A method for preparing alkynylamide compounds

Abstract

The present invention discloses a method for efficiently preparing alkynylamide compounds, which comprises using terminal alkyne 1 and secondary amide 2 with an acyl group (EWG) as raw materials, adding a copper reagent, a ligand, a base, introducing oxygen, and reacting for a period of time under normal temperature conditions to obtain alkynylamide compounds with the characteristics of compound 3, and the reaction formula is (1). The raw materials of this method are cheap and easily available, the steps are simple, the conditions are mild, the use of high-temperature heating and environmentally unfriendly reagents is avoided, and large-scale synthesis can be achieved, with broad application prospects.

Description

Technical Field

[0001] The present invention relates to the field of organic synthesis, in particular to a method for preparing alkyne amide compounds. Background Art

[0002] Alkynamides are compounds in which a nitrogen atom is directly linked to a carbon-carbon triple bond. Due to their unique structure, alkynamides play a crucial role in organic synthesis and are used by numerous research groups in the synthesis of heterocycles. In recent years, they have also been used as coupling agents for peptide compounds, demonstrating their excellent racemization inhibition. Consequently, alkynamides have become important raw materials and reagents in organic synthesis, and their synthesis methods have garnered significant attention. In 1972, Viehe et al. achieved the first synthesis of alkynamides via an elimination reaction. They reacted an amide with an iminium salt to form chloroformamidine hydrochloride, which was then hydrolyzed in aqueous sodium bicarbonate to form an enamide. Finally, t-BuOK was added to undergo an elimination reaction to yield the alkynamide. However, this method is complex and has a limited substrate range (Angew. Chem. Int. Ed. 1972, 11, 917). Rainier et al. used an aziridine reagent to open the ring under the nucleophilic action of alkynyl lithium, followed by reaction with a high-valent iodine salt to produce an alkynamide. This method can synthesize alkynamides containing alkynyl groups, but the substrates are not universal, the yield is not high, and the iodine salt is unstable (J. Org. Chem. 2000, 65, 7272). In 2003, Danheiser et al. used CuI to mediate the direct coupling of amides and alkynyl bromides to synthesize alkynamides. This reaction has the advantages of mild reaction conditions, but requires a chemically equivalent amount of copper reagent, the alkynyl bromide is difficult to prepare, and has a tear-inducing effect (Org. Lett. 2003, 5, 4011). In 2004, Hsung et al. used amides and alkynyl bromides as raw materials, K3PO4 as a base, CuSO4 as a catalyst, and o-phenanthroline as a ligand. The reaction was conducted under toluene reflux, resulting in the efficient preparation of alkynamides. However, this method is not applicable to some simple alkynamides (J. Org. Chem. 2006, 71, 4170). In summary, the existing methods for synthesizing alkynamides all have significant limitations, such as a narrow substrate application range or the need to use a large amount of volatile, flammable, and environmentally unfriendly halogenated reagents, which are basically not suitable for large-scale synthesis. Therefore, developing a process for synthesizing alkynamides with simple steps, mild conditions, and high universality has important practical significance for the application of alkynamides in fine chemicals, pharmaceutical industry, and material synthesis. To this end, we have developed a more gentle and simple method for preparing alkynamides, which uses cheap and readily available raw materials and is easy to synthesize in large quantities. Summary of the Invention

[0003] The present invention aims to provide a method for preparing acetylene amide compounds in large quantities using terminal alkynes and secondary amides as raw materials, which does not require the use of expensive catalysts or ligands, has mild conditions, readily available raw materials, and is efficient.

[0004] A method for synthesizing alkynylamide compounds uses terminal alkyne 1 and secondary amide 2 with an acyl group (EWG) as raw materials. Under the conditions of a copper reagent, a ligand, a base, and an oxygen atmosphere, after reacting at room temperature for a period of time, alkynylamide compounds with the characteristics of compound 3 are obtained. The reaction formula is as follows:

[0005]

[0006] Among them, in the formula, 1 represents a terminal alkyne, 2 represents a secondary amide with an acyl group (EWG), and 3 represents an alkynylamide compound: EWG represents an acyl group, R 1 represents an aryl group, a linear alkyl group, or a cyclic alkyl group, and R 2 represents an alkyl group or an aryl group.

[0007] The steps of the above synthesis method are as follows: In a clean and anhydrous reaction flask, add a secondary amide with an acyl group (EWG), a copper reagent, a ligand, a base, and a molecular sieve. Inject a solvent, evacuate and replace the gas, pass oxygen, slowly add compound 1, and stir at room temperature until compound 1 is completely consumed; then filter the reaction mixture, wash the filter residue, concentrate the filtrate, and the residue is separated by column chromatography or recrystallized to obtain alkynylamide compound 3.

[0008] In the above synthesis method, compound 1 is a terminal alkyne with a hydrogen atom at one end of the alkynyl group and a substituent R 1 where R 1 is a linear alkyl group with 1 to 10 carbons, a cyclic alkyl group with 3 to 10 carbons, a heterocyclic group, or an unsubstituted or substituted aryl group); compound 2 is a secondary amide with an acyl group, where EWG is a sulfonyl group -SO2R or a carbonyl group -COR, and R is a linear alkyl group with 1 to 10 carbons, a cyclic alkyl group with 3 to 10 carbons, a heterocyclic group, or an unsubstituted or substituted aryl group.

[0009] In some embodiments, the molar ratio of compound 1 to compound 2 is 1:0.5 to 1:10. In some embodiments, the molar ratio of compound 1 to compound 2 is 1:1 to 1:5.

[0010] In some embodiments, the molar ratio of compound 1 to the copper reagent is 1:1% to 1:100%. In some embodiments, the molar ratio of compound 1 to the copper reagent is 1:10% to 1:30%;

[0011] In some embodiments, the copper reagent is selected from one or more of CuCl2, CuCl2·2H2O, Cu(OTf)2, CuSO4, CuBr2, Cu(NO3)2, (AcO)2Cu, CuCl, CuBr, CuI, and copper acetylacetonate. In some embodiments, the copper reagent is selected from one or more of Cu(NO3)2, CuCl2, CuCl2·2H2O, and Cu(OTf)2.

[0012] In some embodiments, the molar ratio of Compound 1 to the ligand is 1:1% to 1:100%. In some embodiments, the molar ratio of Compound 1 to the ligand is 1:10% to 1:50%. The ligand is selected from one or more of N,N'-dimethyl ethylenediamine, benzimidazole, 1-methylbenzimidazole, 1,3-disubstituted imidazolium salts, 2,6-dimethylpyridine, pyridine, 1,2-dimethylimidazole, DBU, or morpholine. In some embodiments, the ligand is selected from one or more of 1-methylbenzimidazole, 1,2-dimethylimidazole, DBU, or morpholine.

[0013] In some embodiments, the molar ratio of Compound 1 to the base is 1:0.1 to 1:10. In some embodiments, the molar ratio of Compound 1 to the base is 1:0.2 to 1:3. The base is selected from one or more of K2CO3, Na2CO3, Li2CO3, Cs2CO3, AcONa, K3PO4, Na3PO4, Na2HPO4, K2HPO4, NaOH, LiOH, KOH, alkoxides, sodium hydride, calcium hydride, triethylamine, or DIPEA. In some embodiments, the base is selected from one or more of K2CO3, Na2CO3, Li2CO3, Na2HPO4, or K2HPO4.

[0014] In some embodiments, the solvent is selected from one or more of dichloromethane, acetonitrile, tert-butyl methyl ether, dichloroethane, tetrahydrofuran, ethyl acetate, acetone, toluene, DMF, DMA, or DMSO.

[0015] In the above synthesis method, the reaction temperature is 0 to 100 °C, and 20 to 40 °C is optimal.

[0016] In the above synthesis method, the reaction time is 2 h to 40 h, and 4 h to 24 h is optimal.

[0017] In the above synthesis method, the oxygen source can be pure oxygen, air, and oxygen-containing gas mixtures with an oxygen content greater than 20%, and pure oxygen is optimal.

[0018] In the above synthesis method, the molecular sieve specification is

[0019] This synthetic method uses readily available terminal alkynes and secondary amides as raw materials, does not require the use of expensive catalysts or ligands, has simple operations, and the raw materials are cheap and easy to obtain. It synthesizes alkynamide compounds in high yields under mild reaction conditions and has broad application prospects. Detailed implementation methods

[0020] The following further illustrates the present invention in combination with Examples 1 to 10, but does not limit the present invention.

[0021] Ts: p-toluenesulfonic acid, EA: ethyl acetate, Tol: toluene

[0022] Example 1:

[0023]

[0024] Add N-methyl-p-toluenesulfonamide (15.0 mmol), copper trifluoromethanesulfonate (1.0 mmol), Na2CO3 (15.0 mmol), 1-methylbenzimidazole (2.0 mmol) and molecular sieve (1.8 g) into a clean and anhydrous reaction flask, inject toluene (20 mL), pass oxygen, then add phenylacetylene (5.0 mmol), stir at room temperature for 20 h, and detect by TLC plate; then filter the reaction mixture, wash the filter residue with ethyl acetate, concentrate the filtrate, and separate the residue by column chromatography to obtain 1.2 g of white solid, with a yield of 83%.

[0025] Product characterization: 1 H NMR (600 MHz, CDCl3) δ 7.83 (d, J = 8.22 Hz, 2H), 7.35 (d, J = 8.16 Hz, 4H), 7.31–7.23 (m, 3H), 3.13 (s, 3H), 2.44 (s, 3H). 13 C NMR (150 MHz, CDCl3) δ 145.0, 144.2, 133.2, 131.5, 130.0, 128.4, 128.0, 127.9, 122.7, 84.0, 69.0, 39.4, 21.7; HRMS (ESI) C 16 H 15 NO2SNa [M+Na] + : 308.0712.

[0026] Example 2:

[0027]

[0028] In a clean and anhydrous reaction flask, add N-methyl-p-toluenesulfonamide (15.0 mmol), copper trifluoromethanesulfonate (1.0 mmol), Na2CO3 (15.0 mmol), 1-methylbenzimidazole (2.0 mmol) and molecular sieve (1.8 g). Inject dichloromethane (20 mL), pass oxygen, then add trimethylsilylacetylene (5.0 mmol), stir at room temperature for 20 h, and detect by TLC plate spotting; then filter the reaction mixture, wash the residue with ethyl acetate, concentrate the filtrate, and separate the residue by column chromatography to obtain 0.8 g of white solid with a yield of 59%.

[0029] Product characterization: 1 H NMR(600MHz,CDCl3)δ7.63(d,J=8.22Hz,2H),7.21(d,J=8.22Hz,2H),2.89(s,3H),2.31(s,3H),0.00(s,9H). 13 C NMR(150MHz,CDCl3)δ144.7,133.0,129.6,127.8,96.6,71.2,39.0,21.6,0.0;HRMS(ESI)C 13 H 19 NO2SSiNa[M+Na] + :304.0795.

[0030] Example 3:

[0031]

[0032] In a clean and anhydrous reaction flask, add 2-oxazolidinone (1.5 mmol), copper trifluoromethanesulfonate (0.1 mmol), Na2CO3 (1.5 mmol), 1-methylbenzimidazole (0.2 mmol) and molecular sieve (180 mg). Inject dichloromethane (2 mL), pass oxygen, then add trimethylsilylacetylene (0.5 mmol), stir at room temperature for 20 h, and detect by TLC plate spotting; then filter the reaction mixture, wash the residue with ethyl acetate, concentrate the filtrate, and separate the residue by column chromatography to obtain a white solid with a yield of 84%.

[0033] Product characterization: 1 H NMR(600MHz,CDCl3)δ4.23(t,J=7.99Hz,2H),3.73(t,J=7.99Hz,2H),0.00(s,9H). 13 C NMR(150MHz,CDCl3)δ155.8,91.3,73.7,62.9,46.8,0.0;HRMS(ESI)C8H 14 NO2[M+H] +:184.0791.

[0034] Example 4:

[0035]

[0036] Add N-methylmethanesulfonamide (18.0 mmol), copper (I) trifluoromethanesulfonate (1.2 mmol), Na2CO3 (18.0 mmol), 1-methylbenzimidazole (2.4 mmol) and molecular sieve (2.2 g) into a clean and anhydrous reaction flask, inject dichloromethane (24 mL), pass oxygen, then add trimethylsilylacetylene (6.0 mmol), stir at room temperature for 20 h, and detect by TLC plate; then filter the reaction mixture, wash the residue with ethyl acetate, concentrate the filtrate, and separate the residue by column chromatography to obtain 1.1 g of white solid with a yield of 88%.

[0037] Product characterization: 1 H NMR (600 MHz, CDCl3) δ 3.17 (d, J = 2.10 Hz, 3H), 3.04 (d, J = 2.10 Hz, 3H), 0.15 (s, 9H). 13 C NMR (150 MHz, CDCl3) δ 95.6, 71.8, 38.9, 36.5, 0.0; HRMS (ESI) C7H 15 NO2SSiNa [M+Na] + :228.0483.

[0038] Example 5:

[0039]

[0040] Add N-methyl-p-toluenesulfonamide (1.5 mmol), copper (I) trifluoromethanesulfonate (0.1 mmol), Na2CO3 (1.5 mmol), 1-methylbenzimidazole (0.2 mmol) and molecular sieve (180 mg) into a clean and anhydrous reaction flask, inject dichloromethane (2 mL), pass oxygen, then add cyclopropylacetylene (0.5 mmol), stir at room temperature for 20 h, and detect by TLC plate; then filter the reaction mixture, wash the residue with ethyl acetate, concentrate the filtrate, and separate the residue by column chromatography to obtain white solid with a yield of 75%.

[0041] Product characterization: 1 H NMR (600 MHz, CDCl3) δ 7.68 (d, J = 8.28 Hz, 2H), 7.28 (d, J = 8.28 Hz, 2H), 2.91 (s, 3H), 2.37 (s, 3H), 1.19 (m, 1H), 0.69 (m, 2H), 0.54 (m, 2H). 13C NMR(150MHz, CDCl3)δ145.4,134.0,130.5,128.6,73.8,71.3,40.2,22.5,9.6,0.0; HRMS(ESI)C 13 H 15 NO2SNa[M+Na] + :272.0721.

[0042] Embodiment 6:

[0043]

[0044] 2-oxazolidinone (1.5 mmol), copper trifluoromethanesulfonate (0.1 mmol), Na2CO3 (1.5 mmol), 1-methylbenzimidazole (0.2 mmol) and molecular sieves (180 mg) were added to a clean, anhydrous reaction flask. Dichloromethane (2 mL) was injected, oxygen was passed through, and 1-heptyne (0.5 mmol) was added. The mixture was stirred at room temperature for 20 h and detected by TLC spot plate. The reaction mixture was then filtered, the filter residue was washed with ethyl acetate, the filtrate was concentrated, and the residue was separated by column chromatography to obtain a white solid in a yield of 51%.

[0045] Product characterization: 1 H NMR (600MHz, CDCl3) δ4.35(t,J=7.98Hz,2H),3.81(t,J=7.98Hz,2H),2.23(t,J=7.20Hz,2H),1.46(m,2H),1.33-1.21(m,4H),0.83(t,J=7.14Hz,3H). 13 CNMR(150MHz, CDCl3)δ155.7,70.2,69.0,61.9,46.1,30.0,27.5,21.2,17.3,13.0; HRMS(ESI)C 10 H 16 NO2[M+H] + :182.1182.

[0046] Example 7:

[0047]

[0048] In a clean and anhydrous reaction flask, add N-methyl-p-toluenesulfonamide (1.5 mmol), copper trifluoromethanesulfonate (0.1 mmol), Na2CO3 (1.5 mmol), 1-methylbenzimidazole (0.2 mmol) and molecular sieve (180 mg), inject toluene (2 mL), pass oxygen, then add 4-ethynylanisole (0.5 mmol), stir at room temperature for 20 h, and detect by TLC plate; then filter the reaction mixture, wash the residue with ethyl acetate, concentrate the filtrate, and separate the residue by column chromatography to obtain a white solid with a yield of 93%.

[0049] Product characterization: 1 1H NMR (600 MHz, CDCl3) δ 7.82 (d, J = 8.16 Hz, 2H), 7.36 (d, J = 8.16 Hz, 2H), 7.30 (d, J = 8.70 Hz, 2H), 6.81 (d, J = 8.70 Hz, 2H), 3.78 (s, 3H), 3.12 (s, 3H), 2.44 (s, 3H). 13 13C NMR (150 MHz, CDCl3) δ 159.6, 144.9, 133.5, 133.2, 129.9, 127.9, 114.6, 114.0, 82.6, 68.7, 55.3, 39.5, 21.7; HRMS (ESI) C 17 H 17 NO3SNa [M+Na] + : 308.0804.

[0050] Example 8:

[0051]

[0052] In a clean and anhydrous reaction flask, add 2-azetidinone (1.5 mmol), copper trifluoromethanesulfonate (0.1 mmol), Na2CO3 (1.5 mmol), 1-methylbenzimidazole (0.2 mmol) and molecular sieve (180 mg), inject toluene (2 mL), pass oxygen, then add phenylacetylene (0.5 mmol), stir at room temperature for 20 h, and detect by TLC plate; then filter the reaction mixture, wash the residue with ethyl acetate, concentrate the filtrate, and separate the residue by column chromatography to obtain a white solid with a yield of 85%.

[0053] Product characterization: 1 1H NMR (600 MHz, CDCl3) δ 7.41 (dd, J = 7.17, 3.66 Hz, 2H), 7.33–7.26 (m, 3H), 3.67 (t, J = 4.83 Hz, 2H), 3.06 (t, J = 4.83 Hz, 2H). 1313C NMR (150 MHz, CDCl3) δ 166.8, 131.5, 128.4, 128.2, 122.2, 78.9, 69.9, 43.2, 38.0; HRMS (ESI) C 11 H 10 NO[M + H] + : 172.0762.

[0054] Example 9:

[0055]

[0056] Add N-methyl-p-toluenesulfonamide (1.5 mmol), copper (I) trifluoromethanesulfonate (0.1 mmol), Na2CO3 (1.5 mmol), 1-methylbenzimidazole (0.2 mmol) and molecular sieve (180 mg) into a clean and anhydrous reaction flask, inject toluene (2 mL), purge with oxygen, then add 4-ethynyl-α,α,α-trifluorotoluene (0.5 mmol), stir at room temperature for 20 h, and monitor by TLC; then filter the reaction mixture, wash the residue with ethyl acetate, concentrate the filtrate, and separate the residue by column chromatography to obtain a white solid with a yield of 90%.

[0057] Product characterization: 1 1H NMR (600 MHz, CDCl3) δ 7.73 (d, J = 8.28 Hz, 2H), 7.42 (d, J = 8.28 Hz, 2H), 7.33 (d, J = 8.22 Hz, 2H), 7.27 (d, J = 8.22 Hz, 2H), 3.07 (s, 3H), 2.35 (s, 3H). 13 13C NMR (150 MHz, CDCl3) δ 145.2, 133.2, 131.1, 130.0, 129.6, 129.3, 129.1, 129.0, 127.8, 126.8, 125.3, 125.2, 125.1, 125.0, 123.1, 86.6, 68.4, 39.2; HRMS (ESI) C 18 H 19 F3NO3S[M + H + MeOH] + : 386.1032.

[0058] Example 10:

[0059]

[0060] In a clean and anhydrous reaction flask, add (S)-4-benzyl-2-oxazolidinone (1.5 mmol), copper trifluoromethanesulfonate (0.1 mmol), Na2CO3 (1.5 mmol), 1-methylbenzimidazole (0.2 mmol) and molecular sieve (180 mg). Inject dichloromethane (2 mL), introduce oxygen, then add 4-ethynylanisole (0.5 mmol), stir at room temperature for 20 h, and detect by TLC plate spotting; then filter the reaction mixture, wash the residue with ethyl acetate, concentrate the filtrate, and separate the residue by column chromatography to obtain a white solid with a yield of 94%.

[0061] Product characterization: 1 1H NMR (600 MHz, CDCl3) δ 7.40 (d, J = 8.70 Hz, 2H), 7.31 (t, J = 7.32, 7.37 Hz, 2H), 7.26 (t, J = 7.32 Hz, 1H), 7.21 (d, J = 7.37 Hz, 2H), 6.83 (d, J = 8.70 Hz, 2H), 4.33 - 4.27 (m, 2H), 4.13 - 4.07 (m, 1H), 3.77 (s, 3H), 3.21 (dd, J = 14.01, 3.26 Hz, 1H), 2.97 (dd, J = 14.80, 7.32 Hz, 1H). 13 13C NMR (150 MHz, CDCl3) δ 159.8, 155.8, 134.4, 133.6, 129.5, 129.0, 127.5, 114.2, 114.0, 76.8, 73.0, 67.5, 58.5, 55.4, 37.9; HRMS (ESI) C 19 H 18 NO3 [M + H] + : 308.1281.

[0062] The above is an example of the reagents and reagent dosages for the synthesis of alkynylamides. Using other copper reagents, ligands, bases, and solvents in the claims can also obtain the corresponding alkynylamide products with different yields. The following uses the alkynylamide product of Example 1 to illustrate these conditions, but it is not a limitation of the present invention.

[0063]

[0064] Feeding: phenylacetylene (0.5 mmol), N-methyl-p-toluenesulfonamide (1.5 mmol), copper reagent (0.1 mmol), ligand (0.25 mmol), base (1.5 mmol), molecular sieve (160 mg), O2 (1 atm), solvent (0.25 M), stir at room temperature for 24 hours.

[0065]

[0066]

[0067] From the perspective of Example 1, the role of molecular sieve in the CDC reaction of copper-catalyzed N-methyl-p-toluenesulfonamide 2a and phenylacetylene 1a was investigated, but it is not a limitation to the present invention. It was found that the molecular sieve is indispensable in this reaction. The effect of the molecular sieve is the best; removing the molecular sieve under standard conditions, the reaction does not occur; the reaction also does not occur when anhydrous magnesium sulfate or anhydrous silica gel is used to replace the molecular sieve; however, if a small amount of water is added to the reaction or the molecular sieve that has not been dried anhydrously is used, the reaction yield will be reduced. Based on this, it is judged that the role of the molecular sieve in the reaction is as a water absorbent and to promote surface catalytic oxidation, that is, the key catalytic oxidation process of the reaction occurs on the surface of the molecular sieve.

[0068] The method of the present invention has been described through preferred embodiments. It is obvious that relevant personnel can make changes or appropriate modifications and combinations to the methods and applications described herein within the content, spirit and scope of the present invention to implement and apply the technology of the present invention. Those skilled in the art can draw on the content of this article and appropriately improve the process parameters to achieve it. It should be particularly pointed out that all similar substitutions and modifications are obvious to those skilled in the art, and they are all regarded as included in the present invention.

Claims

1. A method for preparing alkynylamide compounds, which comprises using terminal alkyne 1 and secondary amide 2 as raw materials. Add secondary amide 2, copper reagent, ligand, base and molecular sieve into a reaction vessel, inject a solvent, introduce oxygen, slowly add compound 1, and stir at room temperature until the reaction of compound 1 is completed; after treatment, alkynylamide compound 3 is obtained: ； Among them, In formula 2, EWG represents an acyl group, and R 1 is selected from straight-chain alkyl groups having 1 to 10 carbon atoms, cycloalkyl groups having 3 to 10 carbon atoms, unsubstituted or substituted aryl groups, and R 2 is selected from alkyl groups; The copper reagent is selected from one or more of CuCl2, CuCl2·2H2O, Cu(OTf)2, CuSO4, CuBr2, Cu(NO3)2, (AcO)2Cu, CuCl, CuBr, CuI, copper acetylacetonate; The ligand is N , N' -dimethyl ethylenediamine, benzimidazole, 1-methylbenzimidazole, 1,3-disubstituted imidazolium salt, 2,6-dimethylpyridine, pyridine, 1,2-dimethylimidazole, DBU, morpholine, or one or more thereof; The base is selected from one or more of K2CO3, Na2CO3, Li2CO3, Cs2CO3, AcONa, K3PO4, Na3PO4, Na2HPO4, K2HPO4, NaOH, LiOH, KOH, alkoxide, sodium hydride, calcium hydride, triethylamine, DIPEA; The solvent is selected from one or more of dichloromethane, acetonitrile, tert-butyl methyl ether, dichloroethane, tetrahydrofuran, ethyl acetate, acetone, toluene, DMF, DMA or DMSO; Where EWG is a sulfonyl group -SO2R or a carbonyl group -COR, where R = a linear alkyl group with 1 to 10 carbons, a cycloalkyl group with 3 to 10 carbons, an unsubstituted or substituted aryl group.

2. The method for preparing alkynamide compounds according to claim 1, wherein The molar ratio of compound 1 to the copper reagent used is 1:1% to 1:100%.

3. The method for preparing alkynylamide compounds according to claim 2, wherein The molar ratio of compound 1 to the copper reagent used is 1:10% to 1:30%.

4. The method for preparing alkynamide compounds according to claim 1, wherein The copper reagent is selected from Cu(NO3)2, CuCl2, CuCl2·2H2O, Cu(OTf)2, and the molar ratio of compound 1 to compound 2 is 1:0.5 to 1:

10.

5. The method for preparing alkynamide compounds according to claim 4, characterized in that, The molar ratio of compound 1 to compound 2 is 1:1 to 1:

5.

6. The method for preparing alkynylamide compounds according to claim 1, wherein The molar ratio of compound 1 to the ligand is 1:10% to 1:50%.

7. The method for preparing alkynamide compounds according to claim 1, wherein The ligand is 1-methylbenzimidazole, 1,2-dimethylimidazole, DBU, morpholine.

8. The method for preparing alkynamide compounds according to claim 1, wherein The molar ratio of compound 1 to the base is 1:0.1 to 1:

10.

9. The method for preparing alkynamide compounds according to claim 8, wherein The molar ratio of compound 1 to the base is 1:0.2 to 1:

3.

10. The method for preparing alkynamide compounds according to claim 1, wherein The base is selected from K2CO3, Na2CO3, Li2CO3, Na2HPO4 or K2HPO4.

11. The method for preparing alkynylamide compounds according to claim 1, wherein The solvent is selected from one or more of dichloromethane, acetonitrile, tert-butyl methyl ether, toluene, tetrahydrofuran.

12. The method for preparing alkynamide compounds according to claim 1, wherein The reaction time is 2 h to 40 h.

13. The method for preparing alkynylamide compounds according to claim 1, wherein The oxygen source can be pure oxygen, air, and an oxygen-containing gas mixture with an oxygen content greater than 20%.

14. The method for preparing alkynamide compounds according to claim 1, wherein, The molecular sieve specifications are .

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