A method for the bicyclization of 1,6-alkynols with sulfonylhydrazides and heteropolycyclic compounds

Abstract

The application relates to a method for double ring reaction of 1,6-alkenyl alkyne and sulfonamide, which comprises mixing 1,6-alkenyl alkyne, sulfonamide, a catalyst and an oxidant with water, reacting, and obtaining a heteropolycyclic compound; wherein the catalyst is one or more of tetrabutylammonium iodide, iodine, N-iodosuccinimide, potassium iodide and ammonium iodide; and the oxidant is one or more of tert-butyl hydroperoxide, tert-butyl peroxybenzoate, dibenzoyl peroxide and di-tert-butyl peroxide. The method can realize the double ring reaction of 1,6-alkenyl alkyne and sulfonamide in water phase, the reaction condition is mild, water is used as the reaction solvent, no organic solvent is needed, two new rings are constructed through one-pot reaction, the method has the advantages of wide substrate adaptation range, greenness and high efficiency, and is especially suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The present application relates to a method for the bicyclization reaction of 1,6-alkenyns and sulfonamidohydrazides, in particular to a method for the bicyclization reaction of 1,6-alkenyns and sulfonamidohydrazides in aqueous phase and a heteropolycyclic compound, more particularly to a method for the bicyclization reaction of 1,6-alkenyns and sulfonamidohydrazides in aqueous phase using a combination of tetrabutylammonium iodide (TBAI)-tert-butyl hydroperoxide (TBHP) and a heteropolycyclic compound. BACKGROUND

[0002] Sulfonamidohydrazides are often used as a source of sulfonamidohydrazide radicals due to their stable properties, easy preparation, no odor, low toxicity, and only nitrogen and water as byproducts. Free radical bicyclization reaction can simultaneously construct two or more new rings and form multiple chemical bonds in a one-pot reaction, thus having high ring formation efficiency and step economy, making it one of the most ideal means for assembling various complex heteropolycyclic compounds. There are many reports on the reaction of 1,n-alkenyns and sulfonamidohydrazides as free radical precursors, mainly including: 1) sulfonation reaction of 1,n-alkenyns and sulfonamidohydrazides; 2) halosulfonation reaction of 1,n-alkenyns and sulfonamidohydrazides; 3) bicyclization reaction of 1,n-alkenyns and sulfonamidohydrazides. However, most of these reactions require transition metal catalysts to promote the desired conversion and inhibit side reactions, which inevitably leads to metal residues harmful to the environment, thus limiting their application in the chemical industry to some extent.

[0003] Chinese patent application CN 113336692 A discloses a method for the controlled bicyclization reaction of 1,6-dienes initiated by sulfonamidohydrazide radicals. The method uses 1,6-dienes and sulfonamidohydrazides as raw materials, and performs the reaction in the presence of a catalyst, an oxidant, and a solvent to achieve the controlled bicyclization reaction of 1,6-dienes initiated by sulfonamidohydrazide radicals. The method requires the use of organic solvents such as acetonitrile, which is not green and environmentally friendly, and is not conducive to reducing the cost of the reaction. In addition, the yield of the target product can only reach 76%. SUMMARY

[0004] In view of the deficiencies of the prior art, the present application aims to provide a method for the bicyclization reaction of 1,6-alkenyns and sulfonamidohydrazides in aqueous phase.

[0005] To solve the above technical problems, the technical solution of the present application is as follows:

[0006] A method for the bicyclization reaction of 1,6-alkenyns and sulfonamidohydrazides, which comprises mixing 1,6-alkenyns, sulfonamidohydrazides, a catalyst, and an oxidant with water, and then performing a reaction to obtain a heteropolycyclic compound.

[0007] The catalyst is one or more of tetrabutylammonium iodide, iodine, N-iodosuccinimide, potassium iodide, and ammonium iodide; and the oxidant is one or more of tert-butyl peroxide, tert-butyl perbenzoate, dibenzoyl peroxide, and di-tert-butyl peroxide.

[0008] Thus, the present invention uses 1,6-enyne compounds and sulfonylhydrazide as raw materials, and water as a reaction solvent in the presence of a catalyst and an oxidant to achieve a dicyclization reaction of 1,6-enyne and sulfonylhydrazide to prepare the target product, which has the advantages of being economical and environmentally friendly.

[0009] Furthermore, when mixing, the molar volume ratio of the 1,6-enyne compound, sulfonylhydrazide and water is 0.25-0.3 mmol: 0.35-0.45 mmol: 1-3 mL, the amount of the oxidant is 2-4 equivalents, and the amount of the catalyst is 30-80 mol% (i.e., 30-80 mol% relative to the 1,6-enyne compound).

[0010] Furthermore, the molar volume ratio of 1,6-enyne compound, sulfonylhydrazide and water is 0.22-0.28 mmol: 0.38-0.42 mmol: 1.5-2.5 mL, the amount of oxidant is 2.5-3.5 equivalents, and the amount of catalyst is 50-70 mol%, further 55-65 mol%.

[0011] Preferably, during mixing, the amount of the 1,6-enyne compound is 0.2 mmol, the amount of the sulfonylhydrazine is 0.4 mmol, the amount of the oxidant is 3.0 equivalents, the amount of the catalyst is 50 mol%, and the amount of water is 2.0 mL.

[0012] Furthermore, the reaction is carried out at 50-90°C.

[0013] Further, the reaction is carried out at 60-80°C, and further, the reaction is carried out at 65-85°C.

[0014] Furthermore, the reaction was carried out under an air atmosphere.

[0015] Furthermore, the chemical formula of the 1,6-enyne compound is shown in Formula 1:

[0016]

[0017] The chemical formula of the sulfonylhydrazine is shown in Formula 2:

[0018]

[0019] The chemical formula of the heteropolycyclic compound is shown in Formula I:

[0020]

[0021] Where Y is NR 2 or O; R 1 is selected from phenyl, methoxyphenyl or chlorophenyl; R 2 is selected from phenyl, methoxyphenyl, methylphenyl, chlorophenyl, trifluoromethylphenyl, benzyl or chlorobenzyl; R 3 is selected from phenyl, tolyl, methoxyphenyl, tert-butylphenyl, halophenyl, cyanophenyl, nitrophenyl, mesityl, naphthyl, thienyl or ethyl.

[0022] The reaction formula of the dicyclization reaction of the present invention is as follows:

[0023]

[0024] Furthermore, the reaction solution after the reaction is completed is extracted with ethyl acetate 2-4 times to obtain an organic phase; the organic phase is then dried over anhydrous sodium sulfate, filtered and evaporated to remove the solvent to obtain a mixture; then, the mixture is purified to obtain a heteropolycyclic compound.

[0025] Optionally, purification is performed by silica gel column chromatography. Furthermore, the elution solvent used in the purification process is petroleum ether / ethyl acetate (optionally, the volume ratio of petroleum ether to ethyl acetate is 6:1 to 3:1).

[0026] A heteropolycyclic compound is prepared by the method described above.

[0027] The present invention develops a new method for achieving a dicyclization reaction of 1,6-enyne with sulfonylhydrazide in an aqueous phase. The reaction conditions of this method are mild and water is used as the reaction solvent. No organic solvent is required during the reaction process. Two new rings are constructed through a one-pot reaction. The method has the advantages of a wide range of reaction substrates, green and high efficiency, and is particularly suitable for industrial production. DETAILED DESCRIPTION

[0028] The present invention will be described in detail below with reference to the embodiments. It should be noted that the embodiments and features of the embodiments of the present invention can be combined with each other without conflict.

[0029] The experimental methods described in the following examples are conventional methods unless otherwise specified; the reagents and raw materials can be obtained from commercial channels and / or prepared according to known methods unless otherwise specified.

[0030] Example 1

[0031]

[0032] A Schlenk reaction flask was charged with 70.3 mg (0.2 mmol) of the 1,6-enyne represented by Formula 1a, 74.5 mg (0.4 mmol) of the sulfonylhydrazine represented by Formula 2a, 36.9 mg (50 mol%) of tetrabutylammonium iodide (i.e., 50 mol% of tetrabutylammonium iodide relative to the 1,6-enyne represented by Formula 1a), 54.1 mg (3.0 equiv) of tert-butyl peroxide, and 2.0 mL of H₂O. The reaction flask was then stirred at 70°C until complete consumption of the starting material was observed by TLC or GC-MS analysis, yielding a mixture. After completion of the reaction, the mixture was extracted three times with ethyl acetate. The resulting organic layer was dried over Na₂SO₄, filtered, and the ethyl acetate evaporated. The mixture was then purified by silica gel column chromatography (eluting solvent: petroleum ether / ethyl acetate = 4:1) to obtain the desired product I-1 (90% yield).

[0033] The structural characterization data of the target product I-1 are: 1 H NMR(400MHz, CDCl3)δ:7.37-7.34(m,3H),7.25-7.19(m,7H),7.16-7.12(m,2H),7.09-7.03(m ,4H),6.80(d,J=7.2Hz,2H),5.26(s,2H),5.12(s,1H),4.92(s,1H),3.53(s,2H),2.36(s,3H); 13 C NMR(101MHz, CDCl3)δ:171.0,144.1,143.8,142.9,142.7,140.3,137.5,137.1,130.1,129.7,129.3,128.9,12 8.8,128.3,128.1,127.9,127.5,126.9,126.4,122.9,119.4,54.1,40.3,31.5,30.1,21.6; HRMSm / z(ESI)calcd for C 32 H 28 NO3S([M+H] + )506.1784,found 506.1783.

[0034] Example 2

[0035] The oxidant was replaced by tert-butyl perbenzoate (TBPB) instead of TBHP. The other conditions were the same as those in Example 1. The yield of the target product I-1 was 74%.

[0036] Example 3

[0037] Benzoyl peroxide (BPO) was used as the oxidant instead of TBHP. Other conditions were the same as those in Example 1. The yield of the target product I-1 was 65%.

[0038] Example 4

[0039] Di-tert-butyl peroxide (DTBP) was used as the oxidant instead of TBHP. Other conditions were the same as those in Example 1. The yield of the target product I-1 was 41%.

[0040] Example 5

[0041] The oxidant was replaced by iodobenzene diacetate (PIDA) instead of TBHP. The other conditions were the same as those in Example 1. The yield of the target product I-1 was 0%.

[0042] Example 6

[0043] The amount of oxidant TBHP used was 2.0 equivalents, and the other conditions were the same as in Example 1. The yield of the target product I-1 was 66%.

[0044] Example 7

[0045] The amount of oxidant TBHP used was 4.0 equivalents, and the other conditions were the same as in Example 1. The yield of the target product I-1 was 78%.

[0046] Example 8

[0047] Tetrabutylammonium fluoride (TBAF) was used instead of TBAI, and the other conditions were the same as in Example 1. The yield of the target product I-1 was 0%.

[0048] Example 9

[0049] Iodine was used instead of TBAI, and the other conditions were the same as in Example 1. The yield of the target product I-1 was 22%.

[0050] Example 10

[0051] N-iodosuccinimide (NIS) was used instead of TBAI, and the other conditions were the same as those in Example 1. The yield of the target product I-1 was 14%.

[0052] Example 11

[0053] Potassium iodide was used instead of TBAI, and the other conditions were the same as in Example 1. The yield of the target product I-1 was 55%.

[0054] Example 12

[0055] Ammonium iodide was used instead of TBAI, and the other conditions were the same as in Example 1. The yield of the target product I-1 was 42%.

[0056] Example 13

[0057] The amount of TBAI used was 30 mol%, and the other conditions were the same as in Example 1. The yield of the target product I-1 was 33%.

[0058] Example 14

[0059] The amount of TBAI used was 80 mol %, and the other conditions were the same as in Example 1. The yield of the target product I-1 was 92%.

[0060] Example 15

[0061] The reaction temperature was lowered to 50°C, and the other conditions were the same as in Example 1. The yield of the target product I-1 was 42%.

[0062] Example 16

[0063] The reaction temperature was raised to 90° C., and the other conditions were the same as in Example 1. The yield of the target product I-1 was 71%.

[0064] As can be seen from Examples 1-16 above, the optimal reaction conditions are those of Example 1, namely, the catalyst TBAI (50 mol%), the oxidant TBHP (3.0 equiv), and the solvent HO (2.0 mL), and the reaction temperature is 70°C. Based on the optimal reaction conditions, the inventors further selected 1,6-enyne compounds with different substituents and sulfonylhydrazide compounds as raw materials under these optimal reaction conditions to develop a highly selective bicyclization reaction method.

[0065] It can also be seen that the selection of the types of catalyst and oxidant has a significant impact on the yield of the target product; the higher the reaction temperature is, the better it is. Controlling the reaction temperature within an appropriate range helps to obtain a high yield of the target product.

[0066] Example 17

[0067]

[0068] A Schlenk reaction flask was charged with 70.3 mg (0.2 mmol) of the 1,6-enyne of Formula 1a, 74.5 mg (0.4 mmol) of the sulfonylhydrazide of Formula 2b, 36.9 mg (50 mol%) of tetrabutylammonium iodide, 54.1 mg (3.0 equiv) of tert-butyl peroxide, and 2.0 mL of H₂O. The reaction flask was then stirred at 70°C until complete consumption of the starting material was observed by TLC or GC-MS analysis. After completion of the reaction, the mixture was extracted three times with ethyl acetate. The resulting organic layer was dried over Na₂SO₄, filtered, and the ethyl acetate was evaporated. The mixture was then purified by silica gel column chromatography (eluting solvent: petroleum ether / ethyl acetate = 5:1) to obtain the desired product I-2 (86% yield).

[0069] The structural characterization data of the target product I-2 are as follows: 1 H NMR (400 MHz, CDC13) δ: 7.40-7.37 (m, 3H), 7.30-7.28 (m, 2H), 7.25-7.23 (m, 3H), 7.19-7.17 (m, 2H), 7.15-7.12 (m, 3H), 7.08 (d, J = 7.2 Hz, 2H), 7.03 (s, 1H), 6.79 (d, J = 7.2 Hz, 2H), 5.34 (s, 2H), 5.15 (s, 1H), 4.96 (s, 1H), 3.57 (s, 2H), 2.27 (s, 3H); 13 C NMR (101 MHz, CDC13) δ: 171.0, 143.9, 143.2, 142.6, 140.4, 140.1, 138.7, 137.6, 133.8, 130.0, 129.7, 128.9, 128.7, 128.6, 128.3, 128.2, 128.1, 127.5, 127.1, 126.4, 124.8, 122.6, 119.4, 54.2, 40.3, 31.5, 29.7, 21.0; HRMS m / z (ESI) calcd for C 32 H 28 NO3S ([M+H] + ) 506.1784, found 506.1783.

[0070] Example 18

[0071]

[0072] In a Schlenk flask, 1,6-alkyne 70.3 mg (0.2 mmol) of formula la, sulfonilhydrazide 74.5 mg (0.4 mmol) of formula 2c, tetrabutylammonium iodide 36.9 mg (50 mol%), tert-butyl hydroperoxide 54.1 mg (3.0 equiv) and H2O (2.0 mL) were added. Then the reaction flask was placed at 70 °C and stirred for a certain time until the complete consumption of the starting material was monitored by TLC or GC-MS analysis. After the end of the reaction, the mixture was extracted three times with ethyl acetate. The resulting organic layer was dried over Na2SO4, filtered and the solvent was evaporated. The mixture was then purified by column chromatography on silica gel (elution solvent: petroleum ether / ethyl acetate = 3:1) to obtain the target product I-3 (86% yield).

[0073] The structural characterization data of the target product I-3 are as follows: 1H NMR(500MHz, CDCl3)δ:7.38-7.36(m,3H),7.24-7.20(m,5H),7.12(d,J=7.5Hz,1H),7.08-7.04(m,3H),6.95-6.91( m,3H),6.76(t,J=8.0Hz,1H),6.63-6.61(m,2H),5.39(s,2H),5.12(s,1H),4.97(s,1H),3.54(s,2H),2.47(s,3H); 13 C NMR (126MHz, CDCl3) δ:171.0,143.9,143.7,142.0,140.7,139.0,137.7,136.6,132.7 131.8,130.2,129.8(2),129.0,128.9,128.4,128.2,127.5,127.3,126.5,126.0,121.2,119.7,54.3,40.5,30.2,29.7,20.1; HRMS m / z(ESI)calcd for C 32 H 28 NO3S([M+H] + )506.1784,found 506.1783.

[0074] Example 19

[0075]

[0076] A Schlenk reaction flask was charged with 70.3 mg (0.2 mmol) of the 1,6-enyne of Formula 1a, 80.8 mg (0.4 mmol) of the sulfonylhydrazide of Formula 2d, 36.9 mg (50 mol%) of tetrabutylammonium iodide, 54.1 mg (3.0 equiv) of tert-butyl peroxide, and 2.0 mL of H₂O. The reaction flask was then heated at 70°C and stirred until complete consumption of the starting material was observed by TLC or GC-MS analysis. After completion of the reaction, the mixture was extracted three times with ethyl acetate. The resulting organic layer was dried over Na₂SO₄, filtered, and the solvent evaporated. The mixture was purified by silica gel column chromatography (eluting solvent: petroleum ether / ethyl acetate = 5:1) to obtain the desired product I-4 (90% yield).

[0077] The structural characterization data of the target product I-4 are: 1H NMR (400 MHz, CDC13) δ: 7.29-7.26 (m, 3H), 7.20-7.16 (m, 4H), 7.13-7.07 (m, 5H), 6.96 (d, J = 6.8 Hz, 2H), 6.76-6.74 (m, 2H), 6.67 (d, J = 8.8 Hz, 2H), 5.19 (s, 2H), 5.04 (s, 1H), 4.84 (s, 1H), 3.74 (s, 3H), 3.46 (s, 2H); 13 C NMR (101 MHz, CDC13) δ: 171.0, 163.3, 143.8, 143.0, 142.8, 140.3, 137.5, 131.5, 130.1 (2), 129.7, 128.9, 128.7, 128.3, 128.1, 127.6, 126.8, 126.4, 122.5, 119.4, 114.0, 55.6, 54.1, 40.3, 31.4, 29.6; HRMS m / z (ESI) calcd for C 32 H 28 NO4S ([M+H] + ) 522.1734, found 522.1732.

[0078] Example 20

[0079]

[0080] In a Schlenk flask was added 1,6-alkyne 70.3 mg (0.2 mmol) of Formula la, sulfonhydrazide 91.2 mg (0.4 mmol) of Formula 2e, tetrabutylammonium iodide 36.9 mg (50 mol%), tert-butyl hydroperoxide 54.1 mg (3.0 equiv) and H2O (2.0 mL). The reaction flask was then placed at 70 °C and stirred for a certain time until complete consumption of the starting material was monitored by TLC or GC-MS analysis. After the reaction was completed, the mixture was extracted with ethyl acetate three times. The resulting organic layer was dried over Na2S04, filtered, and the solvent was evaporated. The mixture was then purified by silica gel column chromatography (elution solvent: petroleum ether / ethyl acetate = 6:1) to obtain the target product I-5 (88% yield).

[0081] The structural characterization data of the target product I-5 are as follows: 1H NMR (400 MHz, CDC13) δ: 7.41-7.38 (m, 3H), 7.30-7.28 (m, 5H), 7.24 (t, J = 4.4 Hz, 3H), 7.18-7.13 (m, 3H), 7.09 (d, J = 6.8 Hz, 2H), 6.81 (d, J = 7.2 Hz, 2H), 5.33 (s, 2H), 5.16 (s, 1H), 4.96 (s, 1H), 3.58 (s, 2H), 1.33 (s, 9H); 13 C NMR (101 MHz, CDC13) δ: 171.0, 156.9, 143.8, 142.9, 142.8, 140.4, 137.6, 137.0, 130.0, 129.7, 128.9, 128.7, 128.3, 128.1, 127.6, 127.5, 127.0, 126.4, 125.7, 122.5, 119.4, 54.2, 40.3, 35.1, 31.5, 31.0, 29.7; HRMS m / z (ESI) calcd for C 35 H 34 NO3S ([M+H] + ) 548.2254, found 548.2253.

[0082] Example 21

[0083]

[0084] In a Schlenk flask was added 1,6- enyne 70.3 mg (0.2 mmol) of formula la, sulfonhydrazide 68.8 mg (0.4 mmol) of formula 2f, tetrabutylammonium iodide 36.9 mg (50 mol%), tert-butyl hydroperoxide 54.1 mg (3.0 equiv) and H2O (2.0 mL). The reaction flask was then placed at 70 °C, stirred until complete consumption of the starting material was monitored by TLC or GC-MS analysis. After the reaction was completed, the mixture was extracted with ethyl acetate three times. The resulting organic layer was dried over Na2S04, filtered, and the solvent (ethyl acetate) was evaporated. The mixture was then purified by silica gel column chromatography (elution solvent: petroleum ether / ethyl acetate = 4:1) to obtain the target product I-6 (82% yield).

[0085] The structural characterization data of the target product I-6 are: 1H NMR (400 MHz, CDC13) δ: 7.40-7.36 (m, 1H), 7.30-7.27 (m, 3H), 7.21-7.19 (m, 5H), 7.15-7.12 (m, 3H), 7.09-7.02 (m, 3H), 6.97 (d, J = 7.2 Hz, 2H), 6.70 (d, J = 7.2 Hz, 2H), 5.23 (s, 2H), 5.05 (s, 1H), 4.86 (s, 1H), 3.46 (s, 2H); 13 CNMR (101 MHz, CDC13) δ: 171.0, 143.8, 142.8, 142.7, 140.4, 140.2, 137.5, 133.0, 130.0, 129.7, 128.9, 128.8, 128.7, 128.3, 128.1, 127.7, 127.6, 127.0, 126.4, 123.1, 119.4, 54.1, 40.3, 31.4, 29.7; HRMS m / z (ESI) calcd for C 31 H 26 NO3S ([M+H] + ) 492.1628, found 492.1626.

[0086] Example 22

[0087]

[0088] In a Schlenk flask was added 1,6- enyne 70.3 mg (0.2 mmol) of Formula la, sulfonhydrazide 76.0 mg (0.4 mmol) of Formula 2g, tetrabutylammonium iodide 36.9 mg (50 mol%), tert-butyl hydroperoxide 54.1 mg (3.0 equiv) and H20 (2.0 mL). The reaction flask was then placed at 70 °C, stirred until complete consumption of starting material was monitored by TLC or GC-MS analysis. After the reaction was completed, the mixture was extracted with ethyl acetate three times. The resulting organic layer was dried over Na2S04, filtered, and the solvent was evaporated. The mixture was then purified by silica gel column chromatography (elution solvent: petroleum ether / ethyl acetate = 5:1) to obtain the target product I-7 (77% yield).

[0089] The structural characterization data of the target product I-7 are: 1H NMR(400MHz, CDCl3)δ:7.30-7.27(m,3H),7.20-7.17(m,4H),7.14-7.11(m,3H),7.08(d,J=7.6Hz,2H),6.97(d, J=7.2Hz,2H),6.85(t,J=8.8Hz,2H),6.71(d,J=6.8Hz,2H),5.23(s,2H),5.04(s,1H),4.86(s,1H),3.46(s,2H); 13 C NMR(101MHz,CDCl3)δ:171.0,164.4(d,J C-F =257.2Hz),143.7,142.8,142.6,140.4,137.5,136.1(2),130.6(d,J C-F =9.7Hz),130.0,129.7,128.9,128.4,128.2,127.7,127.0,126.5,123.0,119.5,115.9(d,J C-F =22.7Hz),54.0,40.3,31.4,29.7; 19 FNMR(377MHz, CDCl3)δ:-103.9; HRMS m / z(ESI)calcd for C 31 H 25 FNO3S([M+H] + )510.1534,found510.1532.

[0090] Example 23

[0091]

[0092] A Schlenk reaction flask was charged with 70.3 mg (0.2 mmol) of the 1,6-enyne of Formula 1a, 82.4 mg (0.4 mmol) of the sulfonylhydrazide of Formula 2h, 36.9 mg (50 mol%) of tetrabutylammonium iodide, 54.1 mg (3.0 equiv) of tert-butyl peroxide, and 2.0 mL of H₂O. The reaction flask was then stirred at 70°C until complete consumption of the starting material was observed by TLC or GC-MS analysis. After completion of the reaction, the mixture was extracted three times with ethyl acetate. The resulting organic layer was dried over Na₂SO₄, filtered, and the solvent evaporated. The mixture was then purified by silica gel column chromatography (eluting solvent: petroleum ether / ethyl acetate = 4:1) to obtain the desired product I-8 (80% yield).

[0093] The structural characterization data of the target product I-8 are: 1H NMR(400MHz, CDCl3)δ:7.32-7.29(m,3H),7.20-7.17(m,2H),7.15-7.11(m,5H),7.09-7.06(m,4H) ,6.97(d,J=7.2Hz,2H),6.70(d,J=6.8Hz,2H),5.23(s,2H),5.03(s,1H),4.86(s,1H),3.46(s,2H); 13 C NMR (101MHz, CDCl3) δ: 171.0, 143.7, 142.7, 142.6, 140.4, 139.7, 138.6, 137.5, 130.0, 129.7, 129. 2,129.0(2),128.9,128.4,128.2,127.7,127.0,126.5,123.1,119.5,54.0,40.4,31.4,29.7; HRMS m / z(ESI)calcd for C 31 H 25 ClNO3S([M+H] + )526.1238,found 526.1237.

[0094] Example 24

[0095]

[0096] A Schlenk reaction flask was charged with 70.3 mg (0.2 mmol) of the 1,6-enyne of Formula 1a, 100.0 mg (0.4 mmol) of the sulfonylhydrazine of Formula 2i, 36.9 mg (50 mol%) of tetrabutylammonium iodide, 54.1 mg (3.0 equiv) of tert-butyl peroxide, and 2.0 mL of H₂O. The reaction flask was then heated at 70°C and stirred until complete consumption of the starting material was observed by TLC or GC-MS analysis. After completion of the reaction, the mixture was extracted three times with ethyl acetate. The resulting organic layer was dried over Na₂SO₄, filtered, and the solvent evaporated. The mixture was then purified by silica gel column chromatography (eluting solvent: petroleum ether / ethyl acetate = 6:1) to obtain the desired product I-9 (77% yield).

[0097] The structural characterization data of the target product I-9 are: 1H NMR(400MHz, CDCl3)δ:7.38-7.36(m,4H),7.26-7.22(m,2H),7.21-7.17(m,4H),7.16-7.12(m, 2H),7.08-7.04(m,4H),6.78-6.75(m,2H),5.30(s,2H),5.10(s,1H),4.94(s,1H),3.53(s,2H); 13 C NMR(101MHz, CDCl3)δ:171.0,143.7,142.7,142.6,140.4,139.1,137.5,131.9,130.0,129.7,129. 2,129.0(2),128.4,128.3,128.2,127.7,127.0,126.5,123.1,119.5,54.0,40.4,32.5,29.3; HRMS m / z(ESI)calcd for C 31 H 25 BrNO3S([M+H] + )570.0733,found 570.0731.

[0098] Example 25

[0099]

[0100] A Schlenk reaction flask was charged with 70.3 mg (0.2 mmol) of the 1,6-enyne of Formula 1a, 78.9 mg (0.4 mmol) of the sulfonylhydrazine of Formula 2j, 36.9 mg (50 mol%) of tetrabutylammonium iodide, 54.1 mg (3.0 equiv) of tert-butyl peroxide, and 2.0 mL of H₂O. The reaction flask was then stirred at 70°C for a period of time until complete consumption of the starting material was observed by TLC or GC-MS analysis. After completion of the reaction, the mixture was extracted three times with ethyl acetate. The resulting organic layer was dried over Na₂SO₄, filtered, and the solvent evaporated. The mixture was then purified by silica gel column chromatography (eluting solvent: petroleum ether / ethyl acetate = 4:1) to obtain the desired product I-10 (76% yield).

[0101] The structural characterization data of the target product I-10 are: 1H NMR (400MHz, CDCl3) δ: 7.49 (d, J = 8.4Hz, 2H), 7.39-7.35 (m, 3H), 7.29-7.26 (m, 3H), 7.24-7.22 (m, 1H), 7.21-7.18 (m, 3H) ,7.11(t,J=7.6Hz,2H),7.05(d,J=6.8Hz,2H),6.74(d,J=7.2Hz,2H),5.32(s,2H),5.10(s,1H),4.96(s,1H),3.53(s,2H); 13 C NMR(101MHz, CDCl3)δ:171.0,144.4,143.6,142.4,142.2,140.4,137.4,132.2,129.8,129.6,129.2,1 29.0,128.4,128.2(2),127.8,127.2,126.5,123.6,119.6,117.1,116.4,53.9,40.4,31.9,29.6; HRMS m / z(ESI)calcd for C 32 H 25 N2O3S([M+H] + )517.1580,found 517.1579.

[0102] Example 26

[0103]

[0104] A Schlenk reaction flask was charged with 70.3 mg (0.2 mmol) of the 1,6-enyne of Formula 1a, 86.9 mg (0.4 mmol) of the sulfonylhydrazide of Formula 2k, 36.9 mg (50 mol%) of tetrabutylammonium iodide, 54.1 mg (3.0 equiv) of tert-butyl peroxide, and 2.0 mL of H₂O. The reaction flask was then stirred at 70°C until complete consumption of the starting material was observed by TLC or GC-MS analysis. After completion of the reaction, the mixture was extracted three times with ethyl acetate. The resulting organic layer was dried over Na₂SO₄, filtered, and the solvent evaporated. The mixture was then purified by silica gel column chromatography (eluting solvent: petroleum ether / ethyl acetate = 5:1) to obtain the desired product I-11 (71% yield).

[0105] The structural characterization data of the target product I-11 are: 1H NMR (400MHz, CDCl3) δ: 7.96 (d, J = 8.8Hz, 2H), 7.33-7.28 (m, 3H), 7.24 (s, 1H), 7.21-7.16 (m, 3H), 7.14-7. 11(m,3H),7.05-6.98(m,4H),6.68(d,J=7.6Hz,2H),5.27(s,2H),5.03(s,1H),4.90(s,1H),3.46(s,2H); 13 C NMR(101MHz, CDCl3)δ:171.0,149.9,145.9,143.6,142.5,142.2,140.5,137.4,129.8,129.7,129.3 ,129.1,128.9,128.4,128.3,127.8,127.3,126.5,123.7,123.6,119.7,53.9,40.4,31.4,29.7; HRMS m / z(ESI)calcd for C 31 H 25 N2O5S([M+H] + )537.1479,found537.1480.

[0106] Example 27

[0107]

[0108] A Schlenk reaction flask was charged with 70.3 mg (0.2 mmol) of the 1,6-enyne of Formula 1a, 85.7 mg (0.4 mmol) of the sulfonylhydrazide of Formula 21, 36.9 mg (50 mol%) of tetrabutylammonium iodide, 54.1 mg (3.0 equiv) of tert-butyl peroxide, and 2.0 mL of H₂O. The reaction flask was then stirred at 70°C for a period of time until complete consumption of the starting material was observed by TLC or GC-MS analysis. After completion of the reaction, the mixture was extracted three times with ethyl acetate. The resulting organic layer was dried over Na₂SO₄, filtered, and the solvent evaporated. The mixture was purified by silica gel column chromatography (eluting solvent: petroleum ether / ethyl acetate = 3:1) to obtain the desired product I-12 (80% yield).

[0109] The structural characterization data of the target product I-12 are: 1H NMR(400MHz, CDCl3)δ:7.29(t,J=3.2Hz,3H),7.20-7.17(m,2H),7.16-7.13(m,4H),7.00-6.97(m,3H) ,6.88(t,J=7.6Hz,2H),6.56(s,2H),5.27(s,2H),5.06(s,1H),4.88(s,1H),3.47(s,2H),2.13(s,9H); 13 C NMR(101MHz, CDCl3)δ:171.0,145.4,143.8,142.6,142.0,140.7,138.9,137.6,135.3,131.7,129.8,129. 7,128.9,128.5,128.3,128.1,127.5,126.5,126.4,119.8,119.7,54.1,40.4,31.4,29.7,22.0,20.8; HRMS m / z(ESI)calcd for C 34 H 32 NO3S([M+H] + )534.2097,found534.2095.

[0110] Example 28

[0111]

[0112] A Schlenk reaction flask was charged with 70.3 mg (0.2 mmol) of the 1,6-enyne of Formula 1a, 88.9 mg (0.4 mmol) of the sulfonylhydrazide of Formula 2m, 36.9 mg (50 mol%) of tetrabutylammonium iodide, 54.1 mg (3.0 equiv) of tert-butyl peroxide, and 2.0 mL of H₂O. The reaction flask was then stirred at 70°C for a period of time until complete consumption of the starting material was observed by TLC or GC-MS analysis. After completion of the reaction, the mixture was extracted three times with ethyl acetate. The organic layer was dried over Na₂SO₄, filtered, and the solvent was evaporated. The mixture was purified by silica gel column chromatography (eluting solvent: petroleum ether / ethyl acetate = 6:1) to obtain the desired product I-13 (79% yield).

[0113] The structural characterization data of the target product I-13 are: 1H NMR (400 MHz, CDC13) δ: 7.82 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 8.8 Hz, 1H), 7.71-7.66 (m, 2H), 7.61 (t, J = 7.6 Hz, 1H), 7.53 (t, J = 7.6 Hz, 1H), 7.38-7.36 (m, 2H), 7.33-7.30 (m, 1H), 7.26-7.20 (m, 5H), 7.06-7.02 (m, 3H), 6.96 (t, J = 7.6 Hz, 2H), 6.72 (d, J = 7.2 Hz, 2H), 5.37 (s, 2H), 5.13 (s, 1H), 4.93 (s, 1H), 3.55 (s, 2H); 13 C NMR (101 MHz, CDC13) δ: 171.1, 143.9, 143.1, 142.5, 140.5, 137.6, 136.8, 134.8, 131.8, 130.1, 130.0, 129.7, 129.4, 129.1, 129.0, 128.9, 128.4, 128.2, 127.7, 127.4, 127.3, 127.0, 126.4, 122.9, 122.2, 119.4, 54.3, 40.4, 31.5, 29.7; HRMS m / z (ESI) calcd for C 35 H 28 NO3S ([M+H] + ) 542.1784, found 542.1782.

[0114] Example 29

[0115]

[0116] A Schlenk flask was charged with 1,6- enyne 70.3 mg (0.2 mmol) of Formula la, sulfonhydrazide 71.3 mg (0.4 mmol) of Formula 2n, tetrabutylammonium iodide 36.9 mg (50 mol%), tert-butyl hydroperoxide 54.1 mg (3.0 equiv) and H2O (2.0 mL). The flask was then placed at 70 °C and stirred for a certain time until complete consumption of the starting material was monitored by TLC or GC-MS analysis. After the reaction was completed, the mixture was extracted with ethyl acetate three times. The resulting organic layer was dried over Na2S04, filtered, and the solvent was evaporated. The mixture was then purified by silica gel column chromatography (elution solvent: petroleum ether / ethyl acetate = 4:1) to obtain the target product I-14 (73% yield).

[0117] The structural characterization data of the target product I-14 are as follows: 1H NMR (500 MHz, CDC13) δ: 7.59-7.58 (m, 1H), 7.36-7.33 (m, 3H), 7.24-7.20 (m, 6H), 7.17-7.16 (m, 2H), 7.04 (d, J = 7.0 Hz, 2H), 6.92-6.90 (m, 3H), 5.29 (s, 2H), 5.11 (s, 1H), 4.92 (s, 1H), 3.52 (s, 2H); 13 C NMR (126 MHz, CDC13) δ: 171.1, 143.8, 143.1, 142.4, 140.9, 140.4, 137.6, 135.1, 134.3, 130.1, 129.9, 129.7, 128.9, 128.4, 128.2, 127.7, 127.4, 126.7, 126.5, 123.8, 51.8, 40.4, 29.7, 29.3; HRMS m / z (ESI) calcd for C 29 H 24 NO3S2([M+H] + )498.1192, found 498.1193.

[0118] Example 30

[0119]

[0120] In a Schlenk flask, 1,6-alkyne 70.3 mg (0.2 mmol) of formula la, sulfonhydrazide 49.7 mg (0.4 mmol) of formula 2o, tetrabutylammonium iodide 36.9 mg (50 mol%), tert-butyl hydroperoxide 54.1 mg (3.0 equiv) and H2O (2.0 mL) were added. Then the reaction flask was placed at 70 °C and stirred for a certain time until the complete consumption of the starting material was monitored by TLC or GC-MS analysis. After the reaction was completed, the mixture was extracted with ethyl acetate three times. The resulting organic layer was dried over Na2S04, filtered, and the solvent was evaporated. The mixture was then purified by silica gel column chromatography (elution solvent: petroleum ether / ethyl acetate = 5:1) to obtain the target product I-15 (52% yield).

[0121] The structural characterization data of the target product I-15 are as follows: 1H NMR(500MHz, CDCl3)δ:7.51-7.47(m,1H),7.34(t,J=3.5Hz,3H),7.29(t,J=6.5Hz,3H),7.19-7.17(m,3H),7.12-7.10(m, 2H),7.04(d,J=7.5Hz,2H),5.25(s,2H),5.08(s,1H),4.92(s,1H),3.50(s,2H),2.55-2.51(m,2H),1.10(t,J=7.5Hz,3H); 13 C NMR(126MHz, CDCl3)δ:171.0,143.7,142.8,141.1,140.5,137.5,129.8,129.7,129.4,128. 9,128.4,127.9,127.1,126.5,122.7,121.9,119.6,61.9,55.8,49.2,44.2,40.4,6.4; HRMS m / z(ESI)calcd for C 27 H 26 NO3S([M+H] + )444.1628,found444.1626.

[0122] Example 31

[0123]

[0124] A Schlenk reaction flask was charged with 76.3 mg (0.2 mmol) of the 1,6-enyne of Formula 1b, 74.5 mg (0.4 mmol) of the sulfonylhydrazide of Formula 2a, 36.9 mg (50 mol%) of tetrabutylammonium iodide, 54.1 mg (3.0 equiv) of tert-butyl peroxide, and 2.0 mL of H₂O. The reaction flask was then heated at 70°C and stirred until complete consumption of the starting material was observed by TLC or GC-MS analysis. After completion of the reaction, the mixture was extracted three times with ethyl acetate. The resulting organic layer was dried over Na₂SO₄, filtered, and the solvent evaporated. The mixture was then purified by silica gel column chromatography (eluting solvent: petroleum ether / ethyl acetate = 3:1) to obtain the desired product I-16 (89% yield).

[0125] The structural characterization data of the target product I-16 are: 1H NMR (400 MHz, CDC13) δ: 7.17 (t, J = 8.0 Hz, 5H), 7.11-7.07 (m, 3H), 7.03-6.99 (m, 5H), 6.79-6.74 (m, 4H), 5.14 (s, 2H), 5.04 (s, 1H), 4.85 (s, 1H), 3.78 (s, 3H), 3.44 (s, 2H), 2.29 (s, 3H); 13 C NMR (101 MHz, CDC13) δ: 171.4, 159.2, 144.1, 144.0, 143.0, 142.7, 137.7, 137.2, 133.0, 131.2, 129.7, 129.4, 128.8, 128.3, 128.0, 127.5, 126.9, 126.4, 122.9, 119.1, 113.9, 55.5, 54.3, 40.4, 29.8, 29.3, 21.6; HRMS m / z (ESI) calcd for C 33 H 30 NO4S ([M+H] + ) 536.1890, found 536.1889.

[0126] Example 32

[0127]

[0128] In a Schlenk flask was added 1,6- enyne 73.1 mg (0.2 mmol) of Formula 1c, sulfonhydrazide 74.5 mg (0.4 mmol) of Formula 2a, tetrabutylammonium iodide 36.9 mg (50 mol%), tert-butyl hydroperoxide 54.1 mg (3.0 equiv) and H2O (2.0 mL). The reaction flask was then placed at 70 °C, stirred until complete consumption of starting material was monitored by TLC or GC-MS analysis. After the reaction was completed, the mixture was extracted with ethyl acetate three times. The resulting organic layer was dried over Na2S04, filtered, and the solvent was evaporated. The mixture was then purified by silica gel column chromatography (elution solvent: petroleum ether / ethyl acetate = 6:1) to give the target product I-17 (88% yield).

[0129] The structural characterization data of the target product I-17 are: 1H NMR(400MHz, CDCl3)δ:7.28(t,J=3.2Hz,2H),7.24-7.21(m,3H),7.19-7.15(m,4H),7.08(t,J=8.4Hz,6H ),6.85(d,J=6.8Hz,2H),5.25(s,2H),5.14(s,1H),4.93(s,1H),3.54(s,2H),2.43(s,3H),2.38(s,3H); 13 C NMR (101MHz, CDCl3) δ: 171.2, 144.1, 143.9, 143.0, 142.8, 138.0, 137.8, 137.7, 137.2, 129.8, 129.7, 129. 4,129.3,128.7,128.3,127.9,127.5,127.0,126.4,122.8,119.2,54.1,40.3,31.4,29.7,21.6,21.3; HRMS m / z(ESI)calcd for C 33 H 30 NO3S([M+H] + )520.1941,found520.1942.

[0130] Example 33

[0131]

[0132] A Schlenk reaction flask was charged with 77.2 mg (0.2 mmol) of 1,6-enyne represented by Formula 1d, 74.5 mg (0.4 mmol) of sulfonylhydrazide represented by Formula 2a, 36.9 mg (50 mol%) of tetrabutylammonium iodide, 54.1 mg (3.0 equiv) of tert-butyl peroxide, and 2.0 mL of H₂O. The reaction flask was then stirred at 70°C until complete consumption of the starting material was observed by TLC or GC-MS analysis. After completion of the reaction, the mixture was extracted three times with ethyl acetate. The resulting organic layer was dried over Na₂SO₄, filtered, and the solvent was evaporated. The mixture was then purified by silica gel column chromatography (eluting solvent: petroleum ether / ethyl acetate = 4:1) to obtain the desired product I-18 (83% yield).

[0133] The structural characterization data of the target product I-18 are: 1H NMR(400MHz, CDCl3)δ:7.22-7.19(m,4H),7.16-7.12(m,3H),7.10-7.07(m,2H),7.02-6.96(m ,6H),6.73(d,J=7.2Hz,2H),5.14(s,2H),5.02(s,1H),4.95(s,1H),3.48(s,2H),2.30(s,3H); 13 C NMR(101MHz, CDCl3)δ:170.8,144.2,143.5,142.8,142.7,139.1,137.5,137.1,133.9,131.3,129.7,129.4,12 9.0,128.9,128.5,127.9,127.6,126.9,126.6,123.0,119.7,54.5,40.5,29.3,27.2,21.6; HRMSm / z(ESI)calcd for C 32 H 27 ClNO3S([M+H] + )540.1395,found 540.1393.

[0134] Example 34

[0135]

[0136] A Schlenk reaction flask was charged with 83.9 mg (0.2 mmol) of the 1,6-enyne of Formula 1e, 74.5 mg (0.4 mmol) of the sulfonylhydrazide of Formula 2a, 36.9 mg (50 mol%) of tetrabutylammonium iodide, 54.1 mg (3.0 equiv) of tert-butyl peroxide, and 2.0 mL of H₂O. The reaction flask was then stirred at 70°C for a period of time until complete consumption of the starting material was observed by TLC or GC-MS analysis. After completion of the reaction, the mixture was extracted three times with ethyl acetate. The resulting organic layer was dried over Na₂SO₄, filtered, and the solvent evaporated. The mixture was then purified by silica gel column chromatography (eluting solvent: petroleum ether / ethyl acetate = 5:1) to obtain the desired product I-19 (72% yield).

[0137] The structural characterization data of the target product I-19 are: 1H NMR (400MHz, CDCl3) δ: 7.48 (d, J = 8.4Hz, 2H), 7.20-7.14 (m, 5H), 7.10 (t, J = 4.0Hz, 2H), 7.06 (d, J = 7.6Hz, 2H) ,7.00(t,J=6.4Hz,4H),6.66(d,J=7.6Hz,2H),5.19(s,2H),5.01(d,J=12.8Hz,2H),3.50(s,2H),2.28(s,3H); 13 C NMR (101MHz, CDCl3) δ: 170.7, 144.2, 143.9, 143.3, 142.7, 142.6, 137.4, 137. 1,130.2,129.6,129.4,128.9,128.5,127.8,127.6,127.0,126.6,125.9(q,J C-F =3.6Hz),122.9,120.2,54.6,40.5,29.7,29.3,21.5; 19 F NMR(376MHz, CDCl3)δ:-62.4; HRMS m / z(ESI)calcd for C 33 H 27 F3NO3S([M+H] + )574.1658,found 574.1659.

[0138] Example 35

[0139]

[0140] A Schlenk reaction flask was charged with 73.1 mg (0.2 mmol) of the 1,6-enyne of Formula 1f, 74.5 mg (0.4 mmol) of the sulfonylhydrazide of Formula 2a, 36.9 mg (50 mol%) of tetrabutylammonium iodide, 54.1 mg (3.0 equiv) of tert-butyl peroxide, and 2.0 mL of H₂O. The reaction flask was then stirred at 70°C until complete consumption of the starting material was observed by TLC or GC-MS analysis. After completion of the reaction, the mixture was extracted three times with ethyl acetate. The resulting organic layer was dried over Na₂SO₄, filtered, and the solvent evaporated. The mixture was then purified by silica gel column chromatography (eluting solvent: petroleum ether / ethyl acetate = 4:1) to obtain the desired product I-20 (73% yield).

[0141] The structural characterization data of the target product I-20 are: 1H NMR(400MHz, CDCl3)δ:7.22-7.17(m,7H),7.09-7.06(m,3H),7.01(t,J=7.6Hz,3H),6.92(d,J=8.0Hz,3H ),6.82(d,J=7.6Hz,2H),5.41(s,1H),5.08(s,1H),4.86(s,2H),4.71(s,2H),3.66(s,2H),2.26(s,3H); 13 C NMR(101MHz, CDCl3)δ:173.1,143.7,143.6,142.7,142.6(2),137.7,137.6,136.9,129.8,129.7,1 29.1,128.8(2),128.5,127.9,127.5,127.4,126.5,117.1,53.7,53.0,40.0,29.7,29.3,21.5; HRMS m / z(ESI)calcd for C 33 H 30 NO3S([M+H] + )520.1941,found520.1942.

[0142] Example 36

[0143]

[0144] A Schlenk reaction flask was charged with 80.0 mg (0.2 mmol) of 1,6-enyne represented by Formula 1g, 74.5 mg (0.4 mmol) of sulfonylhydrazide represented by Formula 2a, 36.9 mg (50 mol%) of tetrabutylammonium iodide, 54.1 mg (3.0 equiv) of tert-butyl peroxide, and 2.0 mL of H2O. The reaction flask was then placed at 70°C and stirred until complete consumption of the starting material was observed by TLC or GC-MS analysis. After completion of the reaction, the mixture was extracted three times with ethyl acetate. The resulting organic layer was dried over Na2SO4, filtered, and the solvent evaporated. The mixture was then purified by silica gel column chromatography (eluting solvent: petroleum ether / ethyl acetate = 3:1) to obtain the target product I-21 (67% yield). The structural characterization data of the product are as follows: 1H NMR(400MHz, CDCl3)δ:7.28(t,J=2.4Hz,3H),7.25-7.22(m,4H),7.13(t,J=6.4Hz,3H),7.10-7.06(m,3H),6.98(d, J=8.0Hz,2H),6.86(d,J=6.8Hz,2H),5.48(s,1H),5.27(s,1H),4.88(s,2H),4.70(s,2H),3.76(s,2H),2.33(s,3H); 13 C NMR(101MHz, CDCl3)δ:172.9,143.8,143.4,142.4,137.5,133.1,130.9,129.6,129.3,129.2,129.0,1 28.9,128.8,128.6,128.0,127.8,127.5,127.4,126.6,117.4,53.6,52.3,40.4,34.6,29.6,21.5; HRMS m / z(ESI)calcd for C 33 H 29 ClNO3S([M+H] + )554.1551,found 554.1550.

[0145] Example 37

[0146]

[0147] A Schlenk reaction flask was charged with 76.3 mg (0.2 mmol) of 1,6-enyne represented by Formula 1h, 74.5 mg (0.4 mmol) of sulfonylhydrazide represented by Formula 2a, 36.9 mg (50 mol%) of tetrabutylammonium iodide, 54.1 mg (3.0 equiv) of tert-butyl peroxide, and 2.0 mL of H₂O. The reaction flask was then placed at 70°C and stirred until complete consumption of the starting material was observed by TLC or GC-MS analysis. After completion of the reaction, the mixture was extracted three times with ethyl acetate. The resulting organic layer was dried over Na₂SO₄, filtered, and the solvent was evaporated. The mixture was then purified by silica gel column chromatography (eluting solvent: petroleum ether / ethyl acetate = 6:1) to obtain the target product I-22 (83% yield). The structural characterization data of the product are as follows: 1H NMR(400MHz, CDCl3)δ:7.38-7.34(m,3H),7.28(d,J=3.6Hz,1H),7.22(t,J=6.0Hz,5H),7.10-7.06(m,4H),6.76(d, J=8.4Hz,2H),6.65(d,J=8.4Hz,2H),5.29(s,2H),5.13(s,1H),4.94(s,1H),3.80(s,3H),3.55(s,2H),2.38(s,3H); 13 C NMR(101MHz, CDCl3)δ:171.0,159.9,143.9,142.6,140.4,137.6,137.4,135.2,130.0,129.7,129.2,1 29.0,128.8,128.3,128.1,127.7,126.4,123.3,119.3,112.9,55.3,54.3,40.3,31.5,29.7,21.6; HRMS m / z(ESI)calcd for C 33 H 30 NO4S([M+H] + )536.1890,found 536.1892.

[0148] Example 38

[0149]

[0150] A Schlenk reaction flask was charged with 77.2 mg (0.2 mmol) of the 1,6-enyne of Formula 1i, 74.5 mg (0.4 mmol) of the sulfonylhydrazide of Formula 2a, 36.9 mg (50 mol%) of tetrabutylammonium iodide, 54.1 mg (3.0 equiv) of tert-butyl peroxide, and 2.0 mL of H₂O. The reaction flask was then stirred at 70°C until complete consumption of the starting material was observed by TLC or GC-MS analysis. After completion of the reaction, the mixture was extracted three times with ethyl acetate. The resulting organic layer was dried over Na₂SO₄, filtered, and the solvent evaporated. The mixture was then purified by silica gel column chromatography (eluting solvent: petroleum ether / ethyl acetate = 4:1) to obtain the desired product I-23 (80% yield).

[0151] The structural characterization data of the target product I-23 are: 1H NMR(400MHz, CDCl3)δ:7.30-7.25(m,3H),7.20-7.16(m,4H),7.13-7.10(m,2H),7.06-7.03(m,4H),6.97( d,J=7.2Hz,2H),6.66(d,J=8.4Hz,2H),5.16(s,2H),5.03(s,1H),4.85(s,1H),3.45(s,2H),2.31(s,3H); 13 C NMR(101MHz, CDCl3)δ:171.0,144.4,143.8,143.6,141.3,140.4,137.5,137.0,134.9,130.0,129.7 ,129.4,128.9,128.4,128.2,127.9,127.8,126.5,120.7,119.5,54.1,40.3,29.7,29.3,21.6; HRMS m / z(ESI)calcd for C 32 H 27 ClNO3S([M+H] + )540.1395,found540.1396.

[0152] Example 39

[0153]

[0154] A Schlenk reaction flask was charged with 55.3 mg (0.2 mmol) of the 1,6-enyne of Formula 1j, 80.8 mg (0.4 mmol) of the sulfonylhydrazide of Formula 2d, 36.9 mg (50 mol%) of tetrabutylammonium iodide, 54.1 mg (3.0 equiv) of tert-butyl peroxide, and 2.0 mL of H₂O. The reaction flask was then stirred at 70°C for a period of time until complete consumption of the starting material was observed by TLC or GC-MS analysis. After completion of the reaction, the mixture was extracted three times with ethyl acetate. The resulting organic layer was dried over Na₂SO₄, filtered, and the solvent evaporated. The mixture was then purified by silica gel column chromatography (eluting solvent: petroleum ether / ethyl acetate = 5:1) to obtain the desired product I-24 (81% yield).

[0155] The structural characterization data of the target product I-24 are: 1H NMR (400MHz, CDCl3) δ: 7.34-7.30 (m, 4H), 7.22 (d, J = 8.0Hz, 4H), 7.10-7.07 (m, 2H), 6.88-6.83 ( m,1H),6.75(d,J=8.8Hz,2H),6.27(s,1H),5.51(s,1H),5.35(s,2H),3.81(s,3H),3.64(s,2H); 13 C NMR(101MHz, CDCl3)δ:166.0,163.4,143.6,142.2,139.3,138.4,138.3,130.1,129.9,12 8.2,129.1,128.5,127.7,127.2,126.4,114.9,114.0,69.1,55.7,41.3,39.5,37.9; HRMS m / z(ESI)calcd forC 26 H 23 O5S([M+H] + )447.1261,found 447.1260.

[0156] Example 40

[0157]

[0158] A Schlenk reaction flask was charged with 55.3 mg (0.2 mmol) of 1,6-enyne represented by Formula 1j, 74.5 mg (0.4 mmol) of sulfonylhydrazide represented by Formula 2a, 36.9 mg (50 mol%) of tetrabutylammonium iodide, 54.1 mg (3.0 equiv) of tert-butyl peroxide, and 2.0 mL of H2O. The reaction flask was then placed at 70°C and stirred until complete consumption of the starting material was observed by TLC or GC-MS analysis. After completion of the reaction, the mixture was extracted three times with ethyl acetate. The resulting organic layer was dried over Na2SO4, filtered, and the solvent evaporated. The mixture was then purified by silica gel column chromatography (eluting solvent: petroleum ether / ethyl acetate = 6:1) to obtain the target product I-25 (76% yield). The structural characterization data of the product are as follows: 1 H NMR(400MHz, CDCl3)δ:7.35-7.31(m,4H),7.28(d,J=6.4Hz,2H),7.25(d,J=4.4Hz,2H) ,7.14-7.09(m,5H),6.29(s,1H),5.54(s,1H),5.38(s,2H),3.67(s,2H),2.39(s,3H); 13C NMR(101MHz, CDCl3)δ:166.0,144.3,143.4,142.2,139.3,138.4,137.2,129.3,129.2,12 9.0,128.5,128.4,127.8,127.6,127.2,126.4,123.9,69.0,41.3,39.5,37.9,21.5; HRMS m / z(ESI)calcd for C 26 H 23 O4S([M+H] + )431.1312,found 431.1313.

[0159] Example 41

[0160]

[0161] A Schlenk reaction flask was charged with 55.3 mg (0.2 mmol) of the 1,6-enyne of Formula 1j, 88.9 mg (0.4 mmol) of the sulfonylhydrazide of Formula 2m, 36.9 mg (50 mol%) of tetrabutylammonium iodide, 54.1 mg (3.0 equiv) of tert-butyl peroxide, and 2.0 mL of H₂O. The reaction flask was then stirred at 70°C until complete consumption of the starting material was observed by TLC or GC-MS analysis. After completion of the reaction, the mixture was extracted three times with ethyl acetate. The resulting organic layer was dried over Na₂SO₄, filtered, and the solvent evaporated. The mixture was then purified by silica gel column chromatography (eluting solvent: petroleum ether / ethyl acetate = 6:1) to obtain the desired product I-26 (71% yield).

[0162] The structural characterization data of the target product I-26 are: 1 H NMR(400MHz, CDCl3)δ:7.85(d,J=8.0Hz,1H),7.80(t,J=4.0Hz,2H),7.70(d,J=8.0Hz,1H),7.64(t,J=7.6Hz,1H),7.56(t,J=7.6Hz,1H),7.51-7.4 9(m,1H),7.29(d,J=7.2Hz,2H),7.19-7.17(m,3H),7.08(t,J=7.2Hz,2H) ,7.01-6.99(m,2H),6.25(s,1H),5.46(s,1H),5.44(s,2H),3.60(s,2H); 13C NMR(101MHz, CDCl3)δ:166.0,143.4,141.9,139.3,138.3,136.7,134.9,131.7,130.1,129.4,129.3,129. 2,129.1,128.5,128.4,127.8,127.5(2),127.3,127.2,126.4,124.4,122.2,69.0,41.3,39.5,37.9; HRMS m / z(ESI)calcd for C 29 H 23 O4S([M+H] + )467.1312,found 467.1310.

[0163] Example 42 Control Experiment

[0164]

[0165] When 3.3 equivalents of the free radical inhibitor 2,2,6,6-tetramethylpiperidin-1-oxide (TEMPO) or butylated hydroxytoluene (BHT) were added to the reaction in Example 1, the reaction was completely inhibited. Furthermore, free radical clock experiments using (1-cyclopropylvinyl)benzene as a probe yielded only a 23% yield of the dicyclization product, and 3a was detected by nuclear magnetic resonance analysis. These results suggest that the dicyclization likely occurs via a free radical process.

[0166] It can be seen from this that the reaction mechanism of the dicyclization reaction of the present invention is deduced as shown below:

[0167]

[0168] The above embodiments are only preferred embodiments of the present invention and are not exhaustive of the feasible implementations of the present invention. For those skilled in the art, any obvious modifications made thereto without departing from the principles and spirit of the present invention should be considered to be included in the scope of protection of the claims of the present invention.

Claims

1. A method for the dicyclization reaction of 1,6-enyne compounds and sulfonylhydrazide, characterized in that: The 1,6-enyne compound, sulfonylhydrazide, a catalyst, and an oxidant are mixed with water and reacted to obtain a heteropolycyclic compound; Wherein, the catalyst is one or more of tetrabutylammonium iodide, iodine, N-iodosuccinimide, potassium iodide, and ammonium iodide; the oxidant is one or more of tert-butyl peroxide, tert-butyl perbenzoate, dibenzoyl peroxide, and di-tert-butyl peroxide; The chemical formula of the 1,6-enyne compound is shown in Formula 1: The chemical formula of the sulfonylhydrazine is shown in Formula 2: The chemical formula of the heteropolycyclic compound is shown in Formula I: Where Y is NR 2 or O; R 1 is selected from phenyl, methoxyphenyl or chlorophenyl; R 2 is selected from phenyl, methoxyphenyl, methylphenyl, chlorophenyl, trifluoromethylphenyl, benzyl or chlorobenzyl; R 3 is selected from phenyl, tolyl, methoxyphenyl, tert-butylphenyl, halophenyl, cyanophenyl, nitrophenyl, mesityl, naphthyl, thienyl or ethyl.

2. The bicyclization reaction method according to claim 1, wherein When mixed, the molar volume ratio of the 1,6-enyne compound, sulfonylhydrazide and water is 0.25-0.3 mmol: 0.35-0.45 mmol: 1-3 mL, the amount of the oxidant is 2-4 equivalents, and the amount of the catalyst is 30-80 mol%.

3. The bicyclization reaction method according to claim 1, wherein The molar volume ratio of the 1,6-enyne compound, sulfonylhydrazide and water is 0.22-0.28 mmol: 0.38-0.42 mmol: 1.5-2.5 mL, the amount of the oxidant is 2.5-3.5 equivalents, and the amount of the catalyst is 50-70 mol%.

4. The bicyclization reaction method according to claim 1, wherein The reaction was carried out at 50-90°C.

5. The bicyclization reaction method according to claim 4, wherein The reaction was carried out at 60-80°C.

6. The bicyclization reaction method according to claim 1, characterized in that The reaction was carried out under air atmosphere.

7. The dicyclization reaction method according to any one of claims 1 to 6, characterized in that After the reaction is completed, the reaction solution is extracted with ethyl acetate 2-4 times to obtain an organic phase; the organic phase is then dried over anhydrous sodium sulfate, filtered and evaporated to remove the ethyl acetate to obtain a mixture; then, the mixture is purified to obtain a heteropolycyclic compound.

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