A selective synthesis of N-alkylated products

Abstract

The application provides a selective synthesis method of N-alkylated products and belongs to the technical field of organic synthesis; in the application, a transition metal catalysis strategy is adopted, alcohol and arylamine are used as raw materials, and the synthesis of secondary amine and tertiary amine is realized by controlling reaction conditions; the selective synthesis method of the N-alkylated products provides a new method for the synthesis of secondary amine and tertiary amine; the selective synthesis is simple, efficient, non-toxic, non-polluting and economical and applicable, and has good practical value.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a selective synthesis method for N-alkylation products. Background Technology

[0002] Nitrogen-containing organic compounds are a class of crucial monomers in pharmaceuticals and natural products, widely distributed in nature and widely used in medicine, pesticides, dyes, and polymer synthesis. N-alkylation is an important method for synthesizing nitrogen-containing organic compounds. Traditional N-alkylation reactions use amines as the nitrogen source and haloalkanes or dimethyl sulfate as coupling agents. However, haloalkanes are relatively expensive and toxic, and their byproducts cause environmental pollution, limiting the application of amines as the nitrogen source in N-alkylation reactions. The transition metal-catalyzed hydrogen transfer strategy between alcohols and amines is a novel approach to N-alkylation reactions; however, no literature has yet disclosed how to selectively synthesize secondary and tertiary amines using amines and alcohols as starting materials by controlling reaction conditions. Summary of the Invention

[0003] To address the shortcomings of existing technologies, this invention provides a selective synthesis method for N-alkylation products. In this invention, a transition metal catalysis strategy is employed, using alcohols and aromatic amines as raw materials, and secondary and tertiary amines are synthesized by controlling the reaction conditions. This selective synthesis method for N-alkylation products provides a novel approach for the synthesis of secondary and tertiary amines. The selective synthesis is simple, efficient, non-toxic, pollution-free, and economical, possessing significant practical value.

[0004] The present invention achieves the above-mentioned technical objectives through the following technical means.

[0005] A selective synthesis method for N-alkylated products, specifically comprising the following steps:

[0006] A reaction solution was prepared by dissolving a transition metal catalyst, a phosphine ligand, potassium tert-butoxide, an aromatic amine, and an alcohol in toluene. The reaction solution was heated in an oil bath under stirring. After the reaction was completed, the solution was cooled to room temperature and then diluted with ethyl acetate. After dilution, the organic phase was extracted with a mixture of ethyl acetate and water. The organic phase was washed, dried, allowed to stand, and concentrated to obtain the N-alkylated product.

[0007] Preferably, the transition metal catalyst includes Cu(BTC)-MOF, Cu(BDC)-MOF, Ni(BTC)-MOF, and Fe(BTC)-MOF, with Cu(BTC)-MOF being the preferred catalyst.

[0008] Preferably, the phosphine ligand comprises 1,2-bis(diphenylphosphine)ethane.

[0009] Preferably, the amounts of the transition metal catalyst, phosphine ligand, potassium tert-butoxide, aromatic amine, and alcohol are: 0.05 g / mmol: 4 mg: 1.5 equiv: 0.2 mmol: 0.5 mmol.

[0010] Preferably, the oil bath heating reaction is carried out at 110°C for 8–24 hours.

[0011] Preferably, during the dilution, the ratio of ethyl acetate to alcohol is 5 mL: 0.5 mmol.

[0012] Preferably, in the mixed solution of ethyl acetate and water, the volume ratio of ethyl acetate to water is 1:2.

[0013] Preferably, the aromatic amine comprises:

[0014]

[0015] Preferably, the alcohol comprises:

[0016]

[0017] Preferably, the N-alkylation product includes secondary amines and tertiary amines.

[0018] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0019] In this invention, a transition metal catalysis strategy is employed, using the metal-organic framework Cu(BTC)-MOF as a catalyst, 1,2-bis(diphenylphosphine)ethane and potassium tert-butoxide as additives, and toluene as a solvent, to synthesize secondary and tertiary amines from alcohols and aromatic amines. Selective synthesis is achieved by controlling the reaction time and the ratio of the reactant amine to the alcohol. Compared with previously reported methods, this invention allows for the selective synthesis of secondary or tertiary amine compounds by controlling the reaction time and reactant ratio, offering significant advantages over traditional methods. The selective synthesis method for N-alkylation products described in this invention provides a novel approach for the synthesis of secondary and tertiary amines; furthermore, the alkylating agent used is an inexpensive and readily available alcohol, and the byproduct is water, offering advantages such as being environmentally friendly, having low toxicity, and causing minimal pollution. Attached Figure Description

[0020] Figure 1 This is a flowchart of the selective synthesis of N-monoalkylation products.

[0021] Figure 2 This is a flowchart of the selective synthesis of N-dialkylation products.

[0022] Figure 3 The NMR spectrum of N-benzylaniline is shown in Figure 1.

[0023] Figure 4 The image shows the C1 NMR spectrum of N-benzylaniline.

[0024] Figure 5 The NMR spectrum of N,N-dibenzylaniline is shown in Figure 1.

[0025] Figure 6 The image shows the C1 NMR spectrum of N,N-dibenzylaniline.

[0026] Figure 7 The NMR spectrum of N,N-diallyl aniline is shown in Figure 1.

[0027] Figure 8 The NMR spectrum of N,N-diallyl aniline is shown. Detailed Implementation

[0028] The present invention will be further described below with reference to the accompanying drawings and specific embodiments, but the scope of protection of the present invention is not limited thereto.

[0029] Example 1:

[0030] The synthesis process of the N-alkylated product described in this embodiment is as follows:

[0031]

[0032] The specific steps are as follows:

[0033] Weigh out Cu(BTC)-MOF (0.01 g, 0.05 g / mmol), 1,2-bis(diphenylphosphine)ethane (4.0 mg, 5 mol%), potassium tert-butoxide (33.6 mg, 1.5 equiv), aniline (18.6 mg, 0.2 mmol), and benzyl alcohol (21.6 mg, 0.2 mmol) into a reaction tube. Add 0.5 mL of dry toluene solution to the reaction tube and seal it with a flip-top stopper.

[0034] The reaction tube was then heated to 110°C in an oil bath under magnetic stirring for 24 hours. After the reaction, it was cooled to room temperature, diluted with 5 mL of ethyl acetate, and then extracted three times with ethyl acetate and water. After extraction, the organic phases were combined, washed with saturated brine, dried over anhydrous Na₂SO₄, and allowed to stand. Finally, the organic phase was concentrated and purified by silica gel column chromatography (200-300 mesh silica gel) to obtain the target product 3a. The target product 3a was a colorless oily liquid with a yield of 28.5 mg, representing a yield of 78%.

[0035] Figure 3 The NMR spectrum of N-benzylaniline is shown below. Figure 3 As can be seen from the data, the NMR spectrum of target product 3a is as follows: 1HNMR (400MHz, CDCl3): δ7.37-7.32(m,4H),7.28-7.25(m,1H),7.19-7.15(m,2H),6.75-6.70(m,1H),6.65-6.62(m,2H),4.31(s,2H),4.00(s,1H).

[0036] Figure 4 The NMR C-spectrum of N-benzylaniline is shown below. Figure 4 As can be seen from the data, the NMR C spectrum of target product 3a is as follows: 13 CNMR (100MHz, CDCl3): δ148.3,139.6,129.4,128.8,127.6,127.3,117.7,113.0,48.4.

[0037] IR(neat,cm -1 ):3427,3062,1600,1501,1320,815.

[0038] GC-MS(EI)calcd for C 15 H 17 N 183.10, found: 183.11.

[0039] In summary, this invention successfully synthesized N-alkylated products.

[0040] Example 2:

[0041] The synthesis process of the N-alkylated product described in this embodiment is as follows:

[0042]

[0043] The specific steps are as follows:

[0044] Weigh out Cu(BTC)-MOF (0.01 g, 0.05 g / mmol), 1,2-bis(diphenylphosphine)ethane (4.0 mg, 5 mol%), potassium tert-butoxide (33.6 mg, 1.5 equiv), 2-chloroaniline (25.4 mg, 0.2 mmol), and benzyl alcohol (21.6 mg, 0.2 mmol) into a reaction tube. Add 0.5 mL of dry toluene solution to the reaction tube and seal it with a flap stopper.

[0045] The reaction tube was then heated to 110°C in an oil bath under magnetic stirring for 24 hours. After the reaction, it was cooled to room temperature, diluted with 5 mL of ethyl acetate, and then extracted three times with ethyl acetate and water. After extraction, the organic phases were combined, washed with saturated brine, dried over anhydrous Na₂SO₄, and allowed to stand. Finally, the organic phase was concentrated and purified by silica gel column chromatography (200-300 mesh silica gel) to obtain the target product 3b. The target product 3b was a yellow oily liquid with a yield of 29.9 mg, representing a yield of 69%.

[0046] The target product 3b 1 H NMR (400MHz, CDCl3): δ7.30-7.28(m,3H),7.22-7.19(m,3H),7.02(t,J=5.2Hz,1H),6.58-6.55(m,2H),4.70(s,1H),4.34(s,2H).

[0047] 13 C NMR (100MHz, CDCl3): δ144.0,138.9,129.2,128.9,128.4,127.9,127.5,127.4,117.6,111.7,48.0.

[0048] IR(neat,cm -1 ):3402,3067,1592,1493,812.

[0049] GC-MS(EI)calcd for C 13 H 12 ClN 217.06, found: 217.07.

[0050] In summary, this invention successfully synthesized N-alkylated products.

[0051] Example 3:

[0052] The synthesis process of the N-alkylated product described in this embodiment is as follows:

[0053]

[0054] The specific steps are as follows:

[0055] Weigh out Cu(BTC)-MOF (0.01 g, 0.05 g / mmol), 1,2-bis(diphenylphosphine)ethane (4.0 mg, 5 mol%), potassium tert-butoxide (33.6 mg, 1.5 equiv), 4-nitroaniline (27.6 mg, 0.2 mmol), and benzyl alcohol (21.6 mg, 0.2 mmol) into a reaction tube. Add 0.5 mL of dry toluene solution to the reaction tube and seal it with a flap stopper.

[0056] The reaction tube was then heated to 110°C in an oil bath under magnetic stirring for 24 hours. After the reaction, it was cooled to room temperature, diluted with 5 mL of ethyl acetate, and then extracted three times with ethyl acetate and water. After extraction, the organic phases were combined, washed with saturated brine, dried over anhydrous Na₂SO₄, and allowed to stand. Finally, the organic phase was concentrated and purified by silica gel column chromatography (200-300 mesh silica gel) to obtain the target product 3c. The target product 3c is a yellow solid with a melting point of 102-103°C, a yield of 28.7 mg, and a yield of 63%.

[0057] The target product 3c 1 H NMR (400MHz, CDCl3): δ8.00 (d, J = 6.4Hz, 2H), 7.32-7.23 (m, 5H), 6.50 (d, J = 6.0Hz, 2H), 4.80 (s, 1H), 4.36 (s, 2H).

[0058] 13 C NMR (100MHz, CDCl3): δ153.8,137.3,133.2,129.6,126.3,126.3,126.2,111.1,54.1.

[0059] IR(neat,cm -1 ):3411,1526,1348,1236,873,792,734.

[0060] GC-MS(EI)calcd for C 13 H 12 N2O2 228.08, found: 228.09.

[0061] In summary, this invention successfully synthesized N-alkylated products.

[0062] Example 4:

[0063] The synthesis process of the N-alkylated product described in this embodiment is as follows:

[0064]

[0065] The specific steps are as follows:

[0066] Weigh out Cu(BTC)-MOF (0.01 g, 0.05 g / mmol), 1,2-bis(diphenylphosphine)ethane (4.0 mg, 5 mol%), potassium tert-butoxide (33.6 mg, 1.5 equiv), aniline (18.6 mg, 0.2 mmol), and 4-methylbenzyl alcohol (24.4 mg, 0.2 mmol) into a reaction tube. Add 0.5 mL of dry toluene solution to the reaction tube and seal it with a flap stopper.

[0067] The reaction tube was then heated to 110°C in an oil bath under magnetic stirring for 24 hours. After the reaction, it was cooled to room temperature, diluted with 5 mL of ethyl acetate, and then extracted three times with ethyl acetate and water. After extraction, the organic phases were combined, washed with saturated brine, dried over anhydrous Na₂SO₄, and allowed to stand. Finally, the organic phase was concentrated and purified by silica gel column chromatography (200-300 mesh silica gel) to obtain the target product 3d. The target product 3d was a colorless oily liquid with a yield of 33.5 mg, representing a yield of 85%.

[0068] The target product 3d 1 H NMR (400MHz, CDCl3): δ7.17(d,J=8.0Hz,2H),7.11-7.04(m,4H),6.64-6.61(m,1H),6.56-6.53(m,2H),4.19(s,2H),3.89(s,1H),2.26(s,3H).

[0069] 13 C NMR (100MHz, CDCl3): δ148.3,137.0,136.5,129.4,129.4,127.6,117.6,113.0,48.2,21.2.

[0070] IR(neat,cm -1 ):3423,1601,1447,1368,850,697.

[0071] GC-MS(EI)calcd for C 14 H 15 N 197.12, found:197.12.

[0072] In summary, this invention successfully synthesized N-alkylated products.

[0073] Example 5:

[0074] The synthesis process of the N-alkylated product described in this embodiment is as follows:

[0075]

[0076] The specific steps are as follows:

[0077] Weigh out Cu(BTC)-MOF (0.01 g, 0.05 g / mmol), 1,2-bis(diphenylphosphine)ethane (4.0 mg, 5 mol%), potassium tert-butoxide (33.6 mg, 1.5 equiv), 4-chloro-2-methylaniline (28.2 mg, 0.2 mmol), and 4-methylbenzyl alcohol (24.4 mg, 0.2 mmol) into a reaction tube. Add 0.5 mL of dry toluene solution to the reaction tube and seal it with a flap stopper.

[0078] The reaction tube was then heated to 110°C in an oil bath under magnetic stirring for 24 hours. After the reaction, it was cooled to room temperature, diluted with 5 mL of ethyl acetate, and then extracted three times with ethyl acetate and water. After extraction, the organic phases were combined, washed with saturated brine, dried over anhydrous Na₂SO₄, and allowed to stand. Finally, the organic phase was concentrated and purified by silica gel column chromatography (200-300 mesh silica gel) to obtain the target product 3e. The target product 3e was a colorless oily liquid with a yield of 33.8 mg, representing a yield of 69%.

[0079] The target product 3e 1 H NMR (400MHz, CDCl3): δ7.26-7.23(m,2H),6.97-6.89(m,3H),6.53(d,J=7.2Hz, 1H), 6.38 (d, J = 8.0Hz, 1H), 4.23 (s, 2H), 3.76 (s, 1), 2.20 (s, 3H), 1.99 (s, 3H).

[0080] 13 C NMR (100MHz, CDCl3): δ147.4,137.3,136.0,129.6,129.2,128.0,127.6,127.4,118.2,108.6,48.4,21.3,13.7.

[0081] IR(neat,cm -1 ):3410,1588,1460,1345,876,685.

[0082] GC-MS(EI)calcd for C 15 H 16 ClN 245.09, found: 245.10.

[0083] In summary, this invention successfully synthesized N-alkylated products.

[0084] Example 6:

[0085] The synthesis process of the N-alkylated product described in this embodiment is as follows:

[0086]

[0087] The specific steps are as follows:

[0088] Weigh out Cu(BTC)-MOF (0.01 g, 0.05 g / mmol), 1,2-bis(diphenylphosphine)ethane (4.0 mg, 5 mol%), potassium tert-butoxide (33.6 mg, 1.5 equiv), aniline (18.6 mg, 0.2 mmol), and 4-methoxybenzyl alcohol (27.6 mg, 0.2 mmol) into a reaction tube. Add 0.5 mL of dry toluene solution to the reaction tube and seal it with a flap stopper.

[0089] The reaction tube was then heated to 110°C in an oil bath under magnetic stirring for 24 hours. After the reaction, it was cooled to room temperature, diluted with 5 mL of ethyl acetate, and then extracted three times with ethyl acetate and water. After extraction, the organic phases were combined, washed with saturated brine, dried over anhydrous Na₂SO₄, and allowed to stand. Finally, the organic phase was concentrated and purified by silica gel column chromatography (200-300 mesh silica gel) to obtain the target product 3f. The target product 3f was a colorless oily liquid with a yield of 36.2 mg, representing a yield of 85%.

[0090] The target product 3f 1 H NMR (400MHz, CDCl3): δ7.20 (d, J = 5.2Hz, 2H), 7.09 (s, 2H), 6.80-6.79 (m, 2H) ,6.63(s,1H),6.55(d,J=5.2Hz,2H),4.16(s,2H),3.89(s,1H),3.71(s,3H).

[0091] 13 C NMR (100MHz, CDCl3): δ158.9,148.2,131.5,129.3,128.9,117.6,114.1,113.0,55.4,47.9.

[0092] IR(neat,cm -1 ):3061,1599,1492,1452,982 745.

[0093] GC-MS(EI)calcd for C 14 H 15NO 213.11, found: 213.12.

[0094] In summary, this invention successfully synthesized N-alkylated products.

[0095] Example 7:

[0096] The synthesis process of the N-alkylated product described in this embodiment is as follows:

[0097]

[0098] The specific steps are as follows:

[0099] Weigh out Cu(BTC)-MOF (0.01 g, 0.05 g / mmol), 1,2-bis(diphenylphosphine)ethane (4.0 mg, 5 mol%), potassium tert-butoxide (33.6 mg, 1.5 equiv), 4-chloro-2-methylaniline (28.2 mg, 0.2 mmol), and 4-methoxybenzyl alcohol (27.6 mg, 0.2 mmol) into a reaction tube. Add 0.5 mL of dry toluene solution to the reaction tube and seal it with a flap stopper.

[0100] The reaction tube was then heated to 110°C in an oil bath under magnetic stirring for 24 hours. After the reaction, it was cooled to room temperature, diluted with 5 mL of ethyl acetate, and then extracted three times with ethyl acetate and water. After extraction, the organic phases were combined, washed with saturated brine, dried over anhydrous Na₂SO₄, and allowed to stand. Finally, the organic phase was concentrated and purified by silica gel column chromatography (200-300 mesh silica gel) to obtain 3 g of the target product. The target product 3 g was a colorless oily liquid with a yield of 36.2 mg, representing a yield of 65%.

[0101] The target product 3g 1 H NMR (400MHz, CDCl3): δ7.60(d,J=1.6Hz,1H),7.52(dd,J=6.0Hz,1.2Hz,1H),7.37(d,J=6.4H z,1H),7.28(d,J=6.4Hz,2H),6.88(d,J=6.0Hz,2H),4.46(s,2H),4.39(s,1H),3.81(s,3H).

[0102] 13 C NMR (100MHz, CDCl3): δ159.3,147.6,143.8,130.6,130.0,129.6,125.4,113.9,113.0,109.8,71.6,55.4.

[0103] IR(neat,cm -1):3403,2978,1608,1368,955,764.

[0104] GC-MS(EI)calcd for C 14 H 13 ClN2O3 292.06,found:292.06.

[0105] In summary, this invention successfully synthesized N-alkylated products.

[0106] Example 8:

[0107] The synthesis process of the N-alkylated product described in this embodiment is as follows:

[0108]

[0109] The specific steps are as follows:

[0110] Weigh out Cu(BTC)-MOF (0.01 g, 0.05 g / mmol), 1,2-bis(diphenylphosphine)ethane (4.0 mg, 5 mol%), potassium tert-butoxide (33.6 mg, 1.5 equiv), (36.6 mg, 0.2 mmol), and 4-methylbenzyl alcohol (36.6 mg, 0.3 mmol) into a reaction tube. Add 0.5 mL of dry toluene solution to the reaction tube and seal it with a flap stopper.

[0111] The reaction tube was then heated to 110°C in an oil bath under magnetic stirring for 8 hours. After the reaction, it was cooled to room temperature, diluted with 5 mL of ethyl acetate, and then extracted three times with ethyl acetate and water. After extraction, the organic phases were combined, washed with saturated brine, dried over anhydrous Na₂SO₄, and allowed to stand. Finally, the organic phase was concentrated and purified by silica gel column chromatography (200-300 mesh silica gel) to obtain the target product 5a. The target product 5a is a yellow solid with a melting point of 108-110°C, a yield of 52.8 mg, and a yield of 92%.

[0112] Example 9:

[0113] Combination Figure 2 The flowchart for the selective synthesis of the N-dialkylation product is shown below. In this embodiment, the N-dialkylation product was synthesized.

[0114]

[0115] The specific steps are as follows:

[0116] Weigh out Cu(BTC)-MOF (0.01 g, 0.05 g / mmol), 1,2-bis(diphenylphosphine)ethane (4.0 mg, 5 mol%), potassium tert-butoxide (33.6 mg, 1.5 equiv), aniline (33.6 mg, 0.2 mmol), and benzyl alcohol (54 mg, 0.5 mmol) into a reaction tube. Add 0.5 mL of dry toluene solution to the reaction tube and seal it with a flip-top stopper.

[0117] The reaction tube was then heated to 110°C in an oil bath under magnetic stirring for 24 hours. After the reaction, it was cooled to room temperature, diluted with 5 mL of ethyl acetate, and then extracted three times with ethyl acetate and water. After extraction, the organic phases were combined, washed with saturated brine, dried over anhydrous Na₂SO₄, and allowed to stand. Finally, the organic phase was concentrated and purified by silica gel column chromatography (200-300 mesh silica gel) to obtain the target product 4a. The target product 4a is a white solid with a melting point of 68-69°C and a yield of 43.7 mg, which is 80%.

[0118] The NMR H-spectrum and C-spectrum of the target product 4a are as follows: Figure 5 and Figure 6 As shown in the figure, 1 H NMR (600MHz, CDCl3): δ7.32-7.28(m,4H),7.24-7.21(m,6H),7.17-7.13(m,2H),6.73-6.67(m,3H),4.63(s,4H).

[0119] 13 C NMR (150MHz, CDCl3) δ149.3,138.7,129.3,128.8,127.0,126.8,116.8,112.5,54.3.

[0120] IR(neat,cm -1 ):3058,1597,1504,1358,1230,731.

[0121] GC-MS(EI)calcd for C 20 H 19 N 273.15, found:273.16.

[0122] In summary, this invention successfully synthesized N-dialkylated products.

[0123] Example 10:

[0124] Combination Figure 2The flowchart for the selective synthesis of the N-dialkylation product is shown below. In this embodiment, the N-dialkylation product was synthesized.

[0125]

[0126] The specific steps are as follows:

[0127] Weigh out Cu(BTC)-MOF (0.01 g, 0.05 g / mmol), 1,2-bis(diphenylphosphine)ethane (4.0 mg, 5 mol%), potassium tert-butoxide (33.6 mg, 1.5 equiv), 2-methoxy-4-nitroaniline (33.6 mg, 0.2 mmol), and benzyl alcohol (54 mg, 0.5 mmol) into a reaction tube. Add 0.5 mL of dry toluene solution to the reaction tube and seal it with a flap stopper.

[0128] The reaction tube was then heated to 110°C in an oil bath under magnetic stirring for 24 hours. After the reaction, it was cooled to room temperature, diluted with 5 mL of ethyl acetate, and then extracted three times with ethyl acetate and water. After extraction, the organic phases were combined, washed with saturated brine, dried over anhydrous Na₂SO₄, and allowed to stand. Finally, the organic phase was concentrated and purified by silica gel column chromatography (200-300 mesh silica gel) to obtain the target product 4b. The target product 4b is a white solid with a melting point of 81-83°C, a yield of 45.2 mg, and a yield of 65%.

[0129] Example 11:

[0130] Combination Figure 2 The flowchart for the selective synthesis of the N-dialkylation product is shown below. In this embodiment, the N-dialkylation product was synthesized.

[0131]

[0132] The specific steps are as follows:

[0133] Weigh out Cu(BTC)-MOF (0.01 g, 0.05 g / mmol), 1,2-bis(diphenylphosphine)ethane (4.0 mg, 5 mol%), potassium tert-butoxide (33.6 mg, 1.5 equiv), 4-nitroaniline (27.6 mg, 0.2 mmol), and p-methylbenzyl alcohol (61 mg, 0.5 mmol) into a reaction tube. Add 0.5 mL of dry toluene solution to the reaction tube and seal it with a flap stopper.

[0134] The reaction tube was then heated to 110°C in an oil bath under magnetic stirring for 24 hours. After the reaction, it was cooled to room temperature, diluted with 5 mL of ethyl acetate, and then extracted three times with ethyl acetate and water. After extraction, the organic phases were combined, washed with saturated brine, dried over anhydrous Na₂SO₄, and allowed to stand. Finally, the organic phase was concentrated and purified by silica gel column chromatography (200-300 mesh silica gel) to obtain the target product 4c. The target product 4c is a brownish-yellow solid with a melting point of 109-111°C, a yield of 51.9 mg, and a yield of 75%.

[0135] Example 12:

[0136] Combination Figure 2 The flowchart for the selective synthesis of the N-dialkylation product is shown below. In this embodiment, the N-dialkylation product was synthesized.

[0137]

[0138] The specific steps are as follows:

[0139] Weigh out Cu(BTC)-MOF (0.01 g, 0.05 g / mmol), 1,2-bis(diphenylphosphine)ethane (4.0 mg, 5 mol%), potassium tert-butoxide (33.6 mg, 1.5 equiv), aniline (18.6 mg, 0.2 mmol), and p-methoxybenzyl alcohol (69 mg, 0.5 mmol) into a reaction tube. Add 0.5 mL of dry toluene solution to the reaction tube and seal it with a flip-top stopper.

[0140] The reaction tube was then heated to 110°C in an oil bath under magnetic stirring for 24 hours. After the reaction, it was cooled to room temperature, diluted with 5 mL of ethyl acetate, and then extracted three times with ethyl acetate and water. After extraction, the organic phases were combined, washed with saturated brine, dried over anhydrous Na₂SO₄, and allowed to stand. Finally, the organic phase was concentrated and purified by silica gel column chromatography (200-300 mesh silica gel) to obtain the target product 4d. The target product 4d was a yellow oily liquid with a yield of 54.6 mg, representing a yield of 82%.

[0141] The target product 4d 1 H NMR (400MHz, CDCl3): δ7.18-7.14(m,6H),6.85(d,J=5.6Hz,4H),6.75(d,J=5.2Hz,2H),6.70-6.68(m,1H),4.55(s,4H),3.79(s,6H).

[0142] 13C NMR (100MHz, CDCl3) δ158.3,144.0,132.6,129.8,128.5,126.1,114.4,114.1,55.4,46.8.

[0143] IR(neat,cm -1 ):3041,1566,1338,1250,761,684.

[0144] GC-MS(EI)calcd for C 22 H 23 NO2,333.17,found:333.17.

[0145] In summary, this invention successfully synthesized N-dialkylated products.

[0146] Example 13:

[0147] Combination Figure 2 The flowchart for the selective synthesis of the N-dialkylation product is shown below. In this embodiment, the N-dialkylation product was synthesized.

[0148]

[0149] The specific steps are as follows:

[0150] Weigh out Cu(BTC)-MOF (0.01 g, 0.05 g / mmol), 1,2-bis(diphenylphosphine)ethane (4.0 mg, 5 mol%), potassium tert-butoxide (33.6 mg, 1.5 equiv), 4-nitroaniline (27.6 mg, 0.2 mmol), and p-methoxybenzyl alcohol (69 mg, 0.5 mmol) into a reaction tube. Add 0.5 mL of dry toluene solution to the reaction tube and seal it with a flap stopper.

[0151] The reaction tube was then heated to 110°C in an oil bath under magnetic stirring for 24 hours. After the reaction, it was cooled to room temperature, diluted with 5 mL of ethyl acetate, and then extracted three times with ethyl acetate and water. After extraction, the organic phases were combined, washed with saturated brine, dried over anhydrous Na₂SO₄, and allowed to stand. Finally, the organic phase was concentrated and purified by silica gel column chromatography (200-300 mesh silica gel) to obtain the target product 4e. The target product 4e was a yellow oily liquid with a yield of 55.2 mg, representing a yield of 73%.

[0152] The target product 4e 1H NMR (400MHz, CDCl3): δ7.98 (d, J = 5.6 Hz, 2H), 7.03 (d, J = 5.6 Hz, 4H), 6.81 (d, J = 5.6 Hz, 4H), 6.63 (d, J = 6.0 Hz, 2H), 4.59 (s, 4H), 3.72 (s, 6H).

[0153] 13 C NMR (100MHz, CDCl3) δ159.2,153.9,137.8,128.3,127.7,126.4,114.6,111.2,55.5,53.8.

[0154] IR(neat,cm -1 ):3226,1697,1378,1251,850,736.

[0155] GC-MS(EI)calcd for C 22 H 22 N2O4, 378.15, found: 378.16.

[0156] In summary, this invention successfully synthesized N-dialkylated products.

[0157] Example 14:

[0158] Combination Figure 2 The flowchart for the selective synthesis of the N-dialkylation product is shown below. In this embodiment, the N-dialkylation product was synthesized.

[0159]

[0160] The specific steps are as follows:

[0161] Weigh out Cu(BTC)-MOF (0.01 g, 0.05 g / mmol), 1,2-bis(diphenylphosphine)ethane (4.0 mg, 5 mol%), potassium tert-butoxide (33.6 mg, 1.5 equiv), aniline (18.6 mg, 0.2 mmol), and 4-fluorobenzyl alcohol (63 mg, 0.5 mmol) into a reaction tube. Add 0.5 mL of dry toluene solution to the reaction tube and seal it with a flap stopper.

[0162] The reaction tube was then heated to 110°C in an oil bath under magnetic stirring for 24 hours. After the reaction, it was cooled to room temperature, diluted with 5 mL of ethyl acetate, and then extracted three times with ethyl acetate and water. After extraction, the organic phases were combined, washed with saturated brine, dried over anhydrous Na₂SO₄, and allowed to stand. Finally, the organic phase was concentrated and purified by silica gel column chromatography (200-300 mesh silica gel) to obtain the target product 4f. The target product 4f was a bright yellow oily liquid with a yield of 47.6 mg, representing a yield of 77%.

[0163] The target product 4f 1 H NMR (400MHz, CDCl3): δ7.12-7.10(m,6H),6.94-6.91(m,4H),6.67-6.64(m,3H),4.50(s,4H).

[0164] 13 C NMR (100MHz, CDCl3) δ 162.1 (J C-F =163Hz), 149.0, 134.1 (J) C-F =2Hz), 129.5, 128.4 (J) C-F =5Hz), 117.4, 115.6 (J) C-F =14Hz), 112.9, 53.8.

[0165] 19 F NMR (376MHz, CDCl3): δ-111.93.

[0166] IR(neat,cm -1 ):2983,1532,1472,1358,1246,731.

[0167] GC-MS(EI)calcd for C 20 H 17 F2N 309.13, found: 309.13.

[0168] In summary, this invention successfully synthesized N-dialkylated products.

[0169] Example 15:

[0170] Combination Figure 2 The flowchart for the selective synthesis of the N-dialkylation product is shown below. In this embodiment, the N-dialkylation product was synthesized.

[0171]

[0172] The specific steps are as follows:

[0173] Weigh out Cu(BTC)-MOF (0.01 g, 0.05 g / mmol), 1,2-bis(diphenylphosphine)ethane (4.0 mg, 5 mol%), potassium tert-butoxide (33.6 mg, 1.5 equiv), aniline (18.6 mg, 0.2 mmol), and 4-chlorobenzyl alcohol (71 mg, 0.5 mmol) into a reaction tube. Add 0.5 mL of dry toluene solution to the reaction tube and seal it with a flap stopper.

[0174] The reaction tube was then heated to 110°C in an oil bath under magnetic stirring for 24 hours. After the reaction, it was cooled to room temperature, diluted with 5 mL of ethyl acetate, and then extracted three times with ethyl acetate and water. After extraction, the organic phases were combined, washed with saturated brine, dried over anhydrous Na₂SO₄, and allowed to stand. Finally, the organic phase was concentrated and purified by silica gel column chromatography (200-300 mesh silica gel) to obtain 4 g of the target product. The target product 4 g was a bright yellow oily liquid with a yield of 49.8 mg, representing a yield of 73%.

[0175] The 1H NMR (400MHz, CDCl3) of 4g of the target product was as follows: δ 7.27 (d, J = 5.6Hz, 4H), 7.19-7.15 (m, 6H), 6.74 (t, J = 4.8Hz, 1H), 6.70 (d, J = 5.6Hz, 2H), 4.57 (s, 4H).

[0176] 13C NMR (100MHz, CDCl3) δ148.9,137.0,132.9,129.5,129.0,128.2,117.6,112.9,53.9.

[0177] IR(neat,cm-1):2866,1545,1463,1369,1250,769.

[0178] GC-MS(EI)calcd for C20H17Cl2N(341.07),found:341.07.

[0179] In summary, this invention successfully synthesized N-dialkylated products.

[0180] Example 16:

[0181] Combination Figure 2 The flowchart for the selective synthesis of the N-dialkylation product is shown below. In this embodiment, the N-dialkylation product was synthesized.

[0182]

[0183] The specific steps are as follows:

[0184] Weigh out Cu(BTC)-MOF (0.01 g, 0.05 g / mmol), 1,2-bis(diphenylphosphine)ethane (4.0 mg, 5 mol%), potassium tert-butoxide (33.6 mg, 1.5 equiv), aniline (18.6 mg, 0.2 mmol), and allyl alcohol (29 mg, 0.5 mmol) into a reaction tube. Add 0.5 mL of dry toluene solution to the reaction tube and seal it with a flap stopper.

[0185] The reaction tube was then heated to 110°C in an oil bath under magnetic stirring for 24 hours. After the reaction, it was cooled to room temperature, diluted with 5 mL of ethyl acetate, and then extracted three times with ethyl acetate and water. After extraction, the organic phases were combined, washed with saturated brine, dried over anhydrous Na₂SO₄, and allowed to stand. Finally, the organic phase was concentrated and purified by silica gel column chromatography (200-300 mesh silica gel) to obtain the target product 4h. The target product 4h was a bright yellow oily liquid with a yield of 19 mg, representing a yield of 55%.

[0186] like Figure 7 and Figure 8 As shown, the target product 4h 1 H NMR (600MHz, CDCl3): δ7.20-7.16(m,2H),6.70-6.65(m,3H),5.88-5.79(m,2H),5.18-5.12(m,4H),3.89(d,J=6.0Hz,4H).

[0187] 13 C NMR (150MHz, CDCl3) δ148.9,134.1,129.2,116.4,116.0,112.4,52.8.

[0188] IR(neat,cm -1 ):2983,1534,1328,1147,1089,761.

[0189] GC-MS(EI)calcd for C 12 H 15 173.12, found: 173.12.

[0190] In summary, this invention successfully synthesized N-dialkylated products.

[0191] In summary, this invention can selectively synthesize secondary or tertiary amine compounds by controlling reaction time and raw material ratio. The selective synthesis is simple, efficient, non-toxic, pollution-free, and economical, and has great practical value.

[0192] The embodiments described above are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments. Any obvious improvements, substitutions or modifications that can be made by those skilled in the art without departing from the essence of the present invention shall fall within the protection scope of the present invention.

Claims

1. A method for the selective synthesis of N-alkylated products, characterized in that, include: A reaction solution was prepared by dissolving a transition metal catalyst, a phosphine ligand, potassium tert-butoxide, an aromatic amine, and an alcohol in toluene. The reaction solution was heated in an oil bath under stirring. After the reaction was completed, the solution was cooled to room temperature and then diluted with ethyl acetate. After dilution, the organic phase was extracted with a mixture of ethyl acetate and water. The organic phase was washed, dried, allowed to stand, and concentrated to obtain the N-alkylated product. The transition metal catalyst is Cu(BTC)-MOF; The amounts of the transition metal catalyst, phosphine ligand, potassium tert-butoxide, aromatic amine, and alcohol are: 0.01 g: 4.0 mg: 33.6 mg: 18.6 mg: 21.6 mg. The conditions for the oil bath heating reaction are: reaction at 110℃ for 8~24h; The phosphine ligand comprises 1,2-bis(diphenylphosphine)ethane; The aromatic amine includes any of the following: ； The alcohols include any of the following: 。 2. The selective synthesis method of N-alkylated products according to claim 1, characterized in that, During the dilution, the ratio of ethyl acetate to alcohol was 5 mL: 0.5 mmol.

3. The selective synthesis method of N-alkylated products according to claim 1, characterized in that, In the mixed solution of ethyl acetate and water, the volume ratio of ethyl acetate to water is 1:2.

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