A synthetic method for monosubstituted sulfonyl amidine compounds

Abstract

This invention discloses a method for synthesizing monosubstituted sulfonylamidinium compounds. In an air atmosphere, using commercially available primary sulfonamides and nitriles as substrates, inexpensive trifluoromethanesulfonic anhydride as a catalyst, and trifluorotoluene as a solvent, the product can be efficiently obtained. Compared with existing technologies, this method has the following advantages: inexpensive and readily available reactants; no need for cumbersome synthesis methods; simple reaction system; high atom economy with 100% atom utilization; broad substrate range, compatible with various functional groups; and simple operation.

Description

TECHNICAL FIELD

[0001] The present application relates to a novel synthesis method of monosubstituted sulfonamidate from primary sulfonamides. N The present application relates to a novel synthesis method of monosubstituted sulfonamidate from primary sulfonamides. BACKGROUND

[0002] Amidines are an important class of nitrogen-containing organic compounds, and their unique structure (N-C=N) exists in various natural products and bioactive molecules, N Sulfonamidines are a unique class of amidines, and their skeletons often appear in compounds with physiological activity. Among them, some N Sulfonamidines have therapeutic effects on diseases and exhibit rich pharmacological activities, including anticancer, transport protein inhibition, etc. Some N Etorvidine, a sulfonamidine group, can effectively treat diseases such as peptic ulcer as a gastric acid inhibitor. N Sulfonamidines not only have a wide range of applications in the design of biological drug molecules, but also play an important role in coordination catalysis. N Sulfonamidines can be chelated with some transition metals to form stable complexes to catalyze organic reactions.

[0003]

[0004] In recent years, various N However, the existing synthesis methods have some disadvantages, such as complicated preparation of raw materials, limited practical value, unstable and dangerous raw materials, use of noble metal catalysts, and narrow substrate range. For example: (1) Xia's group used electrochemistry to realize the cross-dehydrogenative coupling reaction of sulfonamides and methyl tertiary amines, and synthesized fully substituted N sulfonamidines. However, this method requires the use of a large excess of methyl tertiary amine, and is only suitable for some simple methyl tertiary amines (see: Xia, W. J. Electrochemically Generated N Iodoaminium Species as Key Intermediates for Selective Methyl Sulphonylimination of Tertiary Amines. Chem. Commun. 2020, 56, 5010-5013.) (2) Aoyama's group reported a catalyst-free tertiary amine / secondary amine oxidative olefin amination, and synthesized N- Sulfonyl amidines. This method can realize the oxidation of amines without metal catalysts, only with oxygen as a green oxidant, but this method needs high-temperature reflux and is only suitable for simple secondary and tertiary amines (see: Aoyama, H. Transition Metal- and Catalyst-Free One-Pot Green Method for the Synthesis of Sulfonyl Amidines. Org. Lett. 2018, 20, 2302-2305.) (2) The group of Prof. Wang Yanguang realized the synthesis of sulfonyl amidines via the direct reaction of sulfonyl azides with amines. RSC Adv. 2020, 10, 26701-26708. N - Sulfonyl amidines. This method can realize the oxidation of amines without metal catalysts, only with oxygen as a green oxidant, but this method needs high-temperature reflux and is only suitable for simple secondary and tertiary amines (see: Aoyama, H. Transition Metal- and Catalyst-Free One-Pot Green Method for the Synthesis of Sulfonyl Amidines. Org. Lett. 2018, 20, 2302-2305.) (2) The group of Prof. Wang Yanguang realized the synthesis of sulfonyl amidines via the direct reaction of sulfonyl azides with amines. RSC Adv. 2020, 10, 26701-26708. N - Sulfonyl amidines. This method can realize the oxidation of amines without metal catalysts, only with oxygen as a green oxidant, but this method needs high-temperature reflux and is only suitable for simple secondary and tertiary amines (see: Aoyama, H. Transition Metal- and Catalyst-Free One-Pot Green Method for the Synthesis of Sulfonyl Amidines. Org. Lett. 2018, 20, 2302-2305.) (2) The group of Prof. Wang Yanguang realized the synthesis of sulfonyl amidines via the direct reaction of sulfonyl azides with amines. RSC Adv. 2020, 10, 26701-26708. N - Sulfonyl amidines. This method can realize the oxidation of amines without metal catalysts, only with oxygen as a green oxidant, but this method needs high-temperature reflux and is only suitable for simple secondary and tertiary amines (see: Aoyama, H. Transition Metal- and Catalyst-Free One-Pot Green Method for the Synthesis of Sulfonyl Amidines. Org. Lett. 2018, 20, 2302-2305.) (2) The group of Prof. Wang Yanguang realized the synthesis of sulfonyl amidines via the direct reaction of sulfonyl azides with amines. RSC Adv. 2020, 10, 26701-26708. N-Sulfoamidine. However, this method requires noble metal catalysts and high temperature conditions, and the reaction conditions are relatively harsh (see: Zhang, ZH Tandem Coupling of Azide with Isonitrile and Boronic Acid: Facile Access to Functionalized Amidines. Angew. Chem. Int. Ed. 2017, 56, 4320–4323.). (6) The Milo group reported the synthesis of a series of structurally diverse compounds by reacting ketones, primary amines and azides with the assistance of molecular sieves. N -Sulfoamidine. However, this method requires high temperatures and uses explosive azide as a raw material, which poses certain risks (see: Milo, A. Metal-Free Multicomponent Strategy for Amidine Synthesis. J. Am. Chem. Soc. 2022, 144, 20672–20679.).

[0005] The inventors' research group previously used primary sulfonamides, alcohols, and nitriles as reaction substrates, and trifluoromethanesulfonic anhydride as an additive, to prepare... N -Sulfoamidine compounds have been synthesized, but the resulting products are disubstituted, and the amount of trifluoromethanesulfonic anhydride used is too large. When the amount is reduced to 0.5 equivalents, only a very low yield of 7% of the disubstituted amidine compound is obtained. Even when using 1 equivalent of trifluoromethanesulfonic anhydride, only a 31% yield of the target product is obtained. Therefore, it is particularly important to develop a method for synthesizing monosubstituted sulfonylamidines that uses abundant and readily available raw materials, operates under mild conditions, and does not involve metals. Summary of the Invention

[0006] The purpose of this invention is to provide a novel and efficient method for synthesizing monosubstituted sulfonylamidinium compounds.

[0007] To achieve the above-mentioned objectives, the technical solution adopted by this invention is as follows:

[0008] A method for synthesizing a monosubstituted sulfonylamidine compound includes the following steps: using sulfonamide and nitrile as reaction substrates, and reacting them in the presence of a sulfonic anhydride catalyst to synthesize the monosubstituted sulfonylamidine compound.

[0009] In the above technical solution, the chemical structural formula of sulfonamide is as follows:

[0010] ;

[0011] The nitrile is R 2 CN;

[0012] The N The chemical structural formulas of sulfonylamidinium compounds are as follows:

[0013] ;

[0014] In the above chemical structural formula, R 1 Selected from alkyl, substituted or unsubstituted aryl, and thiophene groups, wherein the substituents are methyl, fluorine, chlorine, or other similar groups; R 2 It is selected from substituted or unsubstituted alkyl groups, wherein the substituents are alkenyl, phenyl, methoxy, fluorine, chlorine, bromine, nitro, naphthyl, etc.

[0015] In this invention, the reaction temperature is 60-80°C, and the preferred reaction temperature is 70°C.

[0016] In this invention, the reaction time is 20 to 48 hours, with a preferred reaction time of 24 hours.

[0017] In the above technical solution, the reaction is carried out in an organic solvent, such as trifluorotoluene, 1,2-dichloroethane, or cyclohexane. N , N - Dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, ethyl acetate, etc.; trifluorotoluene is the preferred solvent.

[0018] Specifically, under the condition of 70°C, the present invention uses trifluoromethanesulfonic anhydride as a catalyst, sulfonamide and nitrile as raw materials, and trifluorotoluene as a solvent to achieve the addition reaction of nitrile and sulfonamide without the need for other reagents, and obtains the product monosubstituted sulfonylamidine compound.

[0019] In this invention, the molar ratio of nitrile, sulfonamide and trifluoromethanesulfonic anhydride is (2-4):1:(0.5-1), preferably 3:1:0.6.

[0020] In this invention, the reaction substrates are sulfonamides and nitrile compounds, both of which are inexpensive commercial raw materials. The catalyst is trifluoromethanesulfonic anhydride, and the solvent is trifluorotoluene. The reaction of this invention is carried out in air. After the reaction is completed, the mixture is quenched with saturated sodium carbonate solution, dried over anhydrous sodium sulfate, and the solvent and silica gel adsorption are removed by rotary evaporation. The final product can be obtained by simple column chromatography. N -Sulfoamide compounds.

[0021] Due to the application of the above technical solution, the present invention has the following advantages compared with the prior art:

[0022] This invention employs a mild and efficient method to prepare monosubstituted products. N-Sulfoamide compounds. The substrates and catalysts for this reaction are inexpensive and readily available, requiring no prior synthesis or complex reaction conditions, making it more environmentally friendly and milder compared to other reactions. Furthermore, this reaction requires no metal catalysts or additives, resulting in a simple reaction system. It exhibits high atom economy, with 100% atom utilization and no byproduct formation. Moreover, the reaction is a one-pot, one-step process, simplifying operation. Existing synthetic methods... N The technology for synthesizing sulfonylamidinium compounds requires pre-synthesizing reaction raw materials, uses transition metal catalysts that are prone to environmental pollution, and some raw materials are explosive. The reaction conditions are also harsh, resulting in poor procedural economy and substrate universality. In contrast, this invention offers advantages such as inexpensive and readily available reaction raw materials, simple and environmentally friendly reaction conditions, high reaction yield, and easy operation. In conclusion, this invention is highly practical. Attached Figure Description

[0023] Figure 1 This is a single-crystal unit cell structure diagram of compound 3b. Detailed Implementation

[0024] The specific operating method of this invention is a conventional method in the art, using primary sulfonamides and nitriles as substrates, trifluoromethanesulfonic anhydride as catalyst, and trifluorotoluene as reaction solvent. No other substances are required, and the product can be efficiently obtained in air under reaction conditions of 70°C. N -Sulfoamide compounds. This invention employs a mild and efficient strategy to synthesize... N The sulfonylamidinium compound, the primary sulfonamide and nitrile as reaction substrates, and the trifluoromethanesulfonic anhydride as catalyst are all inexpensive commercial products and can be purchased directly. Unless otherwise specified, the following experiments were conducted in air at 70°C, and the yields were isolated yields.

[0025] The present invention will be further described below with reference to examples. The raw materials involved are existing products or can be conventionally obtained according to existing methods. The specific preparation operations and testing are conventional techniques.

[0026] The general formula and method for the reaction are as follows, and the reaction is carried out in air.

[0027]

[0028] Primary sulfonamide 1 (0.2 mmol), trifluorotoluene (1.0 mL), nitrile compound 2 (0.6 mmol), and trifluoromethanesulfonic anhydride (0.12 mmol, 33.9 mg) were added sequentially to a reaction tube. The mixture was then stirred in air at 70°C for 24 hours. The reaction system was quenched with saturated sodium carbonate solution, extracted three times with ethyl acetate, and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, and the solvent and silica gel adsorption were removed by rotary evaporation. The final product was obtained by simple column chromatography.N -Sulfoamide compounds 3.

[0029] Example 1

[0030]

[0031] Primary sulfonamide 1a (0.2 mmol, 42.7 mg), trifluorotoluene (1.0 mL), nitrile compound 2a (0.6 mmol, 70.3 mg), and trifluoromethanesulfonic anhydride (0.12 mmol, 33.9 mg) were added sequentially to a reaction tube. The mixture was then stirred in air at 70°C for 24 hours. The reaction system was quenched with saturated sodium carbonate solution, extracted three times with ethyl acetate, and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, and the solvent and silica gel adsorption were removed by rotary evaporation. The final product was obtained by simple column chromatography. N -Sulfoamide compound 3a, yield 76%. The main test data of the obtained product are as follows. Analysis shows that the actual synthesized product is consistent with the theoretical analysis.

[0032] 1 H NMR (400 MHz, Chloroform- d ) δ 8.07 (s, 1H), 7.83 – 7.80 (m, 2H), 7.49 – 7.46 (m, 2H), 7.32 – 7.28 (m, 3H), 7.21 – 7.18 (m, 2H), 5.95 (s, 1H), 3.62 (s, 2H), 1.33 (s, 9H). 13 C NMR (100 MHz, Chloroform- d ) δ 167.4, 156.0,138.9, 133.4, 129.5, 129.1, 127.9, 126.1, 125.7, 43.6, 35.0, 31.0. HRMS (ESI-TOF): Anal Calcd. For. C 18 H 22 N₂O₂S + Na + : 353.1294, found: 353.1295. IR (neat, cm -1 ): υ 3387, 2963, 1627, 1542, 1411, 1263, 1142, 1083, 832, 679.

[0033] Extended Implementation Examples

[0034] Based on Example 1, single-factor variations were performed, and the results are shown in Table 1.

[0035] Table 1. Single-factor variation conditions and yield

[0036]

[0037] Example 2

[0038]

[0039] Primary sulfonamide 1b (0.2 mmol, 37.4 mg), trifluorotoluene (1.0 mL), nitrile compound 2a (0.6 mmol, 70.3 mg), and trifluoromethanesulfonic anhydride (0.12 mmol, 33.9 mg) were added sequentially to a reaction tube. The mixture was then stirred in air at 70°C for 24 hours. The reaction system was quenched with saturated sodium carbonate solution, extracted three times with ethyl acetate, and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, and the solvent and silica gel adsorption were removed by rotary evaporation. The final product was obtained by simple column chromatography. N -Sulfoamidine compound 3b, yield 55%. Figure 1 The image shows the single-crystal unit cell structure of compound 3b. The main test data for the obtained product are as follows. Analysis shows that the actual synthesized product is consistent with the theoretical analysis.

[0040] 1 H NMR (400 MHz, Chloroform- d ) δ 8.02 (s, 1H), 7.83 – 7.79 (m, 2H), 7.32 – 7.28 (m, 3H), 7.20 – 7.17 (m, 2H), 6.94 – 6.90 (m, 2H), 5.95 (s, 1H), 3.84 (s, 3H), 3.60 (s, 2H). 13 C NMR (100 MHz, Chloroform- d ) δ 167.1, 162.6,133.8, 133.4, 129.5, 129.1, 128.4, 127.9, 113.9, 55.5, 43.6. HRMS (ESI-TOF): Anal Calcd. For. C 15 H 16 N₂O₃S + Na + : 327.0774, found: 327.0769. IR (neat, cm -1): υ3408, 2987, 1638, 1538, 1262, 1133, 1085, 959, 808, 641.

[0041] Example 3

[0042]

[0043] Primary sulfonamide 1c (0.2 mmol, 34.2 mg), trifluorotoluene (1.0 mL), nitrile compound 2a (0.6 mmol, 70.3 mg), and trifluoromethanesulfonic anhydride (0.12 mmol, 33.9 mg) were added sequentially to a reaction tube. The mixture was then stirred in air at 70°C for 24 hours. The reaction system was quenched with saturated sodium carbonate solution, extracted three times with ethyl acetate, and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, and the solvent and silica gel adsorption were removed by rotary evaporation. The final product was obtained by simple column chromatography. N -Sulfoamide compound 3c, yield 75%. The main test data of the obtained product are as follows. Analysis shows that the actual synthesized product is consistent with the theoretical analysis.

[0044] 1 H NMR (400 MHz, Chloroform- d ) δ 8.05 (s, 1H), 7.79 – 7.76 (m, 2H), 7.34 – 7.29 (m, 3H), 7.26 – 7.24 (m, 2H), 7.20 – 7.18 (m, 2H), 5.94 (s, 1H), 3.61 (s, 2H), 2.40 (s, 3H). 13 C NMR (100 MHz, Chloroform- d ) δ 167.4, 143.0,139.0, 133.4, 129.5, 129.3, 129.1, 127.9, 126.3, 43.6, 21.5. HRMS (ESI-TOF): Anal Calcd. For. C 15 H 16 N₂O₂S + Na + : 311.0825, found: 311.0826. IR (neat, cm -1 ): υ3368, 2988, 1653, 1542, 1415, 1274, 1143, 1085, 813, 698.

[0045] Example 4

[0046]

[0047] Primary sulfonamide 1d (0.2 mmol, 31.4 mg), trifluorotoluene (1.0 mL), nitrile compound 2a (0.6 mmol, 70.3 mg), and trifluoromethanesulfonic anhydride (0.12 mmol, 33.9 mg) were added sequentially to a reaction tube. The mixture was then stirred in air at 70°C for 24 hours. The reaction system was quenched with saturated sodium carbonate solution, extracted three times with ethyl acetate, and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, and the solvent and silica gel adsorption were removed by rotary evaporation. The final product was obtained by simple column chromatography. N -Sulfoamide compounds 3d, yield 76%. The main test data of the obtained product are as follows. Analysis shows that the actual synthesized product is consistent with the theoretical analysis.

[0048] 1 H NMR (400 MHz, Chloroform- d ) δ 8.07 (s, 1H), 7.90 – 7.87 (m, 2H), 7.56 – 7.52 (m, 1H), 7.48 – 7.44 (m, 2H), 7.32 – 7.29 (m, 3H), 7.20 – 7.18(m, 2H), 6.00 (s, 1H), 3.62 (s, 2H). 13 C NMR (100 MHz, Chloroform- d ) δ 167.7,141.8, 133.3, 132.3, 129.5, 129.1, 128.7, 128.0, 126.3, 43.6. HRMS (ESI-TOF): Anal Calcd. For. C 14 H 14 N₂O₂S + Na + : 297.0668, found: 297.0665. IR (neat, cm -1 ): υ3440, 2979, 1621, 1539, 1272, 1149, 1079, 759, 692.

[0049] Example 5

[0050]

[0051] Primary sulfonamide 1e (0.2 mmol, 35.0 mg), trifluorotoluene (1.0 mL), nitrile compound 2a (0.6 mmol, 70.3 mg), and trifluoromethanesulfonic anhydride (0.12 mmol, 33.9 mg) were added sequentially to a reaction tube. The mixture was then stirred in air at 70°C for 24 hours. The reaction system was quenched with saturated sodium carbonate solution, extracted three times with ethyl acetate, and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, and the solvent and silica gel adsorption were removed by rotary evaporation. The final product was obtained by simple column chromatography. N -Sulfoamide compound 3e, yield 79%. The main test data of the obtained product are as follows. Analysis shows that the actual synthesized product is consistent with the theoretical analysis.

[0052] 1 H NMR (400 MHz, Chloroform- d ) δ 8.07 (s, 1H), 7.93 – 7.89 (m, 2H), 7.37 – 7.31 (m, 3H), 7.22 – 7.19 (m, 2H), 7.16 – 7.12 (m, 2H), 5.82 (s, 1H), 3.64 (s, 2H). 13 C NMR (100 MHz, Chloroform- d ) δ 167.6, 164.9 (d, J = 253.8Hz), 138.1 (d, J = 3.0 Hz), 133.1, 129.5, 129.2, 129.0 (d, J = 9.3 Hz), 128.1, 115.9 (d, J = 22.5 Hz), 43.7. 19 F NMR (376 MHz, Chloroform- d ) δ -106.12(s, 1F). HRMS (ESI-TOF): Anal Calcd. For. C 14 H 13 FN2O2S+Na + : 315.0574, found:315.0576. IR (neat, cm -1 ): υ 3412, 2988, 1634, 1543, 1397, 1254, 1130, 1085,788, 704.

[0053] Example 6

[0054]

[0055] Primary sulfonamide 1f (0.2 mmol, 38.3 mg), trifluorotoluene (1.0 mL), nitrile compound 2a (0.6 mmol, 70.3 mg), and trifluoromethanesulfonic anhydride (0.12 mmol, 33.9 mg) were added sequentially to a reaction tube. The mixture was then stirred in air at 70°C for 24 hours. The reaction system was quenched with saturated sodium carbonate solution, extracted three times with ethyl acetate, and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, and the solvent and silica gel adsorption were removed by rotary evaporation. The final product was obtained by simple column chromatography. N -Sulfoamide compound 3f, yield 74%. The main test data of the obtained product are as follows. Analysis shows that the actual synthesized product is consistent with the theoretical analysis.

[0056] 1 H NMR (400 MHz, DMSO- d 6) δ 8.92 (s, 1H), 8.11 (s, 1H), 7.75 – 7.71 (m, 2H), 7.56 – 7.52 (m, 2H), 7.29 – 7.21 (m, 5H), 3.56 (s, 2H). 13 C NMR (100MHz, DMSO- d 6) δ 168.1, 141.4, 136.7, 135.6, 128.84, 128.78, 128.3, 127.8,126.9, 42.1. HRMS (ESI-TOF): Anal Calcd. For. C 14 H 13 ClN2O2S+Na + : 331.0278,found: 331.0268. Anal Calcd. For. C 14 H 13 37 ClN2O2S+Na + : 333.0249, found:333.0256. IR (neat, cm -1 ): υ 3395, 2925, 1651, 1543, 1407, 1261, 1080, 795,730, 674.

[0057] Example 7

[0058]

[0059] To a reaction tube, 1 g of primary sulfonamide (0.2 mmol, 34.2 mg), 1.0 mL of trifluorotoluene, 0.6 mmol of nitrile compound 2a (0.6 mmol, 70.3 mg), and 0.12 mmol of trifluoromethanesulfonic anhydride (33.9 mg) were added sequentially. The mixture was then stirred in air at 70°C for 24 hours. The reaction system was quenched with saturated sodium carbonate solution, extracted three times with ethyl acetate, and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, and the solvent and silica gel adsorption were removed by rotary evaporation. The final product was obtained by simple column chromatography. N 3g of a sulfonylamidine compound was synthesized, with a yield of 61%. The main test data of the obtained product are as follows. Analysis shows that the actual synthesized product is consistent with the theoretical analysis.

[0060] 1 H NMR (400 MHz, Chloroform- d ) δ 8.01 (s, 1H), 7.99 (s, 1H), 7.45 –7.41 (m, 1H), 7.33 – 7.28 (m, 5H), 7.22 – 7.20 (m, 2H), 6.04 (s, 1H), 3.64(s, 2H), 2.62 (s, 3H). 13 C NMR (100 MHz, Chloroform- d ) δ 167.5, 139.8, 137.5,133.4, 132.3, 132.1, 129.5, 129.1, 127.9, 127.6, 125.7, 43.6, 20.2. HRMS(ESI-TOF): Anal Calcd. For. C 15 H 16 N₂O₂S + Na + : 311.0825, found: 311.0826. IR(neat, cm -1 ): υ 3384, 2988, 1655, 1541, 1410, 1266, 1145, 1058, 809, 704.

[0061] Example 8

[0062]

[0063] Primary sulfonamide 1h (0.2 mmol, 32.6 mg), trifluorotoluene (1.0 mL), nitrile compound 2a (0.6 mmol, 70.3 mg), and trifluoromethanesulfonic anhydride (0.12 mmol, 33.9 mg) were added sequentially to a reaction tube. The mixture was then stirred in air at 70°C for 24 hours. The reaction system was quenched with saturated sodium carbonate solution, extracted three times with ethyl acetate, and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, and the solvent and silica gel adsorption were removed by rotary evaporation. The final product was obtained by simple column chromatography. N -Sulfoamide compounds were synthesized in 3 hours with a yield of 58%. The main test data of the obtained product are as follows. Analysis shows that the actual synthesized product is consistent with the theoretical analysis.

[0064] 1 H NMR (400 MHz, Chloroform- d ) δ 8.01 (s, 1H), 7.60 – 7.58 (m, 1H), 7.53 – 7.52 (m, 1H), 7.34 – 7.29 (m, 3H), 7.22 – 7.19 (m, 2H), 7.03 – 7.01(m, 1H), 6.08 (s, 1H), 3.64 (s, 2H). 13 C NMR (100 MHz, Chloroform- d ) δ 167.9,142.8, 133.1, 131.2, 131.0, 129.5, 129.2, 128.0, 126.9, 43.5. HRMS (ESI-TOF): Anal Calcd. For. C 12 H 12 N₂O₂S₂ + Na + : 303.0232, found: 303.0229. IR (neat, cm -1 ): υ3418, 2920, 1633, 1542, 1402, 1343, 1127, 1016, 778, 682.

[0065] Example 9

[0066]

[0067] Primary sulfonamide 1i (0.2 mmol, 19.0 mg), trifluorotoluene (1.0 mL), nitrile compound 2a (0.6 mmol, 70.3 mg), and trifluoromethanesulfonic anhydride (0.12 mmol, 33.9 mg) were added sequentially to a reaction tube. The mixture was then stirred in air at 70°C for 24 hours. The reaction system was quenched with saturated sodium carbonate solution, extracted three times with ethyl acetate, and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, and the solvent and silica gel adsorption were removed by rotary evaporation. The final product was obtained by simple column chromatography. N -Sulfoamide compound 3i, yield 66%. The main test data of the obtained product are as follows. Analysis shows that the actual synthesized product is consistent with the theoretical analysis.

[0068] 1 H NMR (400 MHz, Chloroform- d ) δ 7.81 (s, 1H), 7.38 – 7.29 (m, 3H), 7.27 – 7.25 (m, 2H), 5.79 (s, 1H), 3.63 (s, 2H), 2.97 (s, 3H). 13 C NMR (100MHz, Chloroform- d ) δ 167.3, 133.3, 129.5, 129.2, 128.1, 43.6, 42.0. HRMS(ESI-TOF): Anal Calcd. For. C9H 12 N₂O₂S + Na + : 235.0512, found: 235.0510. IR(neat, cm -1 ): υ 3382, 2988, 1648, 1542, 1403, 1270, 1123, 1057, 960, 741, 636.

[0069] Example 10

[0070]

[0071] Primary sulfonamide 1a (0.2 mmol, 42.7 mg), trifluorotoluene (1.0 mL), nitrile compound 2b (0.6 mmol, 41.5 mg), and trifluoromethanesulfonic anhydride (0.12 mmol, 33.9 mg) were added sequentially to a reaction tube. The mixture was then stirred in air at 70°C for 24 hours. The reaction system was quenched with saturated sodium carbonate solution, extracted three times with ethyl acetate, and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, and the solvent and silica gel adsorption were removed by rotary evaporation. The final product was obtained by simple column chromatography. N -Sulfoamide compound 3j, yield 78%. The main test data of the obtained product are as follows. Analysis shows that the actual synthesized product is consistent with the theoretical analysis.

[0072] 1 H NMR (400 MHz, Chloroform- d ) δ 7.92 (s, 1H), 7.81 – 7.78 (m, 2H), 7.47 – 7.44 (m, 2H), 6.73 (s, 1H), 2.20 (t, J = 7.5 Hz, 2H), 1.63 – 1.54 (m,2H), 1.30 (s, 9H), 0.82 (t, J = 7.4 Hz, 3H). 13 C NMR (100 MHz, Chloroform- d ) δ169.8, 155.8, 139.0, 125.9, 125.6, 39.3, 34.9, 31.0, 20.0, 13.1. HRMS (ESI-TOF): Anal Calcd. For. C 14 H 22 N₂O₂S + Na + : 305.1294, found: 305.1294. IR (neat, cm -1 ): υ 3399, 2964, 1648, 1534, 1261, 1144, 1082, 790.

[0073] Example 11

[0074]

[0075] Primary sulfonamide 1a (0.2 mmol, 42.7 mg), trifluorotoluene (1.0 mL), nitrile compound 2c (0.6 mmol, 41.5 mg), and trifluoromethanesulfonic anhydride (0.12 mmol, 33.9 mg) were added sequentially to a reaction tube. The mixture was then stirred in air at 70°C for 24 hours. The reaction system was quenched with saturated sodium carbonate solution, extracted three times with ethyl acetate, and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, and the solvent and silica gel adsorption were removed by rotary evaporation. The final product was obtained by simple column chromatography. N -Sulfoamidine compound 3K, yield 69%. The main test data of the obtained product are as follows. Analysis shows that the actual synthesized product is consistent with the theoretical analysis.

[0076] 1 H NMR (400 MHz, Chloroform- d ) δ 7.92 (s, 1H), 7.81 – 7.78 (m, 2H), 7.47 – 7.44 (m, 2H), 6.56 (s, 1H), 2.47 – 2.40 (m, 1H), 1.30 (s, 9H), 1.11(d, J = 6.9 Hz, 6H). 13 C NMR (100 MHz, Chloroform- d ) δ 174.0, 155.7, 139.1,125.8, 125.6, 36.6, 34.9, 31.0, 19.9. HRMS (ESI-TOF): Anal Calcd. For.C 14 H 22 N₂O₂S + H₂ + : 283.1475, found: 283.1475. IR (neat, cm -1 ): υ 3398, 2966, 1644,1546, 1396, 1257, 1136, 1080, 1025, 854, 762, 642.

[0077] Example 12

[0078]

[0079] Primary sulfonamide 1a (0.2 mmol, 42.7 mg), trifluorotoluene (1.0 mL), nitrile compound 2d (0.6 mmol, 40.3 mg), and trifluoromethanesulfonic anhydride (0.12 mmol, 33.9 mg) were added sequentially to a reaction tube. The mixture was then stirred in air at 70°C for 24 hours. The reaction system was quenched with saturated sodium carbonate solution, extracted three times with ethyl acetate, and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, and the solvent and silica gel adsorption were removed by rotary evaporation. The final product was obtained by simple column chromatography. N -Sulfoamide compound 3l, yield 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.

[0080] 1 H NMR (400 MHz, DMSO- d 6) δ 8.85 (s, 1H), 7.85 (s, 1H), 7.72 – 7.69(m, 2H), 7.55 – 7.51 (m, 2H), 1.66 – 1.60 (m, 1H), 1.28 (s, 9H), 0.83 – 0.81(m, 4H). 13 C NMR (100 MHz, DMSO- d 6) δ 170.9, 154.8, 140.0, 125.8, 125.6, 34.8,30.9, 15.2, 8.7. HRMS (ESI-TOF): Anal Calcd. For. C 14 H 20 N₂O₂S + Na + : 303.1138, found: 303.1138. IR (neat, cm -1 ): υ 3414, 2964, 1645, 1532, 1463, 1259, 1137,1082, 1023, 865, 792, 657.

[0081] Example 13

[0082]

[0083] Primary sulfonamide 1a (0.2 mmol, 42.7 mg), trifluorotoluene (1.0 mL), nitrile compound 2e (0.6 mmol, 80.4 mg), and trifluoromethanesulfonic anhydride (0.12 mmol, 33.9 mg) were added sequentially to a reaction tube. The mixture was then stirred in air at 70°C for 24 hours. The reaction system was quenched with saturated sodium carbonate solution, extracted three times with ethyl acetate, and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, and the solvent and silica gel adsorption were removed by rotary evaporation. The final product was obtained by simple column chromatography. N -Sulfoamide compound 3m, yield 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.

[0084] 1 H NMR (400 MHz, Chloroform- d ) δ 8.19 (s, 1H), 7.85 – 7.82 (m, 2H), 7.52 – 7.48 (m, 2H), 6.68 (s, 1H), 4.46 (q, J = 7.0 Hz, 1H), 1.85 (d, J = 7.0Hz, 3H), 1.32 (s, 9H). 13 C NMR (100 MHz, Chloroform- d ) δ 165.9, 156.3, 138.2,126.2, 125.8, 46.0, 35.1, 31.0, 23.6. HRMS (ESI-TOF): Anal Calcd. For.C 13 H 19 BrN2O2S+H + : 347.0423, found: 347.0419. Anal Calcd. For. C 13 H 19 81 BrN2O2S+H + :349.0403, found: 349.0410. IR (neat, cm -1 ): υ 3321, 2963, 1634, 1558, 1266,1145, 1081, 881, 777, 661.

[0085] Example 14

[0086]

[0087] Primary sulfonamide 1a (0.2 mmol, 42.7 mg), trifluorotoluene (1.0 mL), nitrile compound 2f (0.6 mmol, 40.3 mg), and trifluoromethanesulfonic anhydride (0.12 mmol, 33.9 mg) were added sequentially to a reaction tube. The mixture was then stirred in air at 70°C for 24 hours. The reaction system was quenched with saturated sodium carbonate solution, extracted three times with ethyl acetate, and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, and the solvent and silica gel adsorption were removed by rotary evaporation. The final product was obtained by simple column chromatography. N -Sulfoamide compound 3n, yield 64%. The main test data of the obtained product are as follows. Analysis shows that the actual synthesized product is consistent with the theoretical analysis.

[0088] 1 H NMR (400 MHz, Chloroform- d ) δ 7.98 (s, 1H), 7.82 – 7.79 (m, 2H),7.48 – 7.45 (m, 2H), 6.58 (s, 1H), 5.85 – 5.75 (m, 1H), 5.22 – 5.16 (m, 2H), 3.03 (d, J = 7.0 Hz, 2H), 1.30 (s, 9H). 13 C NMR (100 MHz, Chloroform- d ) δ167.2, 155.9, 138.8, 130.2, 126.0, 125.7, 120.9, 41.5, 34.9, 31.0. HRMS (ESI-TOF): Anal Calcd. For. C 14 H 20 N₂O₂S + H₂ + : 281.1318, found: 281.1317. IR (neat, cm -1 ): υ 3396, 2968, 1652, 1542, 1262, 1143, 1083, 915, 787, 633.

[0089] Example 15

[0090]

[0091] Primary sulfonamide 1a (0.2 mmol, 42.7 mg), trifluorotoluene (1.0 mL), nitrile compound 2 g (0.6 mmol, 88.3 mg), and trifluoromethanesulfonic anhydride (0.12 mmol, 33.9 mg) were added sequentially to a reaction tube. The mixture was then stirred in air at 70°C for 24 hours. The reaction system was quenched with saturated sodium carbonate solution, extracted three times with ethyl acetate, and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, and the solvent and silica gel adsorption were removed by rotary evaporation. The final product was obtained by simple column chromatography. N -Sulfoamidine compound 3o, yield 73%. The main test data of the obtained product are as follows. Analysis shows that the actual synthesized product is consistent with the theoretical analysis.

[0092] 1 H NMR (400 MHz, DMSO- d 6) δ 8.71 (s, 1H), 8.00 (s, 1H), 7.69 – 7.66(m, 2H), 7.51 – 7.48 (m, 2H), 7.16 – 7.13 (m, 2H), 6.84 – 6.80 (m, 2H), 3.71(s, 3H), 3.45 (s, 2H), 1.28 (s, 9H). 13 C NMR (100 MHz, DMSO- d 6) δ 168.1,158.2, 154.8, 139.8, 129.9, 127.6, 125.8, 125.5, 113.7, 55.0, 41.4, 34.7,30.8. HRMS (ESI-TOF): Anal Calcd. For. C 19 H 24 N₂O₃S + H₂ + : 361.1580, found:361.1578. IR (neat, cm -1 ): υ 3389, 2961, 1629, 1511, 1408, 1244, 1084, 1023,814, 676.

[0093] Example 16

[0094]

[0095] Primary sulfonamide 1a (0.2 mmol, 42.7 mg), nitrile compound 2h (0.6 mmol, 81.1 mg), trifluorotoluene (1.0 mL), and trifluoromethanesulfonic anhydride (0.12 mmol, 33.9 mg) were added sequentially to a reaction tube. The mixture was then stirred in air at 70°C for 24 hours. The reaction system was quenched with saturated sodium carbonate solution, extracted three times with ethyl acetate, and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, and the solvent and silica gel adsorption were removed by rotary evaporation. The final product was obtained by simple column chromatography. N -Sulfoamide compound 3p, yield 76%. The main test data of the obtained product are as follows. Analysis shows that the actual synthesized product is consistent with the theoretical analysis.

[0096] 1 H NMR (400 MHz, DMSO- d 6) δ 8.80 (s, 1H), 8.03 (s, 1H), 7.67 – 7.64(m, 2H), 7.49 – 7.47 (m, 2H), 7.26 – 7.22 (m, 2H), 7.09 – 7.04 (m, 2H), 3.51(s, 2H), 1.27 (s, 9H). 13 C NMR (100 MHz, DMSO- d 6) δ 167.5, 161.2 (d, J = 242.7Hz), 154.9, 139.7, 131.9 (d, J = 3.2 Hz), 130.7 (d, J = 8.1 Hz), 125.8,125.5, 115.0 (d, J = 21.3 Hz), 41.2, 34.7, 30.8. 19 F NMR (376 MHz, DMSO- d 6) δ-116.03 (s, 1F). HRMS (ESI-TOF): Anal Calcd. For. C 18 H 21 FN2O2S+H + : 349.1381, found: 349.1380. IR (neat, cm -1 ): υ 3425, 2969, 1643, 1509, 1268, 1144, 1024,809, 778, 630.

[0097] Example 17

[0098]

[0099] Primary sulfonamide 1a (0.2 mmol, 42.7 mg), nitrile compound 2i (0.6 mmol, 97.3 mg), trifluorotoluene (1.0 mL), and trifluoromethanesulfonic anhydride (0.12 mmol, 33.9 mg) were added sequentially to a reaction tube. The mixture was then stirred in air at 70°C for 24 hours. The reaction system was quenched with saturated sodium carbonate solution, extracted three times with ethyl acetate, and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, and the solvent and silica gel adsorption were removed by rotary evaporation. The final product was obtained by simple column chromatography. N -Sulfoamidine compound 3q, yield 64%. The main test data of the obtained product are as follows. Analysis shows that the actual synthesized product is consistent with the theoretical analysis.

[0100] 1 H NMR (400 MHz, DMSO- d 6) δ 8.91 (s, 1H), 8.13 (s, 1H), 8.11 – 8.09(m, 2H), 7.65 – 7.62 (m, 2H), 7.49 – 7.46 (m, 2H), 7.45 – 7.42 (m, 2H), 3.70(s, 2H), 1.26 (s, 9H). 13 C NMR (100 MHz, DMSO- d 6) δ 166.4, 154.9, 146.5,143.7, 139.4, 130.1, 125.8, 125.5, 123.3, 41.6, 34.7, 30.8. HRMS (ESI-TOF): Anal Calcd. For. C 18 H 21 N3O4S+Na + : 398.1145, found: 398.1130. IR (neat, cm -1 ): υ3389, 2966, 1649, 1519, 1344, 1265, 1146, 1081, 807, 659.

[0101] Example 18

[0102]

[0103] Primary sulfonamide 1a (0.2 mmol, 42.7 mg), nitrile compound 2j (0.6 mmol, 111.6 mg), trifluorotoluene (1.0 mL), and trifluoromethanesulfonic anhydride (0.12 mmol, 33.9 mg) were added sequentially to a reaction tube. The mixture was then stirred in air at 70°C for 24 hours. The reaction system was quenched with saturated sodium carbonate solution, extracted three times with ethyl acetate, and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, and the solvent and silica gel adsorption were removed by rotary evaporation. The final product was obtained by simple column chromatography. N -Sulfoamide compound 3r, yield 74%. The main test data of the obtained product are as follows. Analysis shows that the actual synthesized product is consistent with the theoretical analysis.

[0104] 1 H NMR (400 MHz, DMSO- d 6) δ 8.84 (s, 1H), 8.09 (s, 1H), 7.66 – 7.62 (m, 2H), 7.51 – 7.46 (m, 3H), 7.40 (d, J = 2.1 Hz, 1H), 7.20 – 7.17 (m, 1H), 3.55 (s, 2H), 1.27 (s, 9H). 13 C NMR (100 MHz, DMSO- d 6) δ 166.7, 154.9, 139.4,136.7, 130.8, 130.7, 130.4, 129.6, 129.3, 125.8, 125.5, 40.9, 34.7, 30.8.HRMS (ESI-TOF): Anal Calcd. For. C 18 H 20 Cl2N2O2S+H + : 399.0695, found: 399.0675.Anal Calcd. For. C 18 H 20 37 ClClN2O2S+H + : 401.0666, found: 401.0686. IR (neat, cm -1 ): υ 3387, 2961, 1633, 1539, 1393, 1261, 1106, 1024, 874, 822, 665.

[0105] Example 19

[0106]

[0107] Primary sulfonamide 1a (0.2 mmol, 42.7 mg), nitrile compound 2k (0.6 mmol, 100.3 mg), trifluorotoluene (1.0 mL), and trifluoromethanesulfonic anhydride (0.12 mmol, 33.9 mg) were added sequentially to a reaction tube. The mixture was then stirred in air at 70°C for 24 hours. The reaction system was quenched with saturated sodium carbonate solution, extracted three times with ethyl acetate, and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, and the solvent and silica gel adsorption were removed by rotary evaporation. The final product was obtained by simple column chromatography. N -Sulfoamide compound 3s, yield 72%. The main test data of the obtained product are as follows. Analysis shows that the actual synthesized product is consistent with the theoretical analysis.

[0108] 1 H NMR (400 MHz, Chloroform- d ) δ 8.02 (s, 1H), 7.85 – 7.80 (m, 4H), 7.76 – 7.74 (m, 1H), 7.48 – 7.44 (m, 3H), 7.42 – 7.32 (m, 3H), 5.77 (s, 1H), 4.05 (s, 2H), 1.35 (s, 9H). 13 C NMR (100 MHz, Chloroform- d ) δ 167.4, 155.9,138.7, 133.8, 131.8, 129.5, 129.0, 128.8, 128.7, 126.8, 126.21, 126.17,125.7, 125.4, 123.5, 41.7, 35.0, 31.0. HRMS (ESI-TOF): Anal Calcd. For.C 22 H 24 N₂O₂S + H₂ + : 381.1631, found: 381.1628. IR (neat, cm -1 ): υ 3423, 2963, 1612,1543, 1396, 1263, 1148, 1024, 768, 642.

[0109] Example 20

[0110]

[0111] Primary sulfonamide 1a (0.2 mmol, 42.7 mg), nitrile compound 2l (0.6 mmol, 78.7 mg), trifluorotoluene (1.0 mL), and trifluoromethanesulfonic anhydride (0.12 mmol, 33.9 mg) were added sequentially to a reaction tube. The mixture was then stirred in air at 70°C for 24 hours. The reaction system was quenched with saturated sodium carbonate solution, extracted three times with ethyl acetate, and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, and the solvent and silica gel adsorption were removed by rotary evaporation. The final product was obtained by simple column chromatography. N 3t of sulfonylamidine compounds were synthesized, with a yield of 72%. The main test data of the obtained product are as follows. Analysis shows that the actual synthesized product is consistent with the theoretical analysis.

[0112] 1 H NMR (400 MHz, Chloroform- d ) δ 7.97 (s, 1H), 7.79 – 7.75 (m, 2H), 7.45 – 7.43 (m, 2H), 7.25 – 7.19 (m, 5H), 6.06 (s, 1H), 3.64 (q, J = 7.2 Hz, 1H), 1.47 (d, J = 7.2 Hz, 3H), 1.32 (s, 9H). 13 C NMR (100 MHz, Chloroform- d ) δ170.8, 155.8, 139.8, 139.0, 128.9, 127.7, 127.6, 125.9, 125.6, 47.1, 35.0,31.0, 18.5. HRMS (ESI-TOF): Anal Calcd. For. C 19 H 24 N₂O₂S + Na + : 367.1451, found:367.1458. IR (neat, cm -1 ): υ 3414, 2967, 1627, 1542, 1268, 1198, 1080, 890,782, 651.

Claims

1. A method for synthesizing a monosubstituted sulfonyl amidine compound, characterized by, The application relates to a method for synthesizing monosubstituted sulfonamidate compounds by using sulfonamide and nitrile as reaction substrates and in the presence of sulfonic anhydride catalysts; the chemical structural formula of the sulfonamide is as follows: ； The nitrile is R 2 CN; The chemical structural formula of the monosubstituted sulfonamidate compounds is as follows: ； In the above structural formula, R 1 is selected from alkyl, substituted or unsubstituted aryl, thienyl, wherein the substituents are methyl, fluoro or chloro; R 2 is selected from substituted or unsubstituted alkyl, wherein the substituents are alkenyl, phenyl, methoxy, fluoro, chloro, bromo, nitro or naphthyl; The molar ratio of the nitrile and the sulfonamide is (2-4):1; The sulfonic anhydride is trifluoromethanesulfonic anhydride; The reaction is carried out in an organic solvent, air; the organic solvent is one or several of trifluorotoluene, 1,2-dichloroethane, cyclohexane, N , N dimethylformamide, dimethylsulfoxide, tetrahydrofuran, ethyl acetate.

2. The method for synthesizing the monosubstituted sulfonylamidinium compound according to claim 1, characterized in that, The reaction temperature is 60-80 DEG C, and the reaction time is 20-48 hours.

3. The method for synthesizing the monosubstituted sulfonylamidinium compound according to claim 1, characterized in that, The molar ratio of the sulfonamide and the sulfonic anhydride is 1: (0.5-1).

4. The method for synthesizing the monosubstituted sulfonylamidinium compound according to claim 1, characterized in that, After the reaction is completed, the reaction system is quenched by using a saturated sodium carbonate solution, dried by using anhydrous sodium sulfate, and the solvent is removed by using a rotary evaporator; the monosubstituted sulfonamidate compounds can be obtained by simple column chromatography.

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