Method for synthesizing N-N cross-coupling product

Abstract

The invention belongs to the technical field of chemical synthesis, and particularly relates to a method for synthesizing an N-N cross-coupling product. N-alkoxy amide and benzotriazole are used as reaction substrates, iodobenzene diacetate is used as an initiator, N-alkoxy amide, benzotriazole and iodobenzene diacetate are mixed in the form of solid reactants, molecules of the solid reactants collide under the stirring effect, dehydrogenation coupling reaction of N-N bonds is promoted, and the N-N cross-coupling product is obtained. The method does not need to use a solvent, is simple to operate, mild in reaction condition, wide in substrate universality and low in cost, and solves the problem of low yield of an N-N cross-coupling product formed by a preparation method in the prior art.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical synthesis, and particularly relates to a method for synthesizing a NN cross-coupling product. Background Art

[0002] Cross-dehydrogenation coupling reaction is a powerful tool for organic synthesis, involving two direct coupling reactions such as CH / NH / SH. The NN bond skeleton structure is a very important structural unit. Functionalized hydrazines are molecules containing NN bonds, which are commonly found in natural products, functional drug molecules and organic materials. Multi-substituted hydrazine compounds can be obtained through NN cross-coupling reactions. More than 300 drug molecules have been reported to contain NN bonds. In addition, N,N-disubstituted hydrazines in particular have a wide range of physiological and pharmacological activities, such as antihypertensive, anticancer and antibacterial. Therefore, the development of efficient NN cross-coupling preparation methods is challenging and of great research significance.

[0003] The most classic NN cross-coupling reaction is to form hydrazine compounds by metal catalysis. In the prior art, document 1: Zhu, SY; He, WJ; Shen, GC; Bai, ZQ; Song, FF; He, G.; Chen, G. Angew. Chem. Int. Ed. 2024, 63. Document 1 uses ligands to promote iron-catalyzed arylamines and dioxazolone to undergo NN coupling reactions to synthesize hydrazine compounds. The synthesis route is as follows:

[0004]

[0005] Hypervalent iodine reagents have become widely used oxidants due to their better safety, ease of handling and economy than transition metals. Reference 2: Kathiravan, S., Dhillon, P., Zhang, T., Nicholls, IAMalfree cross-dehydrogenative NN coupling of primary amides with Lewis basicamines. Nature Commu., 2024.5, 2643. Reference 2 uses iodobenzene acetate as a terminal oxidant to promote the NN cross-coupling reaction between primary amides and primary and secondary amines. The synthetic route is as follows:

[0006]

[0007] In the above prior art, when using the reaction substrate to carry out the NN cross-coupling reaction, the reaction substrate needs to be dissolved in a solvent to carry out the NN cross-coupling reaction. Since the reaction substrate reacts in the solution, the concentration of the reactant is low, the reaction speed is slow, and the reaction operation is difficult to control. At the same time, by-products are easily produced, and additional purification steps are required, resulting in a low yield of the formed NN cross-coupling product. Summary of the invention

[0008] In order to solve the problem of low yield of NN cross-coupling products formed by the preparation methods in the prior art, the present invention provides a method for synthesizing NN cross-coupling products.

[0009] The first object of the present invention is to provide a method for synthesizing a NN cross-coupling product, comprising the following steps:

[0010] With N-alkoxyamide shown in Formula 1 and benzotriazole shown in Formula 3 as reaction substrates and diacetate iodobenzene as initiator, N-alkoxyamide, benzotriazole and diacetate iodobenzene are mixed as solid reactants, and under stirring, the molecules of the solid reactants collide to promote the dehydrogenation coupling reaction of the NN bond to form the NN cross-coupling product shown in Formula 4. The synthesis route is as follows:

[0011]

[0012] Among them, R 1 is one of phenyl, substituted phenyl, furyl, naphthyl, cyclohexyl, alkyl having 1 to 6 carbon atoms, and alkenyl having 1 to 5 carbon atoms, R 1 The substituent of the substituted phenyl is one of halogen, alkyl having 1 to 4 carbon atoms and alkenyl having 1 to 8 carbon atoms; R 3 It is one of H, methyl, methoxy and trifluoromethyl.

[0013] Preferably, the R 1 is one of phenyl, substituted phenyl, furyl, naphthyl, cyclohexyl, propanyl and pentenyl, R 1 The substituent of the substituted phenyl group is one of a bromine atom, a methyl group, a tert-butyl group and a vinyl group. 1 The substituted phenyl group is a para-substituted phenyl group.

[0014] It should be noted that N-alkoxyamide and benzotriazole form a NN bond through a cross-coupling reaction initiated by diacetyl iodobenzene. As an efficient oxidant, diacetyl iodobenzene can activate the nitrogen atom in N-alkoxyamide, so that N-alkoxyamide and diacetyl iodobenzene undergo a ligand exchange reaction of trivalent iodine to obtain an oxygen-iodine intermediate; the intermediate undergoes intramolecular migration and ligand exchange with benzotriazole, and finally removes iodobenzene, and obtains a NN cross-coupling product through reduction elimination.

[0015] Preferably, the N-alkoxyamide is one of N-ethoxybenzamide, N-ethoxybenzamide having an electron-donating group at the para position, N-ethoxybenzamide having a weak passivating group at the para position, a naphthalene compound, a furan compound and an aliphatic amide.

[0016] Preferably, the N-alkoxyamide is one of 4-bromo-N-ethoxybenzamide, 4-tert-butyl-N-ethoxybenzamide, N-ethoxy-4-vinylbenzamide, N-ethoxy-2-naphthylamide, N-ethoxyfuran-2-carboxamide, N-ethoxy-2-phenylacetamide, N-ethoxycyclohexanecarboxamide, N-ethoxypentenamide and N-alkoxyalkylamide.

[0017] Preferably, the benzotriazole is one of 1H-benzotriazole, 5-methylbenzotriazole and 5-trifluoromethylbenzotriazole.

[0018] Preferably, the molar ratio of the N-alkoxyamide, benzotriazole and iodobenzene diacetate is 1:1-2:0.035-0.1.

[0019] In the present invention, under solvent-free conditions, the reaction substrate exists in a solid form, and the reaction process mainly relies on the local thermal effect generated by physical contact and friction. Therefore, the contact area and frequency between the solid reactants can be increased by mechanical stirring, the mixing effect of the solid reactants can be improved, and the reaction can be promoted. In addition, solvent-free reactions can usually avoid side reactions and impurity interference caused by solvents, and may obtain higher yields and purity. At the same time, solvent-free reactions are more environmentally friendly, avoid the use and processing costs of solvents, and comply with the principles of green chemistry.

[0020] Compared with the prior art, the present invention has the following beneficial effects:

[0021] 1. In the present invention, iodobenzene diacetate is used as an initiator, N-alkoxyamide and benzotriazole are used as reaction substrates under solvent-free conditions, N-alkoxyamide, benzotriazole and iodobenzene diacetate are mixed as solid reactants, and the molecules of the solid reactants are stirred to collide, and a liquid intermediate product is produced on the solid surface. The liquid intermediate product acts as a solvent to promote the reaction; at the same time, iodobenzene diacetate decomposes to produce acetic acid, which further promotes the reaction and synthesizes the NN cross-coupling product. The present invention directly mixes the reaction substrates to maximize the concentration of the reactants, thereby synthesizing a high-yield NN cross-coupling product, which solves the technical problem of low yield of NN cross-coupling products formed by the preparation method of the prior art.

[0022] 2. The present invention can avoid the side reactions and impurity interference caused by the solvent through the solvent-free reaction, and without using a solvent, the concentration of the reactants is the highest, which has significant advantages over the reaction in the solution in terms of reaction speed, reaction operation, yield, etc. At the same time, the addition of no solvent makes the cross-coupling reaction more environmentally friendly, avoids the use and processing costs of solvents, and complies with the principles of green chemistry. DETAILED DESCRIPTION

[0023] In order to enable those skilled in the art to better understand and implement the technical solution of the present invention, the present invention is further described below in conjunction with specific embodiments.

[0024] In the description of the present invention, unless otherwise specified, all reagents used are commercially available and all methods used are conventional techniques in the art.

[0025] In the previous study, the NN cross-coupling reaction of N-alkoxyamides was promoted by iodobenzene diacetate under solvent conditions. Specifically:

[0026] First, iodobenzene diacetate was used as an initiator, N-ethoxy-4-nitrobenzamide shown in Formula 1a and N-ethoxy-4-trifluoromethylbenzamide shown in Formula 1b were used as reaction substrates, and ethyl acetate was used as a solvent to obtain the NN cross-coupling product shown in Formula 2a; the synthesis route is as follows:

[0027]

[0028] On this basis, the N-ethoxy-4-nitrobenzamide substrate was not changed, and the N-ethoxy-4-nitrobenzamide shown in Formula 1a was subjected to a NN cross-coupling reaction with the N-alkoxyamide shown in Formula 1, and the universality of the reaction substrate was explored to obtain the NN cross-coupling product shown in Formula 2; its synthesis route is as follows:

[0029]

[0030] When there is a weak passivating group at the para position of the benzene ring of the N-alkoxyamide, and the electronic effect has no significant effect on the yield of the cross-coupling reaction, the reaction can be smoothly carried out to obtain the corresponding target product; when there is an electron-donating group at the para position of the benzene ring of the N-alkoxyamide, the reaction can be smoothly carried out; when the substituents in the benzene ring of the N-alkoxyamide are at the meta position and the ortho position, the corresponding target product can be obtained; when there are no substituents in the benzene ring of the N-alkoxyamide, the target product can also be obtained; when the N-alkoxyamide is N-ethoxycyclohexanecarboxamide and N-alkoxyalkylamide, the target product can also be obtained; when the N-alkoxyamide is a naphthalene compound, the target product can also be obtained.

[0031] This shows that the above-mentioned NN cross-coupling reaction system exhibits good compatibility and selectivity for a variety of N-alkoxyamide substrates.

[0032] Then we explored the NN cross-coupling reaction in a solvent-free system, specifically:

[0033] Based on the NN cross-coupling reaction system of N-alkoxyamide promoted by diacetate iodobenzene; the present invention uses N-alkoxyamide as substrate, diacetate iodobenzene as initiator, and under solvent-free conditions, mixes N-alkoxyamide, benzotriazole and diacetate iodobenzene as solid reactants to obtain the NN cross-coupling reaction product. The reaction does not require the use of solvents, is simple to operate, has mild reaction conditions, has wide substrate universality, is easy to mass produce, and has low cost.

[0034] In order to explore the corresponding reaction conditions, the present invention uses iodobenzene diacetate as an initiator, first uses N-ethoxybenzamide shown in Formula 1d and 1H-benzotriazole shown in Formula 3a as reaction substrates, mixes N-ethoxybenzamide, 1H-benzotriazole and iodobenzene diacetate as solid reactants, and obtains the NN cross-coupling product shown in Formula 4a; the reaction route is as follows:

[0035]

[0036] The present invention further explores the amount of raw materials used. As the feed ratio of N-alkoxyamide and benzotriazole increases, the reaction yield increases; when the molar ratio of N-alkoxyamide and benzotriazole is 1:2, the reaction yield can be increased to 65%. In this reaction system, using 1 mL of ethyl acetate as a solvent, the reaction yield decreases by 21%. In addition, as the amount of iodobenzene diacetate added increases, the reaction yield increases.

[0037] This further illustrates that, in a solvent-free system, the present invention directly mixes the reaction substrates to maximize the concentration of the reactants, thereby synthesizing a high-yield NN cross-coupling product, thereby solving the technical problem of low yield of NN cross-coupling products formed by the preparation methods of the prior art.

[0038] In some preferred embodiments, the molar ratio of the N-alkoxyamide, benzotriazole and iodobenzene diacetate is 1:1-2:0.035-0.1. More preferably, the molar ratio of the N-alkoxyamide, benzotriazole and iodobenzene diacetate is 1:2:0.1.

[0039] Under preferred reaction conditions, the present invention conducts a universal exploration of the NN cross-coupling reaction of N-alkoxyamide and benzotriazole, that is, the present invention expands the scope of the reaction substrate.

[0040] When the benzene ring of the N-alkoxyamide has an electron-withdrawing group or an electron-donating group at the para position, the yield of the NN cross-coupling product is moderate; when the N-alkoxyamide is a naphthalene or furan compound, the NN cross-coupling product can also be obtained in moderate to good yields; when the N-alkoxyamide is an aliphatic amide, the NN cross-coupling product can also be obtained; when the N-ethoxybenzamide is not changed and is reacted with a monosubstituted benzotriazole, the N center of the product is no longer symmetrical, and a mixture of isomers of the target product is usually obtained.

[0041] The NN cross-coupling reaction system showed good compatibility and selectivity for a variety of N-alkoxyamide substrates.

[0042] In some preferred embodiments, the stirring time is 1 h to 6 h, and the temperature is room temperature.

[0043] Example 1

[0044] This embodiment provides a method for synthesizing a NN cross-coupling product.

[0045] 0.1 mmol of N-ethoxybenzamide, 0.2 mmol of 1H-benzotriazole and 0.1 mmol of iodobenzene diacetate were added to a dry test tube; the mixture was stirred at 500 rpm for 1 h at room temperature, and the reaction slowly changed from a solid state to a yellow liquid state; the reaction progress was monitored by thin layer chromatography, wherein the developing solvent was a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate was 5:1; after the reaction was completed, a NN cross-coupling product was obtained, and its synthesis route is as follows:

[0046]

[0047] Example 2

[0048] This embodiment provides a method for synthesizing a NN cross-coupling product.

[0049] The difference between this embodiment and embodiment 1 is:

[0050] In this embodiment, the molar ratio of N-ethoxybenzamide to 1H-benzotriazole is 1:1.5.

[0051] Example 3

[0052] This embodiment provides a method for synthesizing a NN cross-coupling product.

[0053] The difference between this embodiment and embodiment 1 is:

[0054] In this embodiment, the molar ratio of N-ethoxybenzamide to 1H-benzotriazole is 1:1.

[0055] Example 4

[0056] This embodiment provides a method for synthesizing a NN cross-coupling product.

[0057] The difference between this embodiment and embodiment 1 is:

[0058] The mole of iodobenzene diacetate in this embodiment is 0.065.

[0059] Example 5

[0060] This embodiment provides a method for synthesizing a NN cross-coupling product.

[0061] The difference between this embodiment and embodiment 1 is:

[0062] The mole of iodobenzene diacetate in this embodiment is 0.035.

[0063] Comparative Example 1

[0064] This comparative example provides a method for synthesizing a NN cross-coupling product.

[0065] Add 0.1 mmol of N-ethoxybenzamide, 0.2 mmol of 1H-benzotriazole, 0.1 mmol of iodobenzene diacetate and 1 mL of ethyl acetate into a dry test tube; stir at room temperature at 500 rpm; monitor the reaction progress by thin layer chromatography, wherein the developing solvent is a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is 5:1, to obtain a NN cross-coupling product.

[0066] The difference between this comparative example and Example 1 is:

[0067] In this comparative example, 1 mL of ethyl acetate was used as the solvent.

[0068] Referring to the preparation method of Example 1, the present invention changes the molar ratio of N-ethoxybenzamide and 1H-benzotriazole and the amount of iodobenzene diacetate added to explore the effect of the amount of substrate and the amount of initiator iodobenzene diacetate on the yield of the synthesized NN cross-coupling product. The specific situation is summarized in Table 1:

[0069] Table 1 Summary of the embodiments of the present invention for reaction conditions

[0070]

[0071] As can be seen from Table 1, when the molar ratio of N-ethoxybenzamide to 1H-benzotriazole is 1:2, the reaction yield can be increased to 65%. In addition, as the amount of iodobenzene diacetate added increases, the reaction yield increases. When 1 mL of ethyl acetate is used as a solvent in this reaction system, the reaction yield drops to 21%.

[0072] Example 6

[0073] This embodiment provides a method for synthesizing a NN cross-coupling product.

[0074] Add 0.1 mmol of 4-bromo-N-ethoxybenzamide, 0.2 mmol of 1H-benzotriazole and 0.1 mmol of iodobenzene diacetate to a dry test tube; stir at 500 rpm for 1 hour at room temperature, and the reaction slowly changes from a solid state to a yellow liquid; monitor the reaction progress by thin layer chromatography, wherein the developing solvent is a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is 5:1; after the reaction is completed,

[0075] The NN cross-coupling product shown in formula 4b:

[0076]

[0077] Example 7

[0078] This embodiment provides a method for synthesizing a NN cross-coupling product.

[0079] The difference between this embodiment and embodiment 1 is:

[0080] In this example, 4-tert-butyl-N-ethoxybenzamide was used to replace N-ethoxybenzamide to obtain a NN cross-coupling product with a yield of 57% as shown in Formula 4c:

[0081]

[0082] Example 8

[0083] This embodiment provides a method for synthesizing a NN cross-coupling product.

[0084] The difference between this embodiment and embodiment 1 is:

[0085] In this example, 4-vinyl N-ethoxy-benzamide was used to replace N-ethoxybenzamide to obtain a NN cross-coupling product with a yield of 69% as shown in Formula 4d:

[0086]

[0087] Example 9

[0088] This embodiment provides a method for synthesizing a NN cross-coupling product.

[0089] The difference between this embodiment and embodiment 1 is:

[0090] In this example, N-ethoxy-2-naphthylamide was used to replace N-ethoxybenzamide to obtain a NN cross-coupling product with a yield of 75% as shown in Formula 4e:

[0091]

[0092] Example 10

[0093] This embodiment provides a method for synthesizing a NN cross-coupling product.

[0094] The difference between this embodiment and embodiment 1 is:

[0095] In this example, N-ethoxyfuran-2-carboxamide was used to replace N-ethoxybenzamide to obtain a NN cross-coupling product with a yield of 59% as shown in Formula 4f:

[0096]

[0097] Embodiment 11

[0098] This embodiment provides a method for synthesizing a NN cross-coupling product.

[0099] The difference between this embodiment and embodiment 1 is:

[0100] In this example, N-ethoxy-2-phenylacetamide was used to replace N-ethoxybenzamide to obtain a NN cross-coupling product with a yield of 61% as shown in Formula 4g:

[0101]

[0102] Example 12

[0103] This embodiment provides a method for synthesizing a NN cross-coupling product.

[0104] The difference between this embodiment and embodiment 1 is:

[0105] In this example, N-ethoxycyclohexanecarboxamide was used to replace N-ethoxybenzamide to obtain a NN cross-coupling product with a yield of 47% as shown in Formula 4h:

[0106]

[0107] Example 13

[0108] This embodiment provides a method for synthesizing a NN cross-coupling product.

[0109] The difference between this embodiment and embodiment 1 is:

[0110] In this example, N-ethoxypropionamide was used to replace N-ethoxybenzamide to obtain a NN cross-coupling product with a yield of 53% as shown in Formula 4i:

[0111]

[0112] Embodiment 14

[0113] This embodiment provides a method for synthesizing a NN cross-coupling product.

[0114] The difference between this embodiment and embodiment 1 is:

[0115] In this example, N-ethoxypentenamide was used to replace N-ethoxybenzamide to obtain a NN cross-coupling product with a yield of 40% as shown in Formula 4j:

[0116]

[0117] Embodiment 15

[0118] This embodiment provides a method for synthesizing a NN cross-coupling product.

[0119] The difference between this embodiment and embodiment 1 is:

[0120] In this example, 5-methylbenzotriazole was used to replace 1H-benzotriazole to obtain a 64% yield, as shown in Formulas 4k and 4k ’ NN cross-coupling products shown:

[0121]

[0122] Example 16

[0123] This embodiment provides a method for synthesizing a NN cross-coupling product.

[0124] The difference between this embodiment and embodiment 1 is:

[0125] In this example, 5-methoxybenzotriazole was used to replace 1H-benzotriazole, and the yield was 33%.

[0126] Formula 4l and 4l ’ NN cross-coupling products shown:

[0127]

[0128] Embodiment 17

[0129] This embodiment provides a method for synthesizing a NN cross-coupling product.

[0130] The difference between this embodiment and embodiment 1 is:

[0131] In this example, 5-trifluoromethylbenzotriazole was used to replace 1H-benzotriazole to obtain a 41% yield of the formula 4m and 4m ’ NN cross-coupling products shown:

[0132]

[0133] The present invention conducted NMR verification on the NN cross-coupling products prepared in Example 1 and Example 6 to Example 17, and the NMR data are as follows:

[0134] The data of 4a's H NMR spectrum are as follows: 1 H NMR (600 MHz, CDCl 3 )δ8.04(d,J=6Hz,1H),7.76-7.74(m,2H),7.60-7.56(m,2H),7.42-7.39(m,2H),7.31-7.27(m,2H),4.29(q,J=6.7Hz,2H),1.28(t,J=6Hz,3H).

[0135] The data of the C NMR spectrum of 4a are as follows: 13 C NMR (151 MHz, CDCl 3 )δ170.58,144.57,132.72,131.02,130.92,129.38,128.59,128.34,125.10,120.76,109.15,71.44,13.27.

[0136] The data of 4b's H NMR spectrum are as follows: 1 H NMR (600 MHz, CDCl 3)δ8.06-8.04(m,1H),7.64-7.61(m,2H),7.59-7.55(m,2H),7.45-7.41(m,3H),4.279-4.26(m,2H),1.28(t,J=6Hz,3H).

[0137] The data of 4b's NMR carbon spectrum are as follows: 13 C NMR (151 MHz, CDCl 3 )δ169.64,144.58,131.74,130.96,130.11,129.71,129.57,127.80,125.27,120.90,108.98,71.53,13.27.

[0138] The data of 4c's H NMR spectrum are as follows: 1 H NMR (600 MHz, CDCl 3 )δ8.05(dt,J1=8.3,J2=1Hz,1H),7.74-7.71(m,2H),7.62-7.54(m,2H),7.43-7.3 9(m,1H),7.33-7.30(m,2H),4.30-4.25(m,2H),1.28(q,J=4Hz,12H),1.24(s,9H).

[0139] The data of 4c's NMR carbon spectrum are as follows: 13 C NMR (101MHz, CDCl3) δ170.46,156.66,144.65,131.09,129.30,128.78,127.81,125.38,125.05,120.73,109.35,71.29,34.99,30.90,13.30.

[0140] The data of 4d H NMR spectrum are as follows: 1 H NMR (600 MHz, CDCl 3 )δ8.05-8.03(m,1H),7.74-7.72(m,2H),7.59-7.55(m,2H),7.42-7.40(m,1H),7.32-7.3028(m,2H),6.62( dd,J=17.6,10.9Hz,1H),5.77(d,J=18Hz,1H),5.33(d,J=12Hz,1H),4.31-4.27(m,2H),1.29(t,J=6Hz,3H).

[0141] The data of 4d NMR carbon spectrum are as follows: 13C NMR (151MHz, CDCl3) δ170.25,144.62,141.86,135.54,131.02,129.78,129.40,129.10,126.06,125.13,120.80,116.93,109.17,71.41,13.31.

[0142] The data of H NMR spectrum of 4e are as follows: 1H NMR (400 MHz, CDCl3) δ8.36 (s, 1H), 8.02 (dt, J1=8, J2=1 Hz, 1H), 7.85-7.72 (m, 4H), 7.65 (dt, J1=8, J2=1.0 Hz, 1H), 7.59-7.47 (m, 3H), 7.41-7.37 (m, 1H), 4.38-4.32 (m, 2H), 1.32 (t, J=8 Hz, 3H).

[0143] The data of 4e's NMR carbon spectrum are as follows: 13 C NMR (101 MHz, CDCl 3 )δ170.70,144.62,135.09,132.08,131.08,130.32,129.41,129.15,128.49,1 28.23,128.07,127.67,126.94,125.12,124.23,120.81,109.18,71.51,13.36.

[0144] The data of 4f H NMR spectrum are as follows: 1 H NMR (400 MHz, CDCl 3 )δ8.13-8.11(m,1H),7.61-7.44(m,4H),7.10(dd,J1=3.6,J2=0.8Hz,1H),6 .48(dd,J1=3.6,J2=1.7Hz,1H), 4.33(q,J=7.1Hz,2H), 1.33(q,J=8Hz,3H).

[0145] The data of 4f NMR carbon spectrum are as follows: 13 C NMR (101MHz, CDCl3) δ159.13,147.32,144.64,144.04,131.26,129.38,125.15,120.78,120.65,112.22,109.37,71.82,13.27.

[0146] The data of 4g H NMR spectrum are as follows: 1 H NMR (400 MHz, CDCl 3)δ8.09(dt,J1=8.2,J2=1.0Hz,1H),7.51-7.40(m,2H),7.32-7.20(m,6H),4.15-3.93(m,4H),1.26(t,J=7.1Hz,3H).

[0147] The data of 4g of NMR carbon spectrum are as follows: 13 C NMR (101 MHz, CDCl 3 )δ172.37,144.49,132.57,131.11,129.24,129.22,128.70,127.47,125.05,120.68,109.08,71.73,40.61,13.19.

[0148] The data of 4h H NMR spectrum are as follows: 1 H NMR (400MHz, CDCl3) δ8.12-8.10(m,1H),7.59-7.55(m,1H),7.47-7.43(m,2H) ,4.19(q,J=8Hz,2H),2.64-2.58(m,1H),2.08-1.55(m,7H),1.30-1.24(m,6H).

[0149] The data of 4h NMR carbon spectrum are as follows: 13 C NMR (101 MHz, CDCl 3 )δ177.58,144.65,131.04,129.17,125.04,120.78,109.20,71.73,41.71,29.04,25.47,25.32,13.23.

[0150] The data of 4i's H-NMR spectrum are as follows: 1 H NMR (400 MHz, CDCl 3 )δ8.11(dt,J1=8.0,J2=0.9Hz,1H),7.60-7.56(m,1H),7.50-7.43(m,2H),4.19(q,J=8Hz,2H),2.60(s,2H),1.26(dt,J1=24.0,J2=8.0Hz,6H).

[0151] The data of 4i's NMR carbon spectrum are as follows: 13 C NMR (101 MHz, CDCl 3 )δ175.62,144.56,131.16,129.27,125.08,120.80,109.11,71.72,26.79,13.25,8.38.

[0152] The data of 4j's H NMR spectrum are as follows: 1 H NMR (400 MHz, CDCl 3 )δ8.11(dt,J1=8.4,J2=1Hz,1H),7.61-7.56(m,1H),7.49-7.43(m,2H),5.89-5.79(m,1 H),5.13-5.03(m,2H),4.20(q,J=8.0Hz,2H),2.68-2.45(m,4H),1.30(t,J=8.0Hz,3H).

[0153] The data of 4j's NMR carbon spectrum are as follows: 13 C NMR (101 MHz, CDCl 3 )δ174.01,144.58,136.08,131.12,129.30,125.11,120.82,116.13,109.13,71.78,32.58,28.11,13.25.

[0154] The data of 4k+4k' NMR hydrogen spectrum are as follows: 1 H NMR (400 MHz, CDCl 3 )δ7.93(d),7.78-7.73(m),7.47-7.45(m),7.44-7.37(m),7.34-7.26(m),7.23-7.20(m),4.28(q,J=7Hz,2H),2.52(s,1H minor),2.48(s,2H major),1.28(t,J=8Hz,3H),Major / Minor ratio:1.6:1

[0155] The data of 4k+4k' NMR carbon spectrum are as follows: 13 C NMR (101 MHz, CDCl 3 )δ170.57,170.55,145.21,143.24,140.52,135.34,132.68,132.67,131.46,131.41,130.96,129.43,128 .66,128.57,128.32,128.02,127.30,120.16,119.75,108.61,108.36,77.00,71.37,21.98,21.35,13.29.

[0156] The data of the H NMR spectrum of 4l+4l' are as follows: 1 H NMR (400 MHz, CDCl 3)δ7.85(d),7.76-7.73(m),7.46-7.39(m),7.34-7.27(m),7.20(dd),7.00(dd),6.83(d),4.28(q,J=7.1Hz,2H),3.88(s,1H minor),3.86(s,2H major),1.32-1.26(m,3H),Major / Minor ratio:1.9:1.

[0157] The data of the 4l+4l' NMR carbon spectrum are as follows: 13 C NMR (101 MHz, CDCl 3 )δ170.58,161.54,157.94,145.83,132.73,130.93,130.89,128.63,128.59,128.37,128.35,12 6.24,121.83,121.45,117.12,109.72,99.82,89.65,71.40,71.36,55.99,55.77,13.33,13.30.

[0158] The data of 4m+4m' NMR hydrogen spectrum are as follows: 1 H NMR (400 MHz, CDCl 3 )δ8.38-8.83(m,0.32H,minor),8.20(m,0.63H major),Major / Minor ratio:2.0:1,7.89-7.88(m),7.84-7.79(m),7.72-7.66(m),7.52-7.46(m),4.29(q,J=8Hz,2H),1.26(m,3H).

[0159] The data of carbon NMR spectrum of 4m+4m' are as follows: 13C NMR (101 MHz, CDCl3) δ 170.56, 145.83, 143.89, 133.14, 133.13, 132.59, 131.54 (q, J = 32 Hz), 130.59, 128.84, 128.78, 128.53, 126.8 (q, J = 4 Hz), 122.01 (q, J = 3 Hz), 121.91, 119.10 (q, J = 5 Hz), 110.43, 107.55 (q, J = 6 Hz), 71.76, 71.69, 13.23, 13.20.

[0160] This example refers to the preparation method and reaction conditions of Example 1, and explores the synthesis of NN cross-coupling products using differently substituted N-alkoxyamides and benzotriazole as reaction substrates. The specific conditions are shown in Examples 6 to 17.

[0161] Table 2 Summary of embodiments of the present invention for reaction substrates The present invention expands the scope of reaction substrates. As shown in Table 2, when the benzene ring of the N-alkoxyamide has an electron-withdrawing group or an electron-donating group at the para position, the NN cross-coupling products shown in formulas 4b and 4c can be obtained with a moderate yield; when the benzene ring of the N-alkoxyamide has a vinyl group at the para position, the NN cross-coupling product shown in formula 4d can be obtained with a yield of 69%; when the N-alkoxyamide is N-ethoxy-2-naphthylamide, the NN cross-coupling product shown in formula 4e can be obtained with a yield of 75%, and when the N-alkoxyamide is N-ethoxyfuran-2-carboxamide, the NN cross-coupling product shown in formula 4f can be obtained; when the N-alkoxyamide is an aliphatic amide, the NN cross-coupling products shown in formulas 4g and 4h can also be obtained; when the N-alkoxyamide has an isolated unsaturated bond olefinic group or alkyl group, the NN cross-coupling products shown in formulas 4i and j can also be obtained.

[0162] The present invention does not change the reaction substrate N-ethoxybenzamide, but allows N-ethoxybenzamide to react with monosubstituted benzotriazole, so that the N center of the product is no longer symmetrical; when N-ethoxybenzamide reacts with 5-methylbenzotriazole, an isomer mixture of formula 4k and formula 4k' is obtained; when N-ethoxybenzamide reacts with 5-methoxybenzotriazole, an isomer mixture of formula 4l and formula 4l' is obtained; when N-ethoxybenzamide reacts with 5-trifluoromethylbenzotriazole, an isomer mixture of formula 4m and formula 4m' is obtained.

[0163] It should be noted that when the present invention involves a numerical range, it should be understood that the two endpoints of each numerical range and any value between the two endpoints can be selected. Since the steps and methods used are the same as those in the embodiments, in order to avoid redundancy, the present invention describes a preferred embodiment. Although the preferred embodiments of the present invention have been described, once those skilled in the art know the basic creative concept, they can make additional changes and modifications to these embodiments, and these changes and modifications all fall within the scope of the present invention.

[0164] Obviously, those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. If these modifications and variations of the present invention fall within the scope of the equivalent technology of the present invention, the present invention is also intended to include these modifications and variations.

Claims

1. A method for synthesizing a NN cross-coupling product, characterized in that: The following steps are involved: Using N-alkoxyamide shown in Formula 1 and benzotriazole shown in Formula 3 as reaction substrates and diacetate iodobenzene as an initiator, N-alkoxyamide, benzotriazole and diacetate iodobenzene are mixed as solid reactants, and under stirring, the molecules of the solid reactants collide to promote the dehydrogenation coupling reaction of the N-N bond, thereby obtaining the N-N cross-coupling product shown in Formula 4; The specific reaction formula is as follows: Among them, R 1 is one of phenyl, substituted phenyl, furyl, naphthyl, cyclohexyl, alkyl having 1 to 6 carbon atoms and alkenyl having 1 to 5 carbon atoms; R 1 The substituent of the substituted phenyl group is one of halogen, alkyl having 1 to 4 carbon atoms and alkenyl having 1 to 8 carbon atoms; R 3 It is one of H, methyl, methoxy and trifluoromethyl.

2. The method for synthesizing NN cross-coupling products according to claim 1, characterized in that: R 1 The substituent of the substituted phenyl group is one of a bromine atom, a methyl group, a tert-butyl group and a vinyl group.

3. The method for synthesizing NN cross-coupling products according to claim 1, characterized in that: R 1 The substituted phenyl group is a para-substituted phenyl group.

4. The method for synthesizing NN cross-coupling products according to claim 1, characterized in that: The N-alkoxyamide is one of 4-bromo-N-ethoxybenzamide, 4-tert-butyl-N-ethoxybenzamide, N-ethoxy-4-vinylbenzamide, N-ethoxy-2-naphthylamide, N-ethoxyfuran-2-carboxamide, N-ethoxy-2-phenylacetamide, N-ethoxycyclohexanecarboxamide, N-ethoxypentenamide and N-alkoxyalkylamide.

5. The method for synthesizing NN cross-coupling products according to claim 1, characterized in that: The benzotriazole is one of 1H-benzotriazole, 5-methylbenzotriazole and 5-trifluoromethylbenzotriazole.

6. The method for synthesizing NN cross-coupling products according to claim 1, characterized in that: The molar ratio of the N-alkoxyamide, benzotriazole and iodobenzene diacetate is 1:1-2:0.035-0.

1.

7. The method for synthesizing NN cross-coupling products according to claim 1, characterized in that: The stirring time is 1 h to 6 h, and the temperature is room temperature.

Images