Process for the preparation of all-carbon quaternary carbon center derivatives by radical initiated cross-coupling of olefins with alkynes

Abstract

The application discloses a method for preparing a full-carbon quaternary carbon center derivative through radical-initiated olefin and alkyne cross-coupling, which overcomes the problem that a tertiary carbon radical generated in situ has a large steric hindrance and is difficult to react with a cross-coupling reagent to construct a full-carbon quaternary carbon center by using the guiding effect of a guiding group. The method uses 1,1-disubstituted electron-deficient olefin, O-(tert-butyloxycarbonyl) cyclobutanone oxime compound and terminal alkyne as raw materials, and reacts at room temperature under the presence of a catalyst, a base and a solvent in an inert atmosphere. After the reaction is completed, N-(pyridine-2-yl)-6-cyano-2-aryl-2-alkynyl hexanamide derivatives are obtained through separation and purification. The method has good substrate adaptability and simple operation advantages.

Description

Technical Field

[0001] This invention relates to a method for cross-coupling of free radical-induced 1,1-disubstituted electron-deficient alkenes and alkynes to synthesize derivatives containing all-carbon quaternary carbon centers, belonging to the field of organic synthesis technology. Background Technology

[0002] Full-carbon and quaternary carbon centers are common structural frameworks in organic synthesis, frequently found in natural products, pharmaceuticals, and bioactive molecules. They are important structural units in these molecules; for example, by 2011, 12% of the top 200 prescription drugs sold in the United States contained full-carbon and quaternary carbon centers (Nature, 2014, 516, 181-191). However, due to the complex structure of compounds containing full-carbon and quaternary carbon centers, constructing these stereocenters in a catalytic and enantioselective manner remains a significant challenge. In recent years, the bifunctionalization of alkenes has been established as an excellent strategy for constructing full-carbon and quaternary carbon centers, as it can form two new C-C bonds in a single reaction. However, most full-carbon and quaternary carbon centers are constructed by hydrogenating and alkylating alkenes to C(sp...) 3 )-C(sp 3 These reactions primarily occur between the two components, typically utilizing transition metals as π-acid catalysts to activate the double bond, thereby enabling the activation of sp bonds. 2 Carbon undergoes nucleophilic attack to form alkyl metal intermediates to construct all-carbon quaternary carbon centers (Beilstein J. Org. Chem. 2021, 17, 1–10). In addition, there are also cases where polysubstituted alkenes undergo migration insertion or in-situ generation of tertiary carbon radicals, which are then captured by a nucleophile or electrophile to construct all-carbon quaternary carbon centers. The latter type primarily occurs during intramolecular cyclization (Angew. Chem. Int. Ed. 2020, 59, 2769–2775).

[0003] There are many studies on constructing all-carbon quaternary carbon centers through bifunctionalization of two-component alkenes, but very few studies on three-component alkenes (J.Am.Chem.Soc.2019,141,1887-1892). Among these, studies on constructing all-carbon quaternary carbon centers by radical-initiated bifunctionalization of alkenes to generate tertiary carbon radicals in situ to capture nucleophiles are even fewer, especially those using common unsaturated hydrocarbons. Summary of the Invention

[0004] This invention provides a method for radical-initiated cross-coupling of 1,1-disubstituted electron-deficient alkenes and alkynes to synthesize derivatives containing a full-carbon quaternary carbon center, namely, the synthesis of N-(pyridin-2-yl)-6-cyano-2-aryl-2-ynylhexylamide derivatives. The method of this invention has broad substrate adaptability, mild conditions, and is suitable for large-scale synthesis. The reaction formula is as follows:

[0005]

[0006] The position of the substituents on the aromatic ring is not fixed, and there are one or more substituents on the aromatic ring.

[0007] R 1 Selected from alkyl and aryl groups, preferably methyl, phenyl, methyl-substituted phenyl, or halophenyl;

[0008] R 2 Selected from hydrogen, alkyl, aryl, preferably hydrogen, chlorophenyl, or benzyl;

[0009] R 3 It is selected from alkyl, aryl, preferably phenyl, heteroaryl, haloaryl, cyano-substituted phenyl, ester-substituted phenyl, methyl-substituted phenyl, ethyl-substituted phenyl, n-butyl-substituted phenyl, trifluoromethyl-substituted phenyl, and thiophene.

[0010] The specific steps of the method of the present invention are as follows:

[0011] (1) 1,1-disubstituted electron-deficient olefin, O-(tert-butoxycarbonyl)cyclobutanone oxime compound, terminal alkyne, catalyst, base and solvent were added to the reactor and reacted at room temperature and under an inert atmosphere for 12 hours to generate a mixed product.

[0012] The molar ratio of the 1,1-disubstituted electron-deficient olefin to the O-(tert-butoxycarbonyl)cyclobutanone oxime compound is 1:1-5; the molar ratio of the 1,1-disubstituted electron-deficient olefin to the terminal alkyne is 1:1-4.

[0013] The solvent is selected from acetonitrile, dichloromethane, N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, and N-methylpyrrolidone; the catalyst is selected from copper acetate, copper trifluoromethanesulfonate, copper sulfate, copper isobutyrate, cuprous thiocyanate, cuprous chloride, copper fluoride, copper trifluoroacetylacetonate, copper bromide, copper carbonate, and cuprous thiophene-2-carboxylate, with the catalyst addition amount being 15-30% of the molar amount of the 1,1-disubstituted electron-deficient olefin; the base is selected from potassium tert-butoxide, lithium tert-butoxide, cesium carbonate, potassium dihydrogen phosphate, sodium bicarbonate, sodium carbonate, sodium hydroxide, and triethylamine.

[0014] (2) The mixed product was concentrated under reduced pressure to obtain a crude product, and the crude product was purified by column chromatography to obtain N-(pyridin-2-yl)-6-cyano-2-aryl-2-ynylhexylamide derivative.

[0015] Compared with the prior art, the present invention has the following advantages:

[0016] Using O-(tert-butyloxycarbonyl)cyclobutanone oxime as a radical source, cyanoalkyl radicals are generated under copper catalysis. These cyanoalkyl radicals initiate bifunctionalization of olefins, leading to the in-situ generation of tertiary carbon radicals. The pyridinyl group in the 1,1-disubstituted electron-deficient olefin can coordinate with copper to form a relatively stable copper coordination compound intermediate with the tertiary carbon radical, thus efficiently coupling with a nucleophile to successfully construct a full-carbon quaternary carbon center. This allows for radical-induced cross-coupling of 1,1-disubstituted electron-deficient olefins containing directing groups with alkynes to form compounds containing a full-carbon quaternary carbon center. The method of this invention exhibits good substrate adaptability. Furthermore, the groups contained in the compounds of this invention can undergo corresponding transformations under certain conditions.

[0017] Detailed Implementation

[0018] The present invention will be further described in detail below with reference to the embodiments, but the scope of protection of the present invention is not limited to the content described.

[0019] Example 1: The synthesis of N-(pyridin-2-yl)-6-cyano-2-phenyl-2-(phenylethynyl)hexamamide (4aa) is as follows:

[0020] 0.2 mmol of 1,1-disubstituted electron-deficient olefin (1a), 0.6 mmol of O-(tert-butyloxycarbonyl)cyclobutanone oxime (2a), 0.4 mmol of phenylacetylene (3a), 0.04 mmol of CuTc, 0.4 mmol of KH2PO4, 2 mL of acetonitrile and dichloromethane (1:1) were added sequentially to a 25 mL Young's tube. The mixture was stirred at room temperature under an argon atmosphere for 12 hours to generate a mixed product.

[0021] The mixed products were concentrated under reduced pressure at 40°C to obtain a crude product. The crude product was passed through a silica gel column (200-300 mesh silica gel) and eluented with a mixture of ethyl acetate and petroleum ether (1:8). The eluent was collected and dried over Na2SO4 to obtain 48 mg of N-(pyridin-2-yl)-6-cyano-2-phenyl-2-(phenylethynyl)hexamethyleneamide (4aa), with a yield of 62%. The reaction equation is as follows:

[0022]

[0023] The NMR data of the compound are as follows:

[0024] 1H NMR(600MHz, CDCl3)δ8.87(s,1H),8.26–8.18(m,2H),7.79–7.59(m,5H),7.43–7.36(m,5H),7.34–7.30(m,1H),7.0 4–7.00(m,1H),2.55–2.46(m,1H),2.35(t,J=6.6Hz,2H),2.22–2.14(m,1H),1.83–1.70(m,3H),1.62–1.54(m,1H). 13 C NMR(151MHz, CDCl3)δ169.16(s),150.91(s),147.86(s),139.08(s),138.25(s),131.87(s),128.99(s),128.76(s),128.47(s),127.97( s),126.31(s),121.76(s),120.00(s),119.52(s),113.59(s),90.27 (s),87.34(s),54.14(s),38.83(s),25.33(s),24.92(s),16.97(s).

[0025] Example 2: The synthesis of N-(pyridin-2-yl)-6-cyano-2-phenyl-2-((3-chlorophenyl)ethynyl)hexamethyleneamide (4ab) is as follows:

[0026] 0.2 mmol of 1,1-disubstituted electron-deficient olefin (1a), 0.6 mmol of O-(tert-butyloxycarbonyl)cyclobutanone oxime (2a), 0.4 mmol of 3-chlorophenylacetylene (3b), 0.04 mmol of CuTc, 0.4 mmol of KH2PO4, 2 mL of acetonitrile and dichloromethane (1:1) were added sequentially to a 25 mL Young's tube. The mixture was stirred at room temperature under an argon atmosphere for 12 hours to generate a mixed product.

[0027] The mixed products were concentrated under reduced pressure at 40°C to obtain a crude product. The crude product was passed through a silica gel column (200-300 mesh silica gel) and eluented with a mixture of ethyl acetate and petroleum ether (1:8). The eluent was collected and dried over Na2SO4 to obtain 53 mg of N-(pyridin-2-yl)-6-cyano-2-phenyl-2-((3-chlorophenyl)ethynyl)hexamethyleneamide (4ab), with a yield of 62%. The reaction equation is as follows:

[0028]

[0029] The NMR data of the compound are as follows:

[0030] 1H NMR (500MHz, CDCl3) δ8.73 (s, 1H), 8.26–8.22 (m, 1H), 8.20 (d, J = 8.5Hz, 1H), 7.72–7.67(m,3H),7.60(t,J=2.0Hz,1H),7.50(dt,J=7.5,1.5Hz,1H),7.42– 7.36(m,3H),7.32(t,J=7.5Hz,2H),7.04–7.01(m,1H),2.54–2.45(m,1H),2. 35(t,J=7.0Hz,2H),2.22–2.12(m,1H),1.81–1.66(m,3H),1.60-1.52(m,1H). 13 C NMR(126MHz, CDCl3)δ168.87(s),150.99(s),147.97(s),138.94(s),138.31(s),134.43(s),131.75(s),130.15(s),129.80(s),129.37(s),128 .92(s),128.14(s),126.32(s),123.56(s),120.11(s),119.42(s),113 .70(s),88.82(s),54.29(s),38.87(s),25.41(s),24.96(s),17.02(s).

[0031] Example 3: The synthesis of N-(pyridin-2-yl)-6-cyano-2-phenyl-2-(p-tolylethynyl)hexamamide (4ac) is as follows:

[0032] 0.2 mmol of 1,1-disubstituted electron-deficient olefin (1a), 0.6 mmol of O-(tert-butyloxycarbonyl)cyclobutanone oxime (2a), 0.4 mmol of 4-methylphenylacetylene (3c), 0.04 mmol of CuTc, 0.4 mmol of KH2PO4, 2 mL of acetonitrile and dichloromethane (1:1) were added sequentially to a 25 mL Young's tube. The mixture was stirred at room temperature under an argon atmosphere for 12 hours to generate a mixed product.

[0033] The mixed products were concentrated under reduced pressure at 40°C to obtain a crude product. The crude product was passed through a silica gel column (200-300 mesh silica gel) and eluented with a mixture of ethyl acetate and petroleum ether (1:8). The eluent was collected and dried over Na2SO4 to obtain 43 mg of N-(pyridin-2-yl)-6-cyano-2-phenyl-2-(p-tolueneethynyl)hexamethyleneamide (4ac), with a yield of 53%. The reaction equation is as follows:

[0034]

[0035] The NMR data of the compound are as follows:

[0036] 1 H NMR (500MHz, CDCl3) δ8.85 (s, 1H), 8.25–8.22 (m, 1H), 8.20 (d, J = 8.5Hz, 1H), 7.78–7.73(m,2H),7.71–7.66(m,1H),7.46–7.36(m,4H),7.34–7.26(m,2H), 7.21(d,J=8.0Hz,1H),7.04–6.99(m,1H),2.54–2.46(m,1H),2.38(s,3H),2. 34(t,J=7.0Hz,2H),2.21–2.12(m,1H),1.81–1.67(m,3H),1.64–1.55(m,1H). 13 C NMR(126MHz, CDCl3)δ169.43(s),151.22(s),148.08(s),139.43(s),138.41 (d,J=7.6Hz),132.59(s),130.06(s),129.17(s),128.94(s),128.56(s),128 .12(s),126.55(s),121.83(s),120.14(s),119.62(s),113.82(s),90.71(s) ),87.23(s),54.41(s),39.11(s),25.61(s),25.17(s),21.34(s),17.16(s).

[0037] Example 4: The synthesis of N-(pyridin-2-yl)-6-cyano-2-phenyl-2-(thiophen-3-ylethynyl)hexanoamide (4ad) is as follows:

[0038] 0.2 mmol of 1,1-disubstituted electron-deficient olefin (1a), 0.6 mmol of O-(tert-butyloxycarbonyl)cyclobutanone oxime (2a), 0.4 mmol of 3-ethynthiophene (3d), 0.04 mmol of CuTc, 0.4 mmol of KH2PO4, 2 mL of acetonitrile and dichloromethane (1:1) were added sequentially to a 25 mL Young's tube. The mixture was stirred at room temperature under an argon atmosphere for 12 hours to generate a mixed product.

[0039] The mixed product was concentrated under reduced pressure at 40°C to obtain a crude product. The crude product was passed through a silica gel column (200-300 mesh silica gel) and eluented with a mixture of ethyl acetate and petroleum ether (1:8). The eluent was collected and dried over Na2SO4 to obtain 44 mg of N-(pyridin-2-yl)-6-cyano-2-phenyl-2-(thiophene-3-ylethynyl)hexamethyleneamide (4ad), with a yield of 55%. The reaction equation is as follows:

[0040]

[0041] The NMR data of the compound are as follows:

[0042] 1 H NMR(500MHz, CDCl3)δ8.82(s,1H),8.25–8.22(m,1H),8.20(d,J=8.5Hz,1H),7.76–7.71(m,2H),7.71–7.62(m,2H),7.42–7.36(m,2H),7.35–7.29 (m,2H),7.29–7.26(m,1H),7.04–6.99(m,1H),2.53–2.44(m,1H),2.34(t ,J=7.0Hz,2H),2.21–2.11(m,1H),1.79–1.66(m,3H),1.62–1.52(m,1H). 13 C NMR(126MHz, CDCl3)δ169.44(s),151.28(s),148.16(s),139.42(s),138.52(s),130.20(s),130.12(s),129.05(s),128.25(s),126.63( s),125.97(s),121.07(s),120.27(s),119.72(s),113.93(s),87.38 (s),85.77(s),54.58(s),39.14(s),25.63(s),25.20(s),17.26(s).

[0043] Example 5: The synthesis of N-(pyridin-2-yl)-6-cyano-2-phenyl-2-((4-ethylphenyl)ethynyl)hexanoamide (4ae) is as follows:

[0044] 0.2 mmol of 1,1-disubstituted electron-deficient olefin (1a), 0.6 mmol of O-(tert-butyloxycarbonyl)cyclobutanone oxime (2a), 0.4 mmol of 4-ethylphenylacetylene (3e), 0.04 mmol of CuTc, 0.4 mmol of KH2PO4, 2 mL of acetonitrile and dichloromethane (1:1) were added sequentially to a 25 mL Young's tube. The mixture was stirred at room temperature under an argon atmosphere for 12 hours to generate a mixed product.

[0045] The mixed products were concentrated under reduced pressure at 40°C to obtain a crude product. The crude product was passed through a silica gel column (200-300 mesh silica gel) and eluented with a mixture of ethyl acetate and petroleum ether (1:8). The eluent was collected and dried over Na2SO4 to obtain 43 mg of N-(pyridin-2-yl)-6-cyano-2-phenyl-2-((4-ethylphenyl)ethynyl)hexamethyleneamide (4ae), with a yield of 52%. The reaction equation is as follows:

[0046]

[0047] The NMR data of the compound are as follows:

[0048] 1 H NMR(500MHz, CDCl3)δ8.88(s,1H),8.28–8.15(m,2H),7.79–7.71(m,2H),7.70–

[0049] 7.65(m,1H),7.54(d,J=8.5Hz,2H),7.38(t,J=7.5Hz,2H),7.30(t,J=7.0Hz,1H),7.22(d,J=8.0Hz,2H),7.03–6.98(m,1H),2.68(q,J= 7.5Hz,2H),2.55–2.44(m,1H),2.33(t,J=7.0Hz,2H),2.21–2.09(m,1H),1.79–1.65(m,3H),1.63–1.53(m,1H),1.25(t,J=7.5Hz,3H). 13C NMR(126MHz, CDCl3)δ169.56(s),151.27(s),148.13(s),145.80(s),139. 55(s),138.45(s),132.13(s),128.98(s),128.30(s),128.17(s),126.63 (s),120.19(s),119.70(s),119.25(s),113.86(s),90.79(s),87.00(s), 54.48(s),39.16(s),29.08(s),25.66(s),25.23(s),17.21(s),15.61(s).

[0050] Example 6: The synthesis of N-(pyridin-2-yl)-6-cyano-2-phenyl-2-((4-butylphenyl)ethynyl)hexamethyleneamide (4af) is as follows:

[0051] 0.2 mmol of 1,1-disubstituted electron-deficient olefin (1a), 0.6 mmol of O-(tert-butyloxycarbonyl)cyclobutanone oxime (2a), 0.4 mmol of 4-butylphenylacetylene (3f), 0.04 mmol of CuTc, 0.4 mmol of KH2PO4, 2 mL of acetonitrile and dichloromethane (1:1) were added sequentially to a 25 mL Young's tube. The mixture was stirred at room temperature under an argon atmosphere for 12 hours to generate a mixed product.

[0052] The mixed products were concentrated under reduced pressure at 40°C to obtain a crude product. The crude product was passed through a silica gel column (200-300 mesh silica gel) and eluented with a mixture of ethyl acetate and petroleum ether (1:8). The eluent was collected and dried over Na2SO4 to obtain 44 mg of N-(pyridin-2-yl)-6-cyano-2-phenyl-2-((4-butylphenyl)ethynyl)hexamethyleneamide (4af), with a yield of 49%. The reaction equation is as follows:

[0053]

[0054] The NMR data of the compound are as follows:

[0055] 1H NMR(500MHz, CDCl3)δ8.88(s,1H),8.28–8.16(m,2H),7.78–7.72(m,2H),7.70–7.64(m,1 H),7.55–7.50(m,2H),7.41–7.35(m,2H),7.33–7.27(m,1H),7.20(d,J=8.5Hz,2H),7.03 –6.98(m,1H),2.64(t,J=7.5Hz,2H),2.55–2.43(m,1H),2.34(t,J=6.5Hz,2H),2.22–2.0 9(m,1H),1.80–1.67(m,3H),1.65–1.55(m,3H),1.41–1.31(m,2H),0.93(t,J=7.5Hz,3H). 13 C NMR(126MHz, CDCl3)δ169.60(s),151.30(s),148.16(s),144.50(s),139.57(s) ),138.46(s),132.07(s),129.00(s),128.88(s),128.19(s),126.65(s),120.2 1(s),119.72(s),119.23(s),113.89(s),90.84(s),87.01(s),54.51(s),39.20 (s),35.83(s),33.61(s),25.69(s),25.26(s),22.48(s),17.25(s),14.13(s).

[0056] Example 7: The synthesis of N-(pyridin-2-yl)-6-cyano-2-phenyl-2-((4-fluorophenyl)ethynyl)hexamethyleneamide (4ag) is as follows:

[0057] 0.2 mmol of 1,1-disubstituted electron-deficient alkene (1a), 0.6 mmol of O-(tert-butyloxycarbonyl)cyclobutanone oxime (2a), 0.4 mmol of 4-fluorophenylacetylene (3 g), 0.04 mmol of CuTc, 0.4 mmol of KH2PO4, 2 mL of acetonitrile and dichloromethane (1:1) were added sequentially to a 25 mL Young's tube. The mixture was stirred at room temperature under an argon atmosphere for 12 hours to generate a mixed product.

[0058] The mixed products were concentrated under reduced pressure at 40°C to obtain a crude product. The crude product was passed through a silica gel column (200-300 mesh silica gel) and eluented with a mixture of ethyl acetate and petroleum ether (1:8). The eluent was collected and dried over Na2SO4 to obtain 47 mg of N-(pyridin-2-yl)-6-cyano-2-phenyl-2-((4-fluorophenyl)ethynyl)hexamethyleneamide (4 ag), with a yield of 57%. The reaction equation is as follows:

[0059]

[0060] The NMR data of the compound are as follows:

[0061] 1 H NMR (500MHz, CDCl3) δ8.87(s,1H),8.28-8.17(m,2H),7.75-7.68(m,3H),7.63-7.58(m,2H),7.42-7.36(m,2H),7.34-7.29(m,1H),7.12-7. 06(m,2H),7.05-7.00(m,1H),2.49(td,J=13.0,4.0Hz,1H),2.35(t,J=7.0Hz,2H),2.21-2.11(m,1H),1.83-1.65(m,3H),1.64-1.51(m,1H). 13 C NMR (126MHz, CDCl3) δ169.30 (s), 163.10 (d, J = 250.9Hz), 151.12 (s), 147.79 (s) ),139.24(s),138.64(s),134.09(d,J=8.8Hz),129.00(s),128.22(s),126.51( s),120.18(s),119.58(s),118.12(d,J=3.5Hz),116.00(d,J=22.2Hz),113.92 (s),89.43(s),87.39(s),54.43(s),39.02(s),25.52(s),25.08(s),17.16(s).

[0062] Example 8: The synthesis of N-(pyridin-2-yl)-6-cyano-2-phenyl-2-((4-(trifluoromethyl)phenyl)ethynyl)hexanoamide (4ah) is as follows:

[0063] 0.2 mmol of 1,1-disubstituted electron-deficient olefin (1a), 0.6 mmol of O-(tert-butyloxycarbonyl)cyclobutanone oxime (2a), 0.4 mmol of 4-trifluoromethylphenylacetylene (3h), 0.04 mmol of CuTc, 0.4 mmol of KH2PO4, 2 mL of acetonitrile and dichloromethane (1:1) were added sequentially to a 25 mL Young's tube. The mixture was stirred at room temperature under an argon atmosphere for 12 hours to generate a mixed product.

[0064] The mixed products were concentrated under reduced pressure at 40°C to obtain a crude product. The crude product was passed through a silica gel column (200-300 mesh silica gel) and eluented with a mixture of ethyl acetate and petroleum ether (1:8). The eluent was collected and dried over Na2SO4 to obtain 30 mg of N-(pyridin-2-yl)-6-cyano-2-phenyl-2-((4-(trifluoromethyl)phenyl)ethynyl)hexamethyleneamide (4Ah), with a yield of 33%. The reaction equation is as follows:

[0065]

[0066] The NMR data of the compound are as follows:

[0067] 1 H NMR(500MHz, CDCl3)δ8.73(s,1H),8.25–8.22(m,1H),8.20(d,J=8.0Hz,1H),7.75–7.63(m,7H),7.43–7.37(m,2H),7.36–7.31 (m,1H),7.06–7.01(m,1H),2.56–2.47(m,1H),2.36(t,J=7.0Hz,2H),2.23–2.14(m,1H),1.81–1.68(m,3H),1.62–1.54(m,1H). 13 CNMR(126MHz, CDCl3)δ168.74(s),150.97(s),147.99(s),138.83(s),138.37(s),132.28(s),130. 85(d,J=32.4Hz),128.98(s),128.22(s),126.32(s),125.65(s),125.60–125.39(m),123.80(d,J=

[0068] 272.4Hz),120.17(s),119.42(s),113.71(s),90.12(s),88.85(s),54.37(s),38.84(s),25.35(s),24.92(s),17.04(s).

[0069] Example 9: The synthesis of N-(pyridin-2-yl)-6-cyano-2-phenyl-2-((4-benzonitrile)ethynyl)hexanoamide (4ai) is as follows:

[0070] 0.2 mmol of 1,1-disubstituted electron-deficient olefin (1a), 0.6 mmol of O-(tert-butyloxycarbonyl)cyclobutanone oxime (2a), 0.4 mmol of 4-ethynylbenzenenitrile (3i), 0.04 mmol of CuTc, 0.4 mmol of KH2PO4, 2 mL of acetonitrile and dichloromethane (1:1) were added sequentially to a 25 mL Young's tube. The mixture was stirred at room temperature under an argon atmosphere for 12 hours to generate a mixed product.

[0071] The mixed products were concentrated under reduced pressure at 40°C to obtain a crude product. The crude product was passed through a silica gel column (200-300 mesh silica gel) and eluented with a mixture of ethyl acetate and petroleum ether (1:8). The eluent was collected and dried over Na2SO4 to obtain 44 mg of N-(pyridin-2-yl)-6-cyano-2-phenyl-2-((4-benzonitrile)ethynyl)hexamethyleneamide (4ai), with a yield of 53%. The reaction equation is as follows:

[0072]

[0073] The NMR data of the compound are as follows:

[0074] 1 H NMR(500MHz, CDCl3)δ8.65(s,1H),8.26–8.17(m,2H),7.73–7.66(m,7H),7.43–7.37(m,2H),7.36–7.32(m,1H),7.0 6–7.02(m,1H),2.55–2.47(m,1H),2.36(t,J=7.0Hz,2H),2.23–2.14(m,1H),1.79–1.67(m,3H),1.61–1.52(m,1H). 13 C NMR(126MHz, CDCl3)δ168.71(s),151.13(s),148.20(s),138.84(s),138.63(s),132.78(s),132.46(s),129.25(s),128.52(s),126.90(s),12 6.48(s),120.45(s),119.62(s),118.45(s),113.94(s),112.75(s),92 .30(s),88.67(s),54.66(s),39.01(s),25.49(s),25.07(s),17.25(s).

[0075] Example 10: The synthesis of methyl 4-(7-cyano-3-phenyl-3-(pyridin-2-ylcarbamoyl))-hept-1-yn-1-yl)benzoate (4aj) is as follows:

[0076] 0.2 mmol of 1,1-disubstituted electron-deficient olefin (1a), 0.6 mmol of O-(tert-butyloxycarbonyl)cyclobutanone oxime (2a), 0.4 mmol of methyl 4-ethynylbenzoate (3j), 0.04 mmol of CuTc, 0.4 mmol of KH2PO4, 2 mL of acetonitrile and dichloromethane (1:1) were added sequentially to a 25 mL Young's tube. The mixture was stirred at room temperature under an argon atmosphere for 12 hours to generate a mixed product.

[0077] The mixed products were concentrated under reduced pressure at 40°C to obtain a crude product. The crude product was passed through a silica gel column (200-300 mesh silica gel) and eluented with a mixture of ethyl acetate and petroleum ether (1:8). The eluent was collected and dried over Na2SO4 to obtain 44 mg of methyl 4-(7-cyano-3-phenyl-3-(pyridin-2-ylcarbamoyl))-hept-1-yn-1-yl)benzoate (4aj), with a yield of 53%. The reaction equation is as follows:

[0078]

[0079] The NMR data of the compound are as follows:

[0080] 1 H NMR(500MHz, CDCl3)δ8.76(s,1H),8.27–8.21(m,2H),8.10–8.06(m,2H),7.76–

[0081] 7.68(m,5H),7.44–7.39(m,2H),7.37–7.33(m,1H),7.07–7.03(m,1H),3.97(s,3H),2.58–

[0082] 2.49(m,1H),2.38(t,J=7.0Hz,2H),2.25–2.17(m,1H),1.82–1.71(m,3H),1.63–1.55(m,1H). 13C NMR (126MHz, CDCl3) δ169.05(s), 166.59(s), 151.22(s), 148.21(s), 139. 13(s),138.57(s),132.16(s),130.59(s),129.92(s),129.18(s),128.41( s),126.69(s),126.56(s),120.37(s),119.66(s),113.94(s),90.73(s), 89.67(s),54.63(s),52.54(s),39.10(s),25.63(s),25.19(s),17.26(s).

[0083] Example 11: The synthesis of N-(pyridin-2-yl)-6-cyano-2-(phenylethynyl)-2-(p-tolyl)hexamethyleneamide (4ak) is as follows:

[0084] 0.2 mmol of 1,1-disubstituted electron-deficient alkene (1k), 0.6 mmol of O-(tert-butyloxycarbonyl)cyclobutanone oxime (2a), 0.4 mmol of phenylacetylene (3a), 0.04 mmol of CuTc, 0.4 mmol of KH2PO4, 2 mL of acetonitrile and dichloromethane (1:1) were added sequentially to a 25 mL Young's tube. The mixture was stirred at room temperature under an argon atmosphere for 12 hours to generate a mixed product.

[0085] The mixed product was concentrated under reduced pressure at 40°C to obtain a crude product. The crude product was passed through a silica gel column (200-300 mesh silica gel) and eluented with a mixture of ethyl acetate and petroleum ether (1:8). The eluent was collected and dried over Na2SO4 to obtain 48 mg of N-(pyridin-2-yl)-6-cyano-2-(phenylethynyl)-2-(p-tolyl)hexamethyleneamide (4ak), with a yield of 59%. The reaction equation is as follows:

[0086]

[0087] The NMR data of the compound are as follows:

[0088] 1 H NMR(500MHz, CDCl3)δ8.83(s,1H),8.25–8.16(m,2H),7.70–7.57(m,5H),7.41–

[0089] 7.34(m,3H),7.18(d,J=8.0Hz,2H),7.02–6.97(m,1H),2.52–2.42(m,1H),2 .36–2.30(m,5H),2.20–2.11(m,1H),1.79–1.68(m,3H),1.63–1.53(m,1H).13 C NMR(126MHz, CDCl3)δ169.65(s),151.33(s),148.15(s),138.46(s),138.02(s),136.49(s),132.15(s),129.73(s),129.20(s),128.74(s),12 6.52(s),122.20(s),120.18(s),119.73(s),113.88(s),90.34(s),87. 94(s),54.16(s),39.02(s),25.69(s),25.21(s),21.19(s),17.24(s).

[0090] Example 12: The synthesis of N-(pyridin-2-yl)-6-cyano-2-(4-fluorophenyl)-2-(phenylethynyl)hexamamide (4al) is as follows:

[0091] 0.2 mmol of 1,1-disubstituted electron-deficient olefin (1 l), 0.6 mmol of O-(tert-butyloxycarbonyl)cyclobutanone oxime (2 a), 0.4 mmol of phenylacetylene (3 a), 0.04 mmol of CuTc, 0.4 mmol of KH2PO4, 2 mL of acetonitrile and dichloromethane (1:1) were added sequentially to a 25 mL Young's tube. The mixture was stirred at room temperature under an argon atmosphere for 12 hours to generate a mixed product.

[0092] The mixed products were concentrated under reduced pressure at 40°C to obtain a crude product. The crude product was passed through a silica gel column (200-300 mesh silica gel) and eluented with a mixture of ethyl acetate and petroleum ether (1:8). The eluent was collected and dried over Na2SO4 to obtain 35.7 mg of N-(pyridin-2-yl)-6-cyano-2-(4-fluorophenyl)-2-(phenylethynyl)hexamethyleneamide (4al), with a yield of 44%. The reaction equation is as follows:

[0093]

[0094] The NMR data of the compound are as follows:

[0095] 1 H NMR(500MHz, CDCl3)δ8.89(s,1H),8.28–8.22(m,1H),8.19(d,J=8.5Hz,1H),7.77–7.66(m,3H),7.64–7.59(m,2H),7.43–7.37 (m,3H),7.10–7.01(m,3H),2.52–2.44(m,1H),2.35(t,J=7.0Hz,2H),2.19–2.10(m,1H),1.79–1.67(m,3H),1.64–1.55(m,1H).13 CNMR (126MHz, CDCl3) δ169.06 (s), 162.44 (d, J = 247.8Hz), 150.94 (s), 147.9 9(s),138.30(s),135.02(s),131.93(s),129.17(s),128.58(s),128.24(d,J =8.0Hz),121.66(s),120.15(s),119.40(s),115.60(d,J=21.4Hz),113.69(s) ),90.69(s),87.24(s),53.72(s),39.17(s),25.37(s),24.99(s),17.01(s).

[0096] Example 13: The synthesis of N-(pyridin-2-yl)-6-cyano-2-(4-bromophenyl)-2-(phenylethynyl)hexamamide (4am) is as follows:

[0097] 0.2 mmol of 1,1-disubstituted electron-deficient olefin (1m), 0.6 mmol of O-(tert-butyloxycarbonyl)cyclobutanone oxime (2a), 0.4 mmol of phenylacetylene (3a), 0.04 mmol of CuTc, 0.4 mmol of KH2PO4, 2 mL of acetonitrile and dichloromethane (1:1) were added sequentially to a 25 mL Young's tube. The mixture was stirred at room temperature under an argon atmosphere for 12 hours to generate a mixed product.

[0098] The mixed products were concentrated under reduced pressure at 40°C to obtain a crude product. The crude product was passed through a silica gel column (200-300 mesh silica gel) and eluented with a mixture of ethyl acetate and petroleum ether (1:8). The eluent was collected and dried over Na2SO4 to obtain 25 mg of N-(pyridin-2-yl)-6-cyano-2-(4-bromophenyl)-2-(phenylethynyl)hexamamide (4 mg), with a yield of 27%. The reaction equation is as follows:

[0099]

[0100] The NMR data of the compound are as follows:

[0101] 1H NMR(500MHz, CDCl3)δ8.90(s,1H),8.28–8.22(m,1H),8.19(d,J=8.5Hz,1H),7.76–7.72(m,2H),7.71–7.67(m,1H),7.64–7.59(m,2H),7 .43–7.37(m,3H),7.09–7.01(m,3H),2.53–2.44(m,1H),2.35(t,J=7.0Hz,2H),2.18–2.11(m,1H),1.79–1.70(m,3H),1.64–1.55(m,1H). 13 C NMR(126MHz, CDCl3)δ168.75(s),150.90(s),148.03(s),138.38(s),138.34(s),131.97(s),131.90(s),129.25(s),128.62(s),128.28( s),122.27(s),121.61(s),120.23(s),119.40(s),113.72(s),90.91 (s),86.89(s),53.97(s),39.03(s),25.40(s),25.02(s),17.05(s).

[0102] Example 14: The synthesis of N-(pyridin-2-yl)-6-cyano-2-methyl-2-(phenylethynyl)hexamamide (4an) is as follows:

[0103] 0.2 mmol of 1,1-disubstituted electron-deficient olefin (1n), 0.6 mmol of O-(tert-butyloxycarbonyl)cyclobutanone oxime (2a), 0.4 mmol of phenylacetylene (3a), 0.04 mmol of CuTc, 0.4 mmol of KH2PO4, 2 mL of acetonitrile and dichloromethane (1:1) were added sequentially to a 25 mL Young's tube. The mixture was stirred at room temperature under an argon atmosphere for 12 hours to generate a mixed product.

[0104] The mixed product was concentrated under reduced pressure at 40°C to obtain a crude product. The crude product was passed through a silica gel column (200-300 mesh silica gel) and eluented with a mixture of ethyl acetate and petroleum ether (1:8). The eluent was collected and dried over Na2SO4 to obtain 15 mg of N-(pyridin-2-yl)-6-cyano-2-methyl-2-(phenylethynyl)hexamamide (4an), with a yield of 23%. The reaction equation is as follows:

[0105]

[0106] The NMR data of the compound are as follows:

[0107] 1H NMR(600MHz, CDCl3)δ9.15(s,1H),8.32–8.28(m,1H),8.23(d,J=8.4Hz,1H),7.75–7.69(m,1H),7.55–7.49(m,2H),7.39– 7.31(m,3H),7.09–7.04(m,1H),2.41–2.32(m,2H),2.14–2.06(m,1H),1.80–1.70(m,4H),1.63(s,3H),1.60–1.52(m,1H). 13 C NMR(151MHz, CDCl3)δ171.49(s),150.83(s),148.01(s),138.38(s),131.87(s),128.83(s),128.45(s),121.91(s),12 0.21(s),119.56(s),113.77(s),89.24(s),87.66(s),45.07(s),39.26(s),27.01(s),25.39(s),25.02(s),17.05(s).

[0108] Example 15: The synthesis of N-(pyridin-2-yl)-5-benzyl-6-cyano-2-phenyl-2-(phenylethynyl)hexamamide (4ao) is as follows:

[0109] 0.2 mmol of 1,1-disubstituted electron-deficient alkene (1a), 0.6 mmol of O-(tert-butoxycarbonyl)-3-benzylcyclobutanone oxime (2o), 0.4 mmol of phenylacetylene (3a), 0.04 mmol of CuTc, 0.4 mmol of KH2PO4, 2 mL of acetonitrile and dichloromethane (1:1) were added sequentially to a 25 mL Young's tube. The mixture was stirred at room temperature under an argon atmosphere for 12 hours to generate a mixed product.

[0110] The mixed products were concentrated under reduced pressure at 40°C to obtain a crude product. The crude product was passed through a silica gel column (200-300 mesh silica gel) and eluented with a mixture of ethyl acetate and petroleum ether (1:8). The eluent was collected and dried over Na2SO4 to obtain 48 mg of N-(pyridin-2-yl)-5-benzyl-6-cyano-2-phenyl-2-(phenylethynyl)hexamethyleneamide (4ao), with a yield of 50%. The reaction equation is as follows:

[0111]

[0112] The NMR data of the compound are as follows:

[0113] 1H NMR(500MHz, CDCl3)δ8.84(d,J=12.5Hz,1H),8.25–8.19(m,2H),7.78–7.73(m,2H),7.70 –7.66(m,1H),7.60–7.55(m,2H),7.41–7.36(m,5H),7.32(t,J=7.5Hz,1H),7.27–7.23(m ,2H),7.21–7.17(m,1H),7.16–7.12(m,2H),7.03–6.99(m,1H),2.89–2.79(m,1H),2.64– 2.53(m,2H),2.33–2.20(m,3H),2.08–2.00(m,1H),1.83–1.72(m,1H),1.68–1.61(m,1H). 13 C NMR (126MHz, CDCl3) δ169.44(d,J=6.2Hz), 151.30(d,J=1.8Hz), 148.19(d,J=2.4Hz), 139.36(d,J=3.9Hz), 138.88(d,J=2.9Hz ),138.49(s),132.23(s),129.39–129.20(m),129.09(d,J=2.0Hz),128.84(d,J=1.8Hz),128.73(s),128.30(d,J=2.4Hz),126. 77(d,J=1.5Hz),126.66(d,J=1.4Hz),122.09(s),120.26(s),118.56(s),118.44(s),113.96(d,J=3.0Hz),90.77(d,J=4.3Hz), 87.55 (d, J = 4.2Hz), 54.56 (s), 39.73 (d, J = 19.7Hz), 37.62 (d, J = 11.7Hz), 37.35 (d, J = 10.6Hz), 29.66 (s), 21.35 (d, J = 42.1Hz).

[0114] Example 16: The synthesis of N-(pyridin-2-yl)-5-(4-chlorophenyl)-6-cyano-2-phenyl-2-(phenylethynyl)hexamamide (4ap) is as follows:

[0115] 0.2 mmol of 1,1-disubstituted electron-deficient olefin (1a), 0.6 mmol of O-(tert-butoxycarbonyl)-3-(4-chlorophenyl)cyclobutanone oxime (2p), 0.4 mmol of phenylacetylene (3a), 0.04 mmol of CuTc, 0.4 mmol of KH2PO4, 2 mL of acetonitrile and dichloromethane (1:1) were added sequentially to a 25 mL Young's tube. The mixture was stirred at room temperature under an argon atmosphere for 12 hours to generate a mixed product.

[0116] The mixed products were concentrated under reduced pressure at 40°C to obtain a crude product. The crude product was passed through a silica gel column (200-300 mesh silica gel) and eluented with a mixture of ethyl acetate and petroleum ether (1:8). The eluent was collected and dried over Na2SO4 to obtain 24 mg of N-(pyridin-2-yl)-5-(4-chlorophenyl)-6-cyano-2-phenyl-2-(phenylethynyl)hexamethyleneamide (4ap), with a yield of 24%. The reaction equation is as follows:

[0117]

[0118] The NMR data of the compound are as follows:

[0119] 1 H NMR (500MHz, CDCl3) δ8.79 (s, 1H), 8.24–8.21 (m, 1H), 8.17 (d, J = 8.5Hz, 1H), 7.69 –7.65(m,1H),7.65–7.59(m,4H),7.43–7.39(m,3H),7.37–7.29(m,3H),7.29–7.2 6(m,2H),7.09–7.06(m,2H),7.03–6.99(m,1H),3.04–2.95(m,1H),2.62–2.51(m, 2H),2.43–2.35(m,1H),2.11–2.02(m,1H),2.01–1.92(m,1H),1.87–1.78(m,1H). 13 C NMR(126MHz, CDCl3)δ169.29(s),151.25(s),148.20(s),139.63(s),139. 03(s),138.51(s),133.63(s),132.18(s),129.40(s),129.06(s),128.86( s),128.34(s),126.66(s),122.06(s),120.30(s),118.18(s),113.91(s), 90.68(s),87.56(s),54.38(s),41.94(s),37.55(s),30.99(s),25.76(s).

Claims

1. A method for preparing all-carbon quaternary carbon center derivatives by radical-initiated cross-coupling of olefins and alkynes, characterized in that: Electron-deficient alkenes with 1,1-disubstituted olefins, O Using -(tert-butyloxycarbonyl)cyclobutanone oxime and terminal alkynes as starting materials, the reaction is carried out at room temperature and under an inert atmosphere in the presence of a catalyst, a base, and a solvent. The reaction product is concentrated, separated, and purified to obtain... N -(pyridin-2-yl)-6-cyano-2-aryl-2-ynylhexylamide derivatives; ； Among them, R 1 Selected from alkyl and aryl groups; R 2 Selected from hydrogen, alkyl, aryl; R 3 Selected from aryl; The catalyst is selected from cuprous thiophene-2-carboxylate; The base is selected from potassium dihydrogen phosphate, sodium bicarbonate, and sodium carbonate.

2. The method for preparing all-carbon quaternary carbon center derivatives by radical-initiated cross-coupling of olefins and alkynes according to claim 1, characterized in that: Solvents are selected from acetonitrile, dichloromethane, N , N - Dimethylformamide, dimethyl sulfoxide, tetrahydrofuran N -Methylpyrrolidone.

3. The method for preparing all-carbon quaternary carbon center derivatives by free radical-initiated cross-coupling of olefins and alkynes according to claim 1, characterized in that: 1,1-Disubstituted electron-deficient alkenes and O The molar ratio of -(tert-butyloxycarbonyl)cyclobutanone oxime compounds is 1:1-5; the molar ratio of 1,1-disubstituted electron-deficient alkenes to terminal alkynes is 1:1-4.

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