmol) were added sequentially. The reaction mixture was stirred at 100 °C. After the reaction was complete, the mixture was cooled to room temperature and centrifuged to remove the solids. The resulting substance was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to give the target product. The yield was 76%.

[0154] The NMR detection data of the product sample are as follows:

[0155] 1 H NMR (400 MHz, CDCl3) δ 7.52 – 7.32 (m, 2H), 7.30 – 7.23 (m, 2H), 7.21 – 7.12 (m, 2H), 6.92 – 6.83 (m, 1H), 6.82 – 6.77 (m, 1H), 6.69 – 6.61 (m, 1H), 4.38 (s, 2H), 3.78 (s, 3H), 1.31 (s, 9H).

[0156] 13 C NMR (100 MHz, CDCl3) δ 159.35, 150.76, 141.66, 128.31, 128.07,127.85, 126.14, 121.93, 115.72, 109.40, 55.61, 55.14, 53.24, 28.58.

[0157] Example 19

[0158]

[0159] In a dry, sealed tube, t-BuOK (1.0 mmol), Cu–N3 / OMC (5 mg), DME (1 mL), bromobenzene (0.5 mmol), and azircycloheptanine (1.0 mmol) were added sequentially. The reaction mixture was stirred at 100 °C. After the reaction was complete, the mixture was cooled to room temperature and centrifuged to remove the solids. The resulting substance was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to give the target product. The yield was 75%.

[0160] The NMR detection data of the product sample are as follows:

[0161] 1 H NMR (400 MHz, CDCl3) δ 7.40 – 7.31 (m, 2H), 6.83 (d, J = 8.2 Hz,2H), 6.77 (t, J = 7.3 Hz, 1H), 3.62 – 3.55 (m, 4H), 1.99 – 1.86 (m, 4H), 1.73– 1.63 (m, 4H).

[0162] 13 C NMR (100 MHz, CDCl3) δ 148.98, 129.36, 115.24, 111.26, 49.16, 27.91, 27.28.

[0163] Example 20

[0164]

[0165] In a dry, sealed tube, t-BuOK (1.0 mmol), Cu–N3 / OMC (5 mg), 1,4-dioxane (1 mL), bromobenzene (0.5 mmol), and thiomorpholine (0.75 mmol) were added sequentially. The reaction mixture was stirred at 100 °C. After the reaction was complete, the mixture was cooled to room temperature and centrifuged to remove the solids. The obtained substance was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to give the target product. The yield was 72%.

[0166] The NMR detection data of the product sample are as follows:

[0167] 1H NMR (400 MHz, CDCl3) δ 7.37 – 7.28 (m, 2H), 7.00 – 6.88 (m, 3H), 3.63 – 3.56 (m, 4H), 2.84 – 2.77 (m, 4H).

[0168] 13 C NMR (100 MHz, CDCl3) δ 129.31, 119.95, 117.23, 52.23, 26.89.

[0169] Example 21

[0170]

[0171] In a dry, sealed tube, t-BuOK (1.0 mmol), Cu–N3 / OMC (5 mg), 1,4-dioxane (1 mL), bromobenzene (0.25 mmol), and 2-(piperazin-1-yl)pyrimidine (0.5 mmol) were added sequentially. The reaction mixture was stirred at 100 °C. After the reaction was complete, the mixture was cooled to room temperature and centrifuged to remove the solids. The resulting substance was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to give the target product. The yield was 72%.

[0172] The NMR detection data of the product sample are as follows:

[0173] 1 H NMR (400 MHz, CDCl3) δ 8.38 (d, J = 4.8 Hz, 2H), 7.51 – 7.25 (m,2H), 7.06 – 6.98 (m, 2H), 6.97 – 6.88 (m, 1H), 6.55 (t, J = 4.8 Hz, 1H), 4.07– 4.00 (m, 4H), 3.33 – 3.26 (m, 4H).

[0174] 13 C NMR (100 MHz, CDCl3) δ 161.71, 157.80, 151.40, 129.22, 120.14,116.52, 110.13, 49.34, 43.73.

[0175] Example 22

[0176]

[0177] In a dry, sealed tube, t-BuOK (1.0 mmol), Cu–N3 / OMC (5 mg), DME (1 mL), and 2-(2-bromophenyl)ethyl-1-amine (0.5 mmol) were added sequentially. The reaction mixture was stirred at 100 °C. After the reaction was complete, the mixture was cooled to room temperature and centrifuged to remove the solids. The obtained substance was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to give the target product. The yield was 78%.

[0178] The NMR detection data of the product sample are as follows:

[0179] 1 H NMR (400 MHz, CDCl3) δ 8.19 (br, 1H), 7.71 (d, J = 8.2 Hz, 1H), 7.45 (d, J = 7.5 Hz, 1H), 7.36 – 7.12 (m, 3H), 6.61 (s, 1H).

[0180] 13 C NMR (100 MHz, CDCl3) δ 135.80, 127.88, 124.26, 122.04, 120.80,119.88, 111.13, 102.61.

[0181] Example 23

[0182] In a dry, sealed tube, t-BuOK (1.0 mmol), Cu–N3 / OMC (5 mg), 1,4-dioxane (1 mL), 1-bromo-3-methoxybenzene (0.5 mmol), and n-butanol (1.0 mmol) were added sequentially. The reaction mixture was stirred at 100 °C. After the reaction was complete, the mixture was cooled to room temperature and centrifuged to remove the solids. The resulting substance was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to give the target product. The yield was 77%.

[0183] The NMR detection data of the product sample are as follows:

[0184] 1H NMR (400 MHz, CDCl3) δ 7.24 (t, J = 7.6 Hz, 1H), 6.62 – 6.52 (m,3H), 4.01 (t, J = 6.6 Hz, 2H), 3.85 (s, 3H), 1.92 – 1.74 (m, 2H), 1.69 – 1.48(m, 2H), 1.05 (t, J = 7.4 Hz, 3H).

[0185] 13 C NMR (100 MHz, CDCl3) δ 160.90, 160.50, 129.84, 106.74, 106.12,101.00, 67.69, 55.22, 31.38, 19.31, 13.88.

[0186] Example 24

[0187]

[0188] In a dry, sealed tube, t-BuOK (1.0 mmol), Cu–N3 / OMC (5 mg), 1,4-dioxane (1 mL), 1-bromo-3-methoxybenzene (0.5 mmol), and menthol (1.0 mmol) were added sequentially. The reaction mixture was stirred at 100 °C. After the reaction was complete, the mixture was cooled to room temperature and centrifuged to remove the solids. The resulting substance was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to give the target product. The yield was 62%.

[0189] The NMR detection data of the product sample are as follows:

[0190] 1 H NMR (400 MHz, CDCl3) δ 7.22 (t, J = 8.4 Hz, 1H), 6.62 – 6.48 (m,3H), 4.08 (td, J = 10.5, 4.2 Hz, 1H), 3.84 (s, 3H), 2.33 – 2.19 (m, 2H), 1.77(d, J = 12.2 Hz, 2H), 1.61 – 1.46 (m, 2H), 1.23 – 1.07 (m, 2H), 1.01 – 0.95(m, 6H), 0.84 (d, J = 7.0 Hz, 3H).

[0191] 13C NMR (100 MHz, CDCl3) δ 160.91, 159.68, 129.88, 107.99, 105.72,102.28, 77.46, 55.23, 48.07, 40.33, 34.55, 31.44, 26.11, 23.76, 22.16, 20.78,16.63.

[0192] Example 25

[0193] In a dry, sealed tube, t-BuOK (1.0 mmol), Cu–N3 / OMC (5 mg), 1,4-dioxane (1 mL), 1-bromo-3-methoxybenzene (0.5 mmol), and paroxetine hydrochloride hemihydrate (0.75 mmol) were added sequentially. The reaction mixture was stirred at 100 °C. After the reaction was complete, the mixture was cooled to room temperature and centrifuged to remove the solids. The resulting substance was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to give the target product. The yield was 88%.

[0194] The NMR detection data of the product sample are as follows:

[0195] 1 H NMR (400 MHz, CDCl3) δ 7.32 – 7.21 (m, 3H), 7.14 – 7.02 (m, 2H), 6.72 (dd, J = 8.4, 2.7 Hz, 2H), 6.66 (t, J = 2.2 Hz, 1H), 6.52 (dd, J = 8.0,2.1 Hz, 1H), 6.47 (d, J = 2.5 Hz, 1H), 6.25 (dd, J = 8.4, 2.5 Hz, 1H), 5.94(s, 2H), 4.16 – 4.09 (m, 1H), 3.93 – 3.85 (m, 4H), 3.72 (dd, J = 9.5, 3.0 Hz, 1H), 3.60 (dd, J = 9.5, 7.3 Hz, 1H), 2.97 – 2.84 (m, 2H), 2.74 – 2.65 (m,1H), 2.44 – 2.33 (m, 1H), 2.09 – 1.94 (m, 2H).

[0196] 13C NMR (100 MHz, CDCl3) δ 161.64 (d, J = 244.3 Hz), 160.73, 154.36,152.84, 148.27, 141.73, 139.50 (d, J = 3.2 Hz), 129.93, 128.89 (d, J = 7.8Hz), 115.55 (d, J = 21.2 Hz), 109.56, 107.94, 105.67, 104.43, 103.14, 101.17,98.07, 69.40, 55.21, 53.57, 50.46, 44.21, 41.67, 34.01.

[0197] Example 26

[0198] In a dry, sealed tube, t-BuOK (1.0 mmol), Cu–N3 / OMC (5 mg), 1,4-dioxane (1 mL), bromobenzene (0.5 mmol), and duloxetine hydrochloride (0.75 mmol) were added sequentially. The reaction mixture was stirred at 100 °C. After the reaction was complete, the mixture was cooled to room temperature and centrifuged to remove the solids. The resulting substance was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to give the target product. The yield was 86%.

[0199] The NMR detection data of the product sample are as follows:

[0200] 1 H NMR (400 MHz, CDCl3) δ 8.63 (d, J = 6.6 Hz, 1H), 7.97 (d, J = 9.3Hz, 1H), 7.77 – 7.64 (m, 2H), 7.59 (d, J = 7.0 Hz, 1H), 7.50 – 7.30 (m, 4H),7.24 – 7.18 (m, 1H), 7.11 – 7.04 (m, 1H), 7.01 (d, J = 7.8 Hz, 1H), 6.95 –6.85 (m, 3H), 5.95 – 5.84 (m, 1H), 3.80 (t, J = 5.1 Hz, 2H), 3.07 (s, 3H),2.73 – 2.49 (m, 2H).

[0201] 13C NMR (100 MHz, CDCl3) δ 153.36, 149.34, 145.08, 134.84, 129.41,127.78, 126.77, 126.58, 126.34, 125.90, 125.55, 124.98, 124.89, 122.24,120.94, 116.61, 112.61, 107.19, 74.30, 49.32, 38.67, 36.42.

[0202] Example 27

[0203]

[0204] In a dry, sealed tube, t-BuOK (1.0 mmol), Cu–N3 / OMC (5 mg), 1,4-dioxane (1 mL), 1-bromo-3-methoxy (0.5 mmol), and 1,2:5,6-di-O-isopropylidene-α-D-furanose (1.0 mmol) were added sequentially. The reaction mixture was stirred at 100 °C. After the reaction was complete, the mixture was cooled to room temperature and centrifuged to remove the solids. The resulting substance was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to give the target product. The yield was 55%.

[0205] The NMR detection data of the product sample are as follows:

[0206] 1 H NMR (400 MHz, CDCl3) δ 7.21 (t, J = 8.2 Hz, 1H), 6.60 – 6.51 (m,3H), 4.67 (dd, J = 7.9, 2.6 Hz, 1H), 4.60 – 4.54 (m, 1H), 4.30 (d, J = 7.9Hz, 1H), 4.18 (d, J = 10.1 Hz, 1H), 4.10 – 3.95 (m, 2H), 3.86 – 3.79 (m, 4H), 1.60 (s, 3H), 1.53 (d, J = 4.4 Hz, 6H), 1.38 (s, 3H).

[0207] 13C NMR (100 MHz, CDCl3) δ 160.81, 159.76, 129.90, 109.01, 108.90,106.94, 106.60, 102.19, 101.18, 70.99, 70.20, 70.02, 68.87, 61.20, 55.27,26.61, 25.95, 25.39, 24.04.

[0208] Example 28

[0209]

[0210] In a dry, sealed tube, t-BuOK (1.0 mmol), KI (1.0 mmol), Cu–N3 / OMC (5 mg), DMSO (1 mL), chlorobenzene (0.5 mmol), and morpholine (0.75 mmol, 1.5 equiv) were added sequentially. The reaction mixture was stirred at 100°C. After the reaction was complete, the mixture was cooled to room temperature and centrifuged to remove the solids. The obtained substance was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to give the target product. The yield was 72%.

[0211] The NMR detection data of the product sample are as follows:

[0212] 1 H NMR (400 MHz, CDCl3) δ 7.38 – 7.29 (m, 2H), 7.01 – 6.90 (m, 3H), 4.04 – 3.78 (m, 4H), 3.28 – 3.05 (m, 4H).

[0213] 13 C NMR (100 MHz, CDCl3) δ 151.29, 129.22, 120.09, 115.74, 66.97, 49.39.

[0214] Example 29

[0215]

[0216] In a dry, sealed tube, t-BuOK (1.0 mmol), KI (1.0 mmol), Cu–N3 / OMC (5 mg), DMSO (1 mL), 1-bromo-4-toluene (0.5 mmol), and N-methylaniline (0.75 mmol) were added sequentially. The reaction mixture was stirred at 100 °C. After the reaction was complete, the mixture was cooled to room temperature and centrifuged to remove the solids. The resulting substance was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to give the target product. The yield was 68%.

[0217] The NMR detection data of the product sample are as follows:

[0218] 1 H NMR (400 MHz, CDCl3) δ 7.42 – 7.29 (m, 2H), 7.29 – 7.20 (m, 2H), 7.17 – 7.10 (m, 2H), 7.09 – 7.04 (m, 2H), 7.03 – 6.97 (m, 1H), 3.41 (s, 3H),2.46 (s, 3H).

[0219] 13 C NMR (100 MHz, CDCl3) δ 149.48, 146.72, 132.11, 130.03, 130.01,129.14, 122.67, 119.91, 118.31, 40.42, 20.87.

[0220] Example 30

[0221]

[0222] In a dry, sealed tube, t-BuOK (1.0 mmol), KI (1.0 mmol), Cu–N3 / OMC (5 mg), DMSO (1 mL), 1-chloro-4-fluorobenzene (0.5 mmol), and N-methylaniline (0.75 mmol) were added sequentially. The reaction mixture was stirred at 100°C. After the reaction was complete, the mixture was cooled to room temperature and centrifuged to remove the solids. The resulting substance was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to give the target product. The yield was 65%.

[0223] The NMR detection data of the product sample are as follows:

[0224] 1H NMR (400 MHz, CDCl3) δ 7.36 – 7.28 (m, 2H), 7.10 (m, 4H), 7.00 –6.94 (m, 3H), 3.35 (s, 3H).

[0225] 13 C NMR (100 MHz, CDCl3) δ 157.54, 145.31 (d, J = 2.6 Hz), 129.18,124.27 (d, J = 8.0 Hz), 120.12, 118.12, 116.03 (d, J = 22.4 Hz), 40.56.

[0226] 19 F NMR (376 MHz, CDCl3) δ -120.61.

[0227] Example 31

[0228]

[0229] In a dry, sealed tube, t-BuOK (1.0 mmol), Cu–N3 / OMC (5 mg), 1,4-dioxane (1 mL), 3-methoxyphenyl trifluoromethanesulfonate (0.5 mmol), and morpholine (0.75 mmol) were added sequentially. The reaction mixture was stirred at 100 °C. After the reaction was complete, the mixture was cooled to room temperature and centrifuged to remove the solids. The resulting substance was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to give the target product. The yield was 93%.

[0230] The NMR detection data of the product sample are as follows:

[0231] 1 H NMR (400 MHz, CDCl3) δ 7.27 – 7.19 (m, 1H), 6.63 – 6.54 (m, 1H), 6.52 – 6.45 (m, 2H), 3.96 – 3.86 (m, 4H), 3.84 (s, 3H), 3.22 – 3.12 (m, 4H).

[0232] 13 C NMR (100 MHz, CDCl3) δ 160.65, 152.73, 129.90, 108.49, 104.72,102.23, 66.91, 55.21, 49.30.

[0233] Example 32

[0234]

[0235] In a dry, sealed tube, t-BuOK (1.0 mmol), Cu–N3 / OMC (5 mg), 1,4-dioxane (1 mL), p-toluenetrifluoromethanesulfonate (0.5 mmol), and N-methylaniline (0.75 mmol) were added sequentially. The reaction mixture was stirred at 100 °C. After the reaction was complete, the mixture was cooled to room temperature and centrifuged to remove the solids. The resulting substance was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to give the target product. The yield was 83%.

[0236] The NMR detection data of the product sample are as follows:

[0237] 1 H NMR (400 MHz, CDCl3) δ 7.42 – 7.29 (m, 2H), 7.29 – 7.20 (m, 2H), 7.17 – 7.10 (m, 2H), 7.09 – 7.04 (m, 2H), 7.03 – 6.97 (m, 1H), 3.41 (s, 3H),2.46 (s, 3H).

[0238] 13 C NMR (100 MHz, CDCl3) δ 149.48, 146.72, 132.11, 130.03, 130.01,129.14, 122.67, 119.91, 118.31, 40.42, 20.87.

[0239] Example 33

[0240]

[0241] In a dry, sealed tube, t-BuOK (1.0 mmol), Cu–N3 / OMC (5 mg), 1,4-dioxane (1 mL), 4-fluorophenyl trifluoromethanesulfonate (0.5 mmol), and N-methylaniline (0.75 mmol) were added sequentially. The reaction mixture was stirred at 100 °C. After the reaction was complete, the mixture was cooled to room temperature and centrifuged to remove the solids. The resulting substance was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to give the target product. The yield was 83%.

[0242] The NMR detection data of the product sample are as follows:

[0243] 1H NMR (400 MHz, CDCl3) δ 7.36 – 7.28 (m, 2H), 7.10 (m, 4H), 7.00 –6.94 (m, 3H), 3.35 (s, 3H).

[0244] 13 C NMR (100 MHz, CDCl3) δ 157.54, 145.31 (d, J = 2.6 Hz), 129.18,124.27 (d, J = 8.0 Hz), 120.12, 118.12, 116.03 (d, J = 22.4 Hz), 40.56.

[0245] 19 F NMR (376 MHz, CDCl3) δ -120.61.

[0246] Example 34

[0247] Gram-scale reaction

[0248] In a dry three-necked flask, t-BuOK (200 mmol), Cu–N3 / OMC (5 mg), 1,4-dioxane (200 mL), 1-bromo-3-methoxybenzene (100 mmol), and morpholine (150 mmol) were added sequentially. After stirring the reaction mixture under reflux, the mixture was cooled to room temperature and centrifuged to remove the solids. The resulting product was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the target product. The yield was 95%.

[0249] Example 35

[0250] Catalyst recovery experiment

[0251] In a dry, sealed tube, t-BuOK (1.0 mmol), Cu–N3 / OMC (5 mg), DME (1 mL), 1-bromo-3-methoxybenzene (0.5 mmol), and morpholine (0.75 mmol) were added sequentially. The reaction mixture was stirred at 100 °C and monitored by TLC until the reaction was complete. After the reaction was complete, 10 mL of tetrahydrofuran (THF) was added to the reaction mixture, followed by centrifugation. This washing step was repeated three times. Subsequently, the catalyst was washed with deionized water and ethanol and dried overnight in a vacuum oven at 80 °C. The dried catalyst was used in subsequent reaction cycles.

[0252] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A method for constructing C–N bonds or C–O bonds through a cross-coupling reaction, characterized in that, The process includes the following steps: In the presence of a base, aryl halides, aryl trifluoromethanesulfonates, or heterocyclic aryl bases undergo a coupling reaction with nitrogen- or oxygen-containing nucleophiles in the presence of a copper-based single-atom catalyst to obtain the corresponding C–N or C–O coupling products; wherein, in the copper-based single-atom catalyst, copper active centers are atomically dispersed and anchored on a nitrogen-containing carbon support, forming a coordination structure Cu–N with 3-4 nitrogen atoms. x .

2. The method according to claim 1, characterized in that, The nitrogen-containing carbon support is a nitrogen-doped porous carbon material, selected from ordered mesoporous carbon, disordered porous carbon, carbon nanomaterials, or combinations thereof.

3. The method according to claim 1, characterized in that, The copper active center is Cu(I), Cu(II), or a mixture thereof.

4. The method according to claim 1, characterized in that, The aryl (hetero)electrophilic reagent is selected from aryl bromides, aryl chlorides, aryl trifluoromethanesulfonates, heterocyclic aryl halides, or combinations thereof.

5. The method according to claim 1, characterized in that, The nitrogen-containing nucleophile is selected from aliphatic amines, aromatic amines, heterocyclic amines, primary amines, secondary amines, ammonia, or combinations thereof.

6. The method according to claim 1, characterized in that, The oxygen-containing nucleophile is selected from fatty alcohols, aromatic alcohols, benzyl alcohols, cyclic alcohols, or sterically hindered alcohols.

7. The method according to claim 1, characterized in that, The alkali is selected from alkali metal alkoxides, alkali metal carbonates, hydroxides, or combinations thereof; the reaction temperature is 80–120 °C.

8. The method according to claim 1, characterized in that, The reaction is carried out in an air or inert atmosphere and is suitable for late-stage functionalization of drug molecules or natural products.

9. A copper-based single-atom catalyst, characterized in that: Copper is dispersed in single-atom form and anchored on a nitrogen-containing carbon support, forming Cu–N. x Coordination structure.

10. The catalyst according to claim 9, characterized in that, The Cu–N X In the catalyst, x is 3 or 4, the catalyst has an ordered mesoporous structure, a specific surface area of ​​200–1500 m² / g, and a copper loading of 0.01–5 wt%.

11. A method for preparing the copper-based single-atom catalyst as described in claim 9, characterized in that, The process includes the following steps: constructing a carbon framework using a mesoporous template, introducing a nitrogen-containing precursor and a copper source, performing high-temperature pyrolysis at 700–1000 °C under an inert atmosphere, and obtaining a copper single-atom catalyst after removing the template.

12. The use of a copper-based single-atom catalyst as described in claim 9, characterized in that: The catalyst is used for the C–N or C–O bond coupling reaction of aryl halides, aryl trifluoromethanesulfonates, and amines or alcohols.

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