A method for the synthesis of iodinated sulfonamidated electron-poor olefins

Abstract

The application discloses a novel method for iodinating sulfonamide of electron-deficient olefins, which adopts electron-deficient olefins, sulfonamide and N - iodobutyrolactimide as a reaction substrate, trifluoromethanesulfonic acid as an acid, hexafluoroisopropanol as an additive, and n-hexane as a solvent. Compared with the prior art, the method has the following advantages: a simple reaction system; a wide substrate range, primary and secondary aromatic and aliphatic sulfonamides are suitable for the method; a high reaction yield; and simple operation and cheap and easily available raw materials.

Description

Technical Field

[0001] This invention relates to a novel method for the iodide sulfonamide synthesis of electron-depleted olefins, belonging to the field of organic synthesis technology. Background Technology

[0002] Olefins are an important class of hydrocarbons whose molecular structure contains at least one carbon-carbon double bond. These compounds typically possess unique chemical properties. Olefins have a wide range of applications, serving as fundamental raw materials for many industrial chemical products, including the production of plastics, rubber, and synthetic fibers. Olefins are also used in the energy industry as an important component of fuels and chemical products. In the pharmaceutical field, many drugs also contain olefin structures. These compounds may possess anticancer, anti-infective, anti-inflammatory, and other biological activities. Examples include: Axitinib, an anti-tumor drug primarily used clinically for adult patients with advanced renal cell carcinoma (RCC) who have failed prior treatment with a tyrosine kinase inhibitor or cytokine; Paclitaxel, an anti-tumor drug commonly used to treat various cancers, including ovarian, breast, lung, gastric, and prostate cancer, which inhibits cancer cell division and growth by interfering with the normal division process of tumor cells; Epoxymicheliolide, a structural analogue of Parthenolide, which effectively inhibits the proliferation, invasion, and migration of renal cancer; and Testosterone and its derivatives used in androgen replacement therapy to treat male hypogonadism or androgen deficiency. However, one of the most classic reactions involving olefins as substrates is the bifunctionalization of olefins. The bifunctionalization of olefins not only allows for the economical and efficient one-step synthesis of multi-site reaction products, but also enables the conversion of starting materials into a variety of compounds with biological or pharmaceutical activity. Furthermore, it provides more methods for constructing diverse chemical structures. Therefore, the development of bifunctionalization reactions of olefins is of great importance.

[0003] The development of bifunctionalization reactions of alkenes has been very rapid. In the past decade or so, the main reports have focused on bifunctionalization reactions of alkenes catalyzed by transition metals (such as rhodium, palladium, iron, copper, silver, gold, etc.) and reactions using small organic molecules as catalysts. For example: (1) In 2007, Shi's research group reported the diamineization reaction of conjugated alkenes using cuprous chloride as a catalyst and di-tert-butyldiazacyclopropionate as a nitrogen source. This reaction is carried out at the terminal alkene position, requires deuterated benzene as a solvent, and has a relatively limited substrate range. (Yuan, W.; Du, H.; Zhao, B.; Shi, Y. A Mild Cu(I)-Catalyzed Regioselective Diamination of Conjugated Dienes. Org. Lett. 2007,9, 13, 2589-2591.); (2) In 2010, the Chemler group first reported the asymmetric reaction of intramolecular diaminelation of olefins induced by copper catalyst, which can generate various functionalized nitrogen heterocyclic compounds. The reaction yield is high, but the reaction temperature needs to be carried out at a high temperature of 120℃, and the universality of the reaction substrate is poor. (Sequeira, FC; Turnpenny, BW; Chemler, SR Copper-Promoted and Copper-Catalyzed Intermolecular Alkene Diamination. Angew. Chem. 2010, 122, 6509-6512.); (3) In 2011, Feng's research group reported the chlorosulfonamide reaction of olefins using trivalent scandium as a catalyst. N,N - Using dichloro-p-toluenesulfonamide as a chlorine source, the reaction can achieve high yields and eeValue. The substrate universality of this reaction is poor, only using p-toluenesulfonamide as a sulfonamide substrate, and it is not compatible with other primary and secondary sulfonamides. (Cai, YF; Lui, XH; Jiang, J.; Chen, WL; Lin, LL; Feng, XM CatalyticAsymmetric Chloroamination Reaction of α, β-Unsaturated γ-Keto Esters and Chalcones. J. Am. Chem. Soc. 2011, 133, 5636-5639.); (4) In 2011, the Minakata group reported an iodination sulfonation reaction of alkenes using chloramine salts and elemental iodine. This reaction has good compatibility with electron-rich alkenes and general alkenes, but poor substrate universality for electron-poor alkenes, and the source of sulfonamides is also very limited. (Minakata, S.; Hayakawa, J. Iodoamidation of olefins with chloramine salts and iodine in aqueous media. Chem. Commun. 2011, 47, 1905-1907.); (5) In 2021, Leboeuf's group reported a method for achieving halogenation sulfonamide and halogenation lactone formation of olefins without the participation of metals and oxidants, promoted by hexafluoroisopropanol. The substrates for this reaction are limited to general olefins, and the substrate universality for intermolecular halogenation sulfonamide formation is poor (Qi, CX; Force, G.; Gandon, V.; Leboeuf, D. Hexafluoroisopropanol-Promoted Haloamidation and Halolactonization of Unactivated Alkenes. Angew. Chem. Int. Ed. 2021, 60, 946-953.).

[0004] In summary, the currently reported methods for the iodination sulfonamideation of electron-depleted olefins all have certain limitations, such as high reaction temperatures, the need for transition metal catalysts, harsh reaction conditions, and poor substrate universality. Therefore, it is particularly important to develop a method for the iodination sulfonamideation of electron-depleted olefins that is rich in raw materials, has a wide range of substrate adaptability, and is green, mild, efficient, and environmentally friendly. Summary of the Invention

[0005] The purpose of this invention is to provide a green and efficient method for the iodination and sulfonation of electron-poor olefins.

[0006] To achieve the above-mentioned objectives, the technical solution adopted by this invention is as follows:

[0007] A method for the iodination sulfonamideation of electron-deficient olefins includes the following steps: using an electron-deficient olefin, a sulfonamide, and... N -Iodosuccinimide is used as a reaction substrate and reacts in the presence of acid and alcohol additives to achieve iodination and sulfonation of electron-depleted olefins.

[0008] Specifically, this invention uses trifluoromethanesulfonic acid as the acid and hexafluoroisopropanol as an additive at room temperature, along with electron-depleted olefins, sulfonamides, and... N Using iodosuccinimide as a raw material and n-hexane as a solvent, the iodination sulfonamide of electron-depleted olefins is achieved to obtain the product iodinated sulfonamide compound.

[0009] In the above technical solution, the reaction is carried out in a solvent, and the organic solvent is acetone. N,N - Dimethylformamide, acetonitrile, dichloromethane, ethylene glycol dimethyl ether, n-hexane, tetrahydrofuran, ethyl acetate, toluene, etc.; n-hexane is preferred as the solvent.

[0010] In the above technical solution, the chemical structural formula of the electron-depleted olefin is as follows:

[0011] ;

[0012] The chemical structural formula of the sulfonamide compound is as follows:

[0013] ;

[0014] The chemical structural formula of the iodide sulfonamide compound, the iodide sulfonamide product of the electron-depleted olefin, is as follows:

[0015] ;

[0016] In the above chemical structural formula, R 1 Selected from substituted or unsubstituted alkyl groups, R 2 Selected from alkyl, substituted or unsubstituted (hetero)aryl groups, R 3 Selected from alkyl or hydrogen.

[0017] In the substituted alkyl, substituted aryl, and substituted heteroaryl groups, the substituents are independently selected from methyl, tert-butyl, fluorine, chlorine, ester, methoxy, trifluoromethyl, and trifluoromethoxy groups; for example, the substituted alkyl group contains a fluorine substituent group; the substituted aryl group contains methyl, tert-butyl, fluorine, chlorine, ester, methoxy, trifluoromethyl, and trifluoromethoxy substituent groups; the substituted heteroaryl group contains a chlorine substituent group; preferably, the substituted alkyl group is a C2 alkyl group, the substituted aryl group is a phenyl group, and the substituted heteroaryl group is a thiophene group.

[0018] In the above technical solution, the reaction time is 18–24 hours, and the temperature is 25°C–40°C. Preferably, the reaction time is 24 hours, and the temperature is 25°C.

[0019] In this invention, the acid comprises Brønsted acid and Lewis acid; the alcohol additive is a fluorinated small molecule alcohol. Preferably, the acid is trifluoroacetic acid, trifluoroacetic anhydride, trifluoromethanesulfonic acid, trifluoromethanesulfonic acid anhydride, boron trifluoride ethyl ether, or trimethylsilyl trifluoromethanesulfonate; more preferably, the acid is trifluoromethanesulfonic acid; the fluorinated small molecule alcohol is hexafluoroisopropanol.

[0020] In this invention, electron-depleted olefins, sulfonamides, N The molar ratio of iodosuccinimide to trifluoromethanesulfonic acid is (1-2):1:(1-2):(0.1-1); the preferred molar ratio is 2:1:2:1.

[0021] In this invention, the reaction substrates are inexpensive electron-depleted olefins, sulfonamides, and... N -Iodosuccinimide, with hexane as the solvent, trifluoromethanesulfonic acid as the acid, and hexafluoroisopropanol as the additive, are all readily available. The reaction of this invention is carried out in air. After the reaction, the product is purified conventionally, for example, by quenching the reaction system with a saturated sodium carbonate aqueous solution, followed by extraction three times with ethyl acetate, combining the organic phases, drying with anhydrous magnesium sulfate, removing the solvent and silica gel adsorption using a rotary evaporator, and obtaining the iodinated sulfonamide product of the electron-depleted olefin by simple column chromatography.

[0022] Due to the application of the above technical solution, the present invention has the following advantages compared with the prior art:

[0023] This invention achieves the iodination sulfonamideation of electron-depleted olefins using a green, mild, and environmentally friendly method. The reaction can occur at room temperature and requires a low activation energy. Furthermore, the substrates and additives used are inexpensive and readily available, eliminating the need for pre-synthesis or complex reaction systems, making it greener, milder, and more environmentally friendly compared to other reactions. The reaction is also a one-pot, one-step process, simplifying the operation. Existing methods for the iodination sulfonamideation of electron-depleted olefins require expensive transition metal catalysts or pre-synthesized substrates, involve harsh reaction conditions, and suffer from poor procedural economy and substrate versatility. In contrast, this invention offers advantages such as a wide substrate range, simple reaction conditions and operation, high product yield, and a green, mild, and environmentally friendly approach. Attached Figure Description

[0024] Figure 1 The 1H NMR spectrum of compound 4a is shown.

[0025] Figure 2 This is the carbon NMR spectrum of compound 4a.

[0026] Figure 3 This is a single-crystal unit cell structure diagram of compound 4g.

[0027] Figure 4 The 1H NMR spectrum of compound 4l is shown.

[0028] Figure 5 This is the carbon NMR spectrum of compound 4l. Detailed Implementation

[0029] In this invention, hexafluoroisopropanol is used as an additive and trifluoromethanesulfonic acid as an acid at room temperature, along with electron-depleted olefins, sulfonamides, and... N Using iodosuccinimide as a raw material and n-hexane as a solvent, the reaction achieves the iodination sulfonamideation of electron-depleted olefins. This invention employs a green, environmentally friendly, mild, efficient, and energy-saving strategy to synthesize the iodination sulfonamideation product of electron-depleted olefins. The reaction substrates are electron-depleted olefins, sulfonamides, and... N - Iodosuccinimide, the organic solvents n-hexane and trifluoromethanesulfonic acid, and the additive hexafluoroisopropanol are all commercially available products. The following experiments were conducted in air at 25°C, and the yield was the separation yield.

[0030] The invention will be further described below with reference to examples. The specific preparation operations and performance tests are conventional techniques.

[0031] Example 1

[0032]

[0033] Add to the reaction tube in sequence N- Iodosuccinimide 3 (0.4 mmol, 90.0 mg), sulfonamide 1a (0.2 mmol, 42.7 mg), n-hexane (2 mL), hexafluoroisopropanol (200 µL), electron-depleted olefin 2a (0.4 mmol, 51.3 mg), trifluoromethanesulfonic acid (0.2 mmol, 30.0 mg); then stirred at 25 °C in air for 24 hours; after the reaction was completed, the reaction system was quenched with saturated sodium carbonate aqueous solution, and then extracted three times with ethyl acetate. The organic phases were combined and dried with anhydrous magnesium sulfate. The solvent and silica gel adsorption were removed by rotary evaporation. The electron-depleted olefin iodinated sulfonamide product 4a was obtained by simple column chromatography with a yield of 87%. Figure 1 The image shows the 1H NMR spectrum of compound 4a. Figure 2 The following is the carbon NMR spectrum of compound 4a. The main test data of the obtained product are as follows. Analysis shows that the actual synthesized product is consistent with the theoretical analysis.

[0034] 1 H NMR (400 MHz, Chloroform- d ) δ 7.78 – 7.75 (m, 2H), 7.54 – 7.50 (m,2H), 5.45 – 5.40 (m, 1H), 4.51 (dd, J 1.34 (s, 9H), 0.93 (t, J = 7.4 Hz, 3H). 13 C NMR (100 MHz, Chloroform- d ) δ 170.6, 156.7, 136.7, 126.7, 126.2, 66.1, 47.2, 35.1, 31.0,30.2, 18.9, 17.0, 13.6.

[0035] Extended Implementation Examples

[0036] Based on Example 1, single-factor variations were performed, and the results are shown in Table 1.

[0037]

[0038] Example 2

[0039]

[0040] Add to the reaction tube in sequence N The reaction mixture consisted of iodosuccinimide 3 (0.4 mmol, 90.0 mg), sulfonamide 1b (0.2 mmol, 31.4 mg), n-hexane (2 mL), hexafluoroisopropanol (200 µL), electron-depleted olefin 2a (0.4 mmol, 51.3 mg), and trifluoromethanesulfonic acid (0.2 mmol, 30.0 mg). The mixture was stirred at 25 °C in air for 24 hours. After the reaction was complete, the reaction system was quenched with saturated sodium carbonate solution, and then extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous magnesium sulfate, and the solvent and silica gel adsorption were removed by rotary evaporation. The electron-depleted olefin iodinated sulfonamide product 4b was obtained by simple column chromatography with a yield of 95%. The main test data of the obtained product are as follows. Analysis shows that the actual synthesized product is consistent with the theoretical analysis.

[0041] 1 H NMR (400 MHz, Chloroform- d ) δ 7.86 – 7.84 (m, 2H), 7.61 – 7.57 (m,1H), 7.54 – 7.50 (m, 2H), 5.47 (t, J = 6.8 Hz, 1H), 4.49 (dd, J 0.92 (t, J = 7.4 Hz, 3H). 13 C NMR (100MHz, Chloroform- d ) δ 170.6, 139.9, 132.9, 129.2, 126.8, 66.1, 47.2, 30.1,18.9, 16.8, 13.6.

[0042] Example 3

[0043]

[0044] Add to the reaction tube in sequence NThe following mixture was prepared: iodosuccinimide 3 (0.4 mmol, 90.0 mg), sulfonamide 1c (0.2 mmol, 38.3 mg), n-hexane (2 mL), hexafluoroisopropanol (200 µL), electron-depleted olefin 2a (0.4 mmol, 51.3 mg), and trifluoromethanesulfonic acid (0.2 mmol, 30.0 mg). The mixture was stirred at 25 °C in air for 24 hours. After the reaction was complete, the reaction system was quenched with saturated sodium carbonate solution, and then extracted three times with ethyl acetate. The organic phases were combined and dried over anhydrous magnesium sulfate. The solvent and silica gel adsorption were removed by rotary evaporation. The electron-depleted olefin iodinated sulfonamide product 4c was obtained by simple column chromatography in 84% yield. The main test data of the obtained product are as follows. Analysis shows that the actual synthesized product is consistent with the theoretical analysis.

[0045] 1 H NMR (400 MHz, Chloroform- d ) δ 7.81 – 7.77 (m, 2H), 7.51 – 7.48 (m,2H), 5.50 (t, J = 6.7 Hz, 1H), 4.50 (dd, J = 9.3, 5.3 Hz, 1H), 4.19 – 4.06(m, 2H), 3.51 – 3.43 (m, 1H), 3.41 – 3.34 (m, 1H), 1.65 – 1.58 (m, 2H), 1.43– 1.34 (m, 2H), 0.93 (t, J = 7.4 Hz, 3H). 13 C NMR (100 MHz, Chloroform- d ) δ170.6, 139.5, 138.4, 129.5, 128.4, 66.2, 47.2, 30.1, 18.9, 16.5, 13.6.

[0046] Example 4

[0047]

[0048] Add to the reaction tube in sequence NThe reaction mixture consisted of iodosuccinimide 3 (0.4 mmol, 90.0 mg), sulfonamide 1d (0.2 mmol, 35.0 mg), n-hexane (2 mL), hexafluoroisopropanol (200 µL), electron-depleted olefin 2a (0.4 mmol, 51.3 mg), and trifluoromethanesulfonic acid (0.2 mmol, 30.0 mg). The mixture was stirred at 25 °C in air for 24 hours. After the reaction was complete, the reaction system was quenched with saturated sodium carbonate solution, and then extracted three times with ethyl acetate. The organic phases were combined and dried over anhydrous magnesium sulfate. The solvent and silica gel adsorption were removed by rotary evaporation. The electron-depleted olefin iodide sulfonamide product 4d was obtained by simple column chromatography with a yield of 87%. The main test data of the obtained product are as follows. Analysis shows that the actual synthesized product is consistent with the theoretical analysis.

[0049] 1 H NMR (400 MHz, Chloroform- d ) δ 7.89 – 7.85 (m, 2H), 7.22 – 7.18 (m,2H), 5.48 (t, J = 6.7 Hz, 1H), 4.50 (dd, J = 9.3, 5.3 Hz, 1H), 4.19 – 4.07(m, 2H), 3.50 – 3.43 (m, 1H), 3.40 – 3.34 (m, 1H), 1.65 – 1.58 (m, 2H), 1.43– 1.34 (m, 2H), 0.93 (t, J = 7.4 Hz, 3H). 13 C NMR (100 MHz, Chloroform- d ) δ170.6, 165.2 (d, J = 255.4 Hz), 135.9 (d, J = 3.1 Hz), 129.7 (d, J = 9.3 Hz), 116.5 (d, J = 22.6 Hz), 66.2, 47.2, 30.2, 18.9, 16.6, 13.6. 19 F NMR (376 MHz, Chloroform- d ) δ -104.61.

[0050] Example 5

[0051]

[0052] Add to the reaction tube in sequence N The reaction mixture consisted of iodosuccinimide 3 (0.4 mmol, 90.0 mg), sulfonamide 1e (0.2 mmol, 45.9 mg), n-hexane (2 mL), hexafluoroisopropanol (200 µL), electron-depleted olefin 2a (0.4 mmol, 51.3 mg), and trifluoromethanesulfonic acid (0.2 mmol, 30.0 mg). The mixture was stirred at 25 °C in air for 24 hours. After the reaction was complete, the reaction system was quenched with saturated sodium carbonate solution, and then extracted three times with ethyl acetate. The organic phases were combined and dried over anhydrous magnesium sulfate. The solvent and silica gel adsorption were removed by rotary evaporation. The electron-depleted olefin iodinated sulfonamide product 4e was obtained by simple column chromatography in 79% yield. The main test data of the obtained product are as follows. Analysis shows that the actual synthesized product is consistent with the theoretical analysis.

[0053] 1 H NMR (400 MHz, Chloroform- d ) δ 8.08 – 8.05 (m, 1H), 7.84 – 7.82 (m,1H), 7.65 – 7.63 (m, 2H), 6.69 (t, J = 6.5 Hz, 1H), 4.46 – 4.40 (m, 3H), 4.18 – 4.05 (m, 2H), 3.58 – 3.51 (m, 1H), 3.49 – 3.42 (m, 1H), 1.64 – 1.57 (m, 2H), 1.42 – 1.34 (m, 5H), 0.92 (t, J = 7.4 Hz, 3H). 13 C NMR (100 MHz, Chloroform- d ) δ 170.2, 167.3, 139.1, 132.6, 131.7, 130.8, 130.7, 129.2, 66.0,62.6, 47.6, 30.1, 18.9, 17.0, 14.0, 13.6.

[0054] Example 6

[0055]

[0056] Add to the reaction tube in sequence NThe reaction mixture consisted of iodosuccinimide 3 (0.4 mmol, 90.0 mg), sulfonamide 1f (0.2 mmol, 49.1 mg), n-hexane (2 mL), hexafluoroisopropanol (200 µL), electron-depleted olefin 2a (0.4 mmol, 51.3 mg), and trifluoromethanesulfonic acid (0.2 mmol, 30.0 mg). The mixture was stirred at 25 °C in air for 24 hours. After the reaction was complete, the reaction system was quenched with saturated sodium carbonate solution, and then extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous magnesium sulfate, and the solvent and silica gel adsorption were removed by rotary evaporation. The electron-depleted olefin iodinated sulfonamide product 4f was obtained by simple column chromatography with a yield of 97%. The main test data of the obtained product are as follows. Analysis shows that the actual synthesized product is consistent with the theoretical analysis.

[0057] 1 H NMR (400 MHz, Chloroform- d ) δ 8.25 (d, J = 2.5 Hz, 1H), 7.93 (dd, J = 8.9, 2.5 Hz, 1H), 7.07 (d, J = 8.9 Hz, 1H), 5.57 (t, J = 6.7 Hz, 1H), 4.49 (dd, J = 9.3, 5.4 Hz, 1H), 4.17 – 4.05 (m, 2H), 3.96 (s, 3H), 3.88 (s,3H), 3.48 – 3.41 (m, 1H), 3.37 – 3.30 (m, 1H), 1.63 – 1.56 (m, 2H), 1.41 –1.32 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H). 13 C NMR (100 MHz, Chloroform- d ) δ170.5, 164.8, 162.2, 132.3, 131.2, 130.9, 120.5, 112.3, 66.1, 56.4, 52.3,47.1, 30.1, 18.9, 16.9, 13.5.

[0058] Example 7

[0059]

[0060] Add to the reaction tube in sequenceN - Iodosuccinimide 3 (0.4 mmol, 90.0 mg), sulfonamide 1 g (0.2 mmol, 45.0 mg), n-hexane (2 mL), hexafluoroisopropanol (200 µL), electron-depleted olefin 2a (0.4 mmol, 51.3 mg), trifluoromethanesulfonic acid (0.2 mmol, 30.0 mg); then stirred at 25 °C in air for 24 hours; after the reaction was completed, the reaction system was quenched with saturated sodium carbonate aqueous solution, and then extracted three times with ethyl acetate. The organic phases were combined and dried with anhydrous magnesium sulfate. The solvent and silica gel adsorption were removed by rotary evaporation. The electron-depleted olefin iodide sulfonamide product 4 g was obtained by simple column chromatography, with a yield of 76%. Figure 3 The single-crystal unit cell structure of compound 4g is shown below. The main test data of the obtained product are as follows. Analysis shows that the actual synthesized product is consistent with the theoretical analysis.

[0061] 1 H NMR (400 MHz, Chloroform- d ) δ 7.99 (d, J = 8.2 Hz, 2H), 7.79 (d, J = 8.2 Hz, 2H), 5.66 (t, J = 6.7 Hz, 1H), 4.52 (dd, J 0.93 (t, J = 7.4 Hz, 3H). 13 C NMR (100 MHz, Chloroform- d ) δ 170.6, 143.5 (d, J = 1.1 Hz), 134.6 (q, J = 32.9 Hz), 127.4, 126.4 (q, J = 3.7 Hz), 123.1 (q, J = 273.0 Hz), 66.3, 47.2, 30.1, 18.9, 16.4,13.6. 19 F NMR (376 MHz, Chloroform- d) δ -63.15.

[0062] Example 8

[0063]

[0064] Add to the reaction tube in sequence N The reaction mixture consisted of iodosuccinimide 3 (0.4 mmol, 90.0 mg), sulfonamide 1h (0.2 mmol, 48.2 mg), n-hexane (2 mL), hexafluoroisopropanol (200 µL), electron-depleted olefin 2a (0.4 mmol, 51.3 mg), and trifluoromethanesulfonic acid (0.2 mmol, 30.0 mg). The mixture was stirred at 25 °C in air for 24 hours. After the reaction was complete, the reaction system was quenched with saturated sodium carbonate solution, and then extracted three times with ethyl acetate. The organic phases were combined and dried over anhydrous magnesium sulfate. The solvent and silica gel adsorption were removed by rotary evaporation. The electron-depleted olefin iodide sulfonamide product 4h was obtained by simple column chromatography with a yield of 63%. The main test data of the obtained product are as follows. Analysis shows that the actual synthesized product is consistent with the theoretical analysis.

[0065] 1 H NMR (400 MHz, Chloroform- d ) δ 8.01 (dd, J = 8.1, 1.7 Hz, 1H), 7.67– 7.62 (m, 1H), 7.44 – 7.40 (m, 2H), 5.51 (t, J = 6.6 Hz, 1H), 4.47 (dd, J 0.93 (t, J = 7.4 Hz, 3H). 13 CNMR (100 MHz, Chloroform- d ) δ 170.5, 145.9 (q, J = 1.6 Hz), 134.7, 131.9,130.6, 126.6, 120.2 (q, J = 261.4 Hz), 119.9 (q, J= 1.9 Hz), 66.2, 47.3,30.2, 18.9, 16.4, 13.6. 19 F NMR (376 MHz, Chloroform- d ) δ -56.12.

[0066] Example 9

[0067]

[0068] Add to the reaction tube in sequence N - Iodosuccinimide 3 (0.4 mmol, 90.0 mg), sulfonamide 1i (0.2 mmol, 39.5 mg), n-hexane (2 mL), hexafluoroisopropanol (200 µL), electron-depleted olefin 2a (0.4 mmol, 51.3 mg), trifluoromethanesulfonic acid (0.2 mmol, 30.0 mg); then, at 25 °C in air, the mixture was stirred for 24 hours as usual. After the reaction was completed, the reaction system was quenched with saturated sodium carbonate aqueous solution, and then extracted three times with ethyl acetate. The organic phases were combined and dried with anhydrous magnesium sulfate. The solvent and silica gel adsorption were removed by rotary evaporation. The electron-depleted olefin iodide sulfonamide product 4i was obtained by simple column chromatography with a yield of 66%. The main test data of the obtained product are as follows. The analysis shows that the actual synthesized product is consistent with the theoretical analysis.

[0069] 1 H NMR (400 MHz, Chloroform- d ) δ 7.41 (d, J = 4.0 Hz, 1H), 6.93 (d, J = 4.0 Hz, 1H), 5.57 (t, J = 6.7 Hz, 1H), 4.53 (dd, J 0.94 (t, J = 7.4 Hz, 3H). 13 C NMR (100 MHz, Chloroform- d) δ 170.6, 138.6, 137.7, 131.7, 126.8, 66.3, 47.4, 30.2, 18.9,16.2, 13.6.

[0070] Example 10

[0071]

[0072] Add to the reaction tube in sequence N The reaction mixture consisted of iodosuccinimide 3 (0.4 mmol, 90.0 mg), sulfonamide 1j (0.2 mmol, 45.9 mg), n-hexane (2 mL), hexafluoroisopropanol (200 µL), electron-depleted olefin 2a (0.4 mmol, 51.3 mg), and trifluoromethanesulfonic acid (0.2 mmol, 30.0 mg). The mixture was stirred at 25 °C in air for 24 hours. After the reaction was complete, the reaction system was quenched with saturated sodium carbonate solution, and then extracted three times with ethyl acetate. The organic phases were combined and dried over anhydrous magnesium sulfate. The solvent and silica gel adsorption were removed by rotary evaporation. The electron-depleted olefin iodinated sulfonamide product 4j was obtained by simple column chromatography in 67% yield. The main test data of the obtained product are as follows. Analysis shows that the actual synthesized product is consistent with the theoretical analysis.

[0073] 1 H NMR (400 MHz, Chloroform- d ) δ 7.99 (dd, J = 7.7, 1.5 Hz, 1H), 7.57– 7.43 (m, 3H), 5.11 – 5.08 (m, 1H), 4.96 – 4.88 (m, 2H), 4.37 (dd, J = 9.5,5.3 Hz, 1H), 4.17 – 4.04 (m, 2H), 3.93 (s, 3H), 3.37 – 3.30 (m, 1H), 3.27 –3.20 (m, 1H), 1.64 – 1.57 (m, 2H), 1.42 – 1.33 (m, 2H), 0.92 (t, J = 7.4 Hz, 3H). 13 C NMR (100 MHz, Chloroform- d) δ 170.6, 167.5, 133.2, 132.4, 131.1, 130.5, 130.1, 128.9, 66.0, 56.3, 52.5, 47.5, 30.1, 18.9, 17.6, 13.6.

[0074] Example 11

[0075]

[0076] Add to the reaction tube in sequence N The reaction mixture consisted of iodosuccinimide 3 (0.4 mmol, 90.0 mg), sulfonamide 1k (0.2 mmol, 37.0 mg), n-hexane (2 mL), hexafluoroisopropanol (200 µL), electron-depleted olefin 2a (0.4 mmol, 51.3 mg), and trifluoromethanesulfonic acid (0.2 mmol, 30.0 mg). The mixture was stirred at 25 °C in air for 24 hours. After the reaction was complete, the reaction system was quenched with saturated sodium carbonate solution, and then extracted three times with ethyl acetate. The organic phases were combined and dried over anhydrous magnesium sulfate. The solvent and silica gel adsorption were removed by rotary evaporation. The electron-depleted olefin iodinated sulfonamide product 4k was obtained by simple column chromatography with a yield of 97%. The main test data of the obtained product are as follows. Analysis shows that the actual synthesized product is consistent with the theoretical analysis.

[0077] 1 H NMR (400 MHz, Chloroform- d ) δ 7.66 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 4.68 (dd, J = 9.9, 5.5 Hz, 1H), 4.21 – 4.11 (m, 2H), 3.49 –3.44 (m, 1H), 3.42 – 3.36 (m, 1H), 2.80 (s, 3H), 2.42 (s, 3H), 1.68 – 1.61(m, 2H), 1.45 – 1.36 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H). 13 C NMR (100 MHz, Chloroform- d) δ 170.7, 143.9, 133.5, 129.8, 127.5, 65.9, 55.0, 37.7, 30.2,21.5, 18.9, 17.9, 13.6.

[0078] Example 12

[0079]

[0080] Add to the reaction tube in sequence N -Iodosuccinimide 3 (0.4 mmol, 90.0 mg), sulfonamide 1 (0.2 mmol, 19.0 mg), n-hexane (2 mL), hexafluoroisopropanol (200 µL), electron-depleted olefin 2a (0.4 mmol, 51.3 mg), trifluoromethanesulfonic acid (0.2 mmol, 30.0 mg); then stirred at 25 °C in air for 24 hours; after the reaction was completed, the reaction system was quenched with saturated sodium carbonate aqueous solution, and then extracted three times with ethyl acetate. The organic phases were combined and dried with anhydrous magnesium sulfate. The solvent and silica gel adsorption were removed by rotary evaporation. The electron-depleted olefin iodinated sulfonamide product 4l was obtained by simple column chromatography with a yield of 90%. Figure 4 The 1H NMR spectrum of compound 4l is shown. Figure 5 The following is the carbon NMR spectrum of compound 4l. The main test data of the obtained product are as follows. The analysis shows that the actual synthesized product is consistent with the theoretical analysis.

[0081] 1 H NMR (400 MHz, Chloroform- d ) δ 5.31 (t, J = 6.7 Hz, 1H), 4.54 (dd, J = 9.2, 5.2 Hz, 1H), 4.22 – 4.10 (m, 2H), 3.67 – 3.59 (m, 1H), 3.56 – 3.49(m, 1H), 2.98 (s, 3H), 1.67 – 1.60 (m, 2H), 1.45 – 1.35 (m, 2H), 0.93 (t, J =7.4 Hz, 3H). 13 C NMR (100 MHz, Chloroform- d ) δ 170.6, 66.2, 47.2, 41.0, 30.2, 18.9, 17.3, 13.6.

[0082] Example 13

[0083]

[0084] Add to the reaction tube in sequence N The reaction mixture consisted of iodosuccinimide 3 (0.4 mmol, 90.0 mg), sulfonamide 1a (0.2 mmol, 42.7 mg), n-hexane (2 mL), hexafluoroisopropanol (200 µL), electron-depleted olefin 2b (0.4 mmol, 34.4 mg), and trifluoromethanesulfonic acid (0.2 mmol, 30.0 mg). The mixture was stirred at 25 °C in air for 24 hours. After the reaction was complete, the reaction system was quenched with saturated sodium carbonate solution, and then extracted three times with ethyl acetate. The organic phases were combined and dried over anhydrous magnesium sulfate. The solvent and silica gel adsorption were removed by rotary evaporation. The electron-depleted olefin iodinated sulfonamide product 4m was obtained by simple column chromatography with a yield of 81%. The main test data of the obtained product are as follows. Analysis shows that the actual synthesized product is consistent with the theoretical analysis.

[0085] 1 H NMR (400 MHz, Chloroform- d ) δ 7.78 – 7.74 (m, 2H), 7.54 – 7.50 (m,2H), 5.50 (t, J = 6.7 Hz, 1H), 4.52 (dd, J = 9.5, 5.4 Hz, 1H), 3.72 (s, 3H), 3.51 – 3.44 (m, 1H), 3.41 – 3.34 (m, 1H), 1.33 (s, 9H). 13 C NMR (100 MHz, Chloroform- d ) δ 171.0, 156.8, 136.7, 126.7, 126.2, 53.2, 47.2, 35.1, 31.0,16.4.

[0086] Example 14

[0087]

[0088] Add to the reaction tube in sequence NThe following mixture was prepared: iodosuccinimide 3 (0.4 mmol, 90.0 mg), sulfonamide 1a (0.2 mmol, 42.7 mg), n-hexane (2 mL), hexafluoroisopropanol (200 µL), electron-depleted olefin 2c (0.4 mmol, 61.6 mg), and trifluoromethanesulfonic acid (0.2 mmol, 30.0 mg). The mixture was stirred at 25 °C in air for 24 hours. After the reaction was complete, the reaction system was quenched with saturated sodium carbonate solution, and then extracted three times with ethyl acetate. The organic phases were combined and dried over anhydrous magnesium sulfate. The solvent and silica gel adsorption were removed by rotary evaporation. The electron-depleted olefin iodinated sulfonamide product 4n was obtained by simple column chromatography in 61% yield. The main test data of the obtained product are as follows. Analysis shows that the actual synthesized product is consistent with the theoretical analysis.

[0089] 1 H NMR (400 MHz, Chloroform- d ) δ 7.79 – 7.76 (m, 2H), 7.56 – 7.53 (m,2H), 5.49 (t, J = 6.7 Hz, 1H), 4.61 – 4.45 (m, 3H), 3.57 – 3.49 (m, 1H), 3.46– 3.39 (m, 1H), 1.35 (s, 9H). 13 C NMR (100 MHz, Chloroform- d ) δ 169.3, 157.0,136.5, 126.7, 126.3, 122.5 (q, J = 275.8 Hz), 61.3 (q, J = 37.1 Hz), 47.1,35.2, 31.0, 14.9. 19 F NMR (376 MHz, Chloroform- d ) δ -73.46.

[0090] Example 15

[0091]

[0092] Add to the reaction tube in sequence NThe reaction mixture consisted of iodosuccinimide 3 (0.4 mmol, 90.0 mg), sulfonamide 1k (0.2 mmol, 37.0 mg), n-hexane (2 mL), hexafluoroisopropanol (200 µL), electron-depleted olefin 2d (0.4 mmol, 40.1 mg), and trifluoromethanesulfonic acid (0.2 mmol, 30.0 mg). The mixture was stirred at 25 °C in air for 24 hours. After the reaction was complete, the reaction system was quenched with saturated sodium carbonate solution, and then extracted three times with ethyl acetate. The organic phases were combined and dried over anhydrous magnesium sulfate. The solvent and silica gel adsorption were removed by rotary evaporation. The electron-depleted olefin iodide sulfonamide product 4o was obtained by simple column chromatography with a yield of 88%. The main test data of the obtained product are as follows. Analysis shows that the actual synthesized product is consistent with the theoretical analysis.

[0093] 1 H NMR (400 MHz, Chloroform-d) δ 7.65 (d, J = 8.3 Hz, 2H), 7.32 (d, J= 8.0 Hz, 2H), 4.66 (dd, J = 9.9, 5.6 Hz, 1H), 4.25 – 4.17 (m, 2H), 3.48 –3.36 (m, 2H), 2.80 (s, 3H), 2.42 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H). 13 C NMR (100 MHz, Chloroform-d) δ 170.6, 143.9, 133.5, 129.8, 127.4, 62.1, 55.0, 37.6, 21.5, 17.9, 13.6.

[0094] The method for iodination sulfonamide of electron-depleted olefins disclosed in this invention specifically involves, at room temperature, using trifluoromethanesulfonic acid as the acid and hexafluoroisopropanol as the additive, in an organic solvent, using electron-depleted olefins, sulfonamides, and... N Using iodosuccinimide as a raw material, the iodination sulfonamide of electron-depleted olefins is achieved to obtain the product iodinated sulfonamide compound.

Claims

1. A method for the iodination sulfonamideation of electron-depleted olefins, characterized in that, In n-hexane, electron-depleted olefins, sulfonamides, and N-iodosuccinimide are used as reaction substrates, and the reaction is carried out in the presence of trifluoromethanesulfonic acid and hexafluoroisopropanol additives to achieve the iodination and sulfonamideation of electron-depleted olefins; the chemical structural formula of the electron-depleted olefins is as follows: ； The chemical structural formula of the sulfonamide is as follows: ； The iodine sulfonamide product of electron-depleted olefins is an iodine sulfonamide compound, whose chemical structural formula is as follows: ； In the formula, R 1 Selected from substituted or unsubstituted alkyl groups; R 2 Selected from alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, R 3 Selected from alkyl or hydrogen; Among substituted alkyl, substituted aryl, and substituted heteroaryl groups, the substituents are independently selected from methyl, tert-butyl, fluorine, chlorine, ester, methoxy, trifluoromethyl, and trifluoromethoxy.

2. The method for iodide sulfonamideation of electron-depleted olefins according to claim 1, characterized in that, The molar ratio of electron-depleted olefin, sulfonamide, N-iodosuccinimide and acid is (1-2):1:(1-2):(0.1-1).

3. The method for iodide sulfonamideation of electron-depleted olefins according to claim 1, characterized in that, The reaction takes place in air.

4. The method for iodide sulfonamideation of electron-depleted olefins according to claim 1, characterized in that, The reaction time is 18 to 24 hours, and the temperature is 25℃ to 40℃.

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