Method for synthesizing N-sulfonyl amidine compound by using copper-catalyzed calcium carbide as acetylene source and application of N-sulfonyl amidine compound

Abstract

The invention provides a method for synthesizing an N-sulfonyl amidine compound by using copper-catalyzed calcium carbide as an acetylene source and application, and relates to the technical field of preparation of sulfonyl amidin.The method comprises the steps that calcium carbide is used as a solid acetylene source and subjected to a multi-component one-pot room-temperature reaction with a sulfonyl azide compound and an amine compound, and the N-sulfonyl amidine compound is directly synthesized; the calcium carbide is cheap and easy to obtain, the preparation method is efficient and easy to operate, the substrate application range is wide, and the industrial application value is high.

Description

Technical Field

[0001] The invention relates to the technical field of preparation of sulfonyl amidines, and in particular to a method and application of synthesizing N-sulfonyl amidine compounds by using copper-catalyzed calcium carbide as an acetylene source. Background Art

[0002] N-Sulfonylamidine is a common functional group found in some drugs, natural products and bioactive compounds. Due to its high polarity, high structural rigidity and rich hydrogen bond structure, compounds containing this type of functional group have been widely studied in the fields of medicine, chemistry, agriculture, organic synthesis and so on.

[0003] In the prior art, the representative synthesis methods of N-sulfonylamidines are as follows: (A) Synthesis of N-sulfonylamidines using sulfonyl azide as a precursor: For example, in 2005 and 2008, the Chang group used copper-catalyzed three-component coupling of sulfonyl azide, terminal alkyne and amine, and the amine was nucleophilically added to the in situ generated enone imine intermediate to generate N-sulfonylamidines. The defect was that N-sulfonylacetamidine could not be synthesized; in 2013, the Hatanaka group reported the generation of N-sulfonylamidines by coupling sulfonyl azide and thioamide. The disadvantage of this method was that the raw material thioamide was difficult to synthesize and expensive; in 2017, the Odell group used palladium-catalyzed ligand-free carbonylation cycloaddition decarboxylation cascade reaction to generate N-sulfonylamidines from sulfonyl azide. Azide and substituted amides are used to synthesize N-sulfonylamidines under low CO pressure. This method uses precious metal palladium as a catalyst and has relatively harsh reaction conditions. (B) Synthesis of N-sulfonylamidines using sulfonamide as a precursor: For example, in 2015, Stahl's group reported the synthesis of N-sulfonylamidines by copper-catalyzed aerobic oxidative coupling of sulfonamide, terminal alkyne and amine in an oxygen atmosphere. This method requires heating in a high-purity oxygen atmosphere and the conditions are relatively harsh. In 2018, Wan's group used amides and diazoacetates to generate ylides in situ. Mn catalyzed the formation of ylides and the interception reaction of sulfonamides to generate N-sulfonylamidines. This reaction requires heating under reflux, and the preparation process of the raw material diazoacetate is relatively cumbersome. (C) Synthesis of N-sulfonylamidines using N,N-dibromoarylsulfonamide as precursor: In 2020, the Phukan research group reported a method for synthesizing N-sulfonylamidines using N,N-dibromoarylsulfonamide, tert-butyl isonitrile and nitrile as raw materials. The tert-alkyl group migrated to the unsaturated nitrogen center of the nitrile by breaking the CN single bond of the isonitrile, and a highly toxic byproduct, bromonitrile, was generated (the relevant equation is shown below). The above preparation methods use different raw materials as precursors to synthesize N-sulfonylamidines, which have certain development prospects, but still have some disadvantages, such as harsh reaction conditions, the use of precious metal catalysts, difficult to obtain starting materials, and the generation of highly toxic byproducts. Therefore, it is crucial to find a simpler method to synthesize N-sulfonylamidine compounds using cheap and readily available starting materials.

[0004] Summary of the invention

[0005] In view of this, the present invention provides a method for synthesizing N-sulfonyl amidine compounds using copper-catalyzed calcium carbide as an acetylene source, wherein the raw material is cheap and readily available.

[0006] It is also necessary to provide an application of the synthesized N-sulfonyl amidine compounds.

[0007] The technical solution adopted by the present invention to solve its technical problem is:

[0008] A method for synthesizing N-sulfonyl amidine compounds using copper-catalyzed calcium carbide as an acetylene source comprises the following steps:

[0009] S1: dissolving a sulfonyl azide compound 1, an amine compound 2, calcium carbide, an initiator, and a copper catalyst in a solvent for a one-pot reaction to obtain a mixture containing an N-sulfonyl amidine compound 3;

[0010] S2: Extracting, washing, drying, concentrating, and column chromatography the mixture containing N-sulfonyl amidine compound 3 to obtain a pure product of N-sulfonyl amidine compound 3. The synthetic route is as follows:

[0011]

[0012] Wherein: R is an alkyl group, an aryl group or a heterocyclic ring; R 1 is alkyl, aryl or heteroaryl; R 2 is H or alkyl.

[0013] The N-sulfonyl amidine compound synthesized by the above method is used, wherein the N-sulfonyl amidine compound is converted into a 2-methylbenzimidazole compound in the presence of m-chloroperbenzoic acid (mCPBA) oxidant.

[0014] Compared with the prior art, the present invention has the following beneficial effects:

[0015] The present invention uses calcium carbide as a solid acetylene source to directly synthesize N-sulfonylamidine compounds by a multi-component one-pot room temperature reaction with sulfonyl azide compounds and amine compounds; calcium carbide is cheap and easy to obtain, the preparation method is efficient and easy to operate, the substrate has a wide range of adaptability, and the industrial application value is high. Figure 1 As shown, the present invention uses water as an initiator to make calcium carbide first generate acetylenic calcium hydroxide, and then react in the presence of a Cu catalyst to convert it into the corresponding acetylenic cuprous A, A coordinates with the sulfonyl azide compound 1 to gradually form a triazole ring intermediate C, C is further hydrolyzed to obtain an N-sulfonyl triazole copper species D, D opens the ring to release nitrogen and is converted into an ketene imine intermediate E, E is added with an amine compound to finally generate an N-sulfonyl amidine compound 3. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 Schematic diagram of the synthesis of N-sulfonyl amidine compounds using copper-catalyzed calcium carbide as an acetylene source.

[0017] Figure 2 This is the single crystal X-ray diffraction analysis diagram of the product obtained in Example 1 (CCDC: 2326726).

[0018] Figure 3 The product obtained in Example 1 1 H NMR spectrum.

[0019] Figure 4 The product obtained in Example 1 13 C NMR spectrum.

[0020] Figure 5 The product obtained in Example 7 1 H NMR spectrum.

[0021] Figure 6 The product obtained in Example 7 13 C NMR spectrum.

[0022] Figure 7 This is the single crystal X-ray diffraction analysis diagram of the product obtained in Example 12 (CCDC: 2329274).

[0023] Figure 8 The product obtained in Example 12 1 H NMR spectrum.

[0024] Fig. 9 The product obtained in Example 12 13 C NMR spectrum.

[0025] Fig.10 This is the single crystal X-ray diffraction analysis diagram of the product obtained in Example 17 (CCDC: 2325497).

[0026] Fig.11 The product obtained in Example 17 1 H NMR spectrum.

[0027] Fig.12 The product obtained in Example 17 13 C NMR spectrum.

[0028] Fig.13 The product obtained in Example 19 1 H NMR spectrum.

[0029] Fig.14 The product obtained in Example 19 13C NMR spectrum.

[0030] Fig.15 The product obtained in Example 20 1 H NMR spectrum.

[0031] Fig.16 The product obtained in Example 20 13 C NMR spectrum.

[0032] Fig.17 The product obtained in Example 31 1 H NMR spectrum.

[0033] Fig.18 The product obtained in Example 31 13 C NMR spectrum.

[0034] Fig.19 The product obtained in Example 32 1 H NMR spectrum.

[0035] Fig. 20 The product obtained in Example 32 13 C NMR spectrum.

[0036] Fig.21 This is the single crystal X-ray diffraction analysis diagram of the product obtained in Example 41 (CCDC: 2326784).

[0037] Fig. 22 The product obtained in Example 41 1 H NMR spectrum.

[0038] Fig.23 The product obtained in Example 41 13 C NMR spectrum.

[0039] Fig.24 The product obtained in Example 55 1 H NMR spectrum.

[0040] Fig.25 The product obtained in Example 55 13 C NMR spectrum.

[0041] Fig.26 The product obtained in Example 59 1 H NMR spectrum.

[0042] Fig. 27 The product obtained in Example 59 13 C NMR spectrum. DETAILED DESCRIPTION

[0043] The technical solutions and technical effects of the embodiments of the present invention are further described in detail below in conjunction with the accompanying drawings of the present invention.

[0044] For ease of understanding, the present invention is further illustrated by the following examples:

[0045] Embodiment 1:

[0046] Materials: Calcium carbide was purchased from McLean Chemical Company (China, purity: 98%) and ground into powder (about 50-100 mesh) in a ceramic mortar before use. The reaction solvent was an ultra-dry solvent or distilled for more than one hour before use to remove moisture. All reagents required for the reaction were commercially available analytical grade reagents (purchased from Adamas, Aldrich and Energy Chemical) and were used without further purification unless otherwise specified. The reaction progress was monitored by thin layer chromatography (TLC) on silica gel GF-254 plates with a UV detector. Column chromatography was performed with silica gel (200-300 mesh) as the stationary phase and petroleum ether (60-90°C) and ethyl acetate as the eluent to purify the product.

[0047] Tosyl azide 1a (1 mmol), piperidine 2a (1 mmol), calcium carbide, copper catalyst and water were dissolved in a solvent (3 mL), stirred at room temperature for reaction, and after completion of the reaction, the mixture was filtered to remove solids, extracted with dichloromethane (10 mL × 3), and washed with saturated ammonium chloride solution (10 mL × 3) and saturated brine (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was separated by column chromatography using petroleum ether and ethyl acetate (v / v 3:1) as eluents to obtain pure product 3a.

[0048] The above method was used to investigate the effects of copper catalyst, solvent, calcium carbide / water, and reaction time on the synthesis yield. The experimental settings and results are shown in Table 1.

[0049]

[0050] Table 1

[0051]

[0052]

[0053] As shown in Table 1, the copper catalyst and its dosage (experiments 1-10) were screened to determine Cu(MeCN) 4 BF 4(0.1mmol) is the best catalyst (Experiment 9). The solvent also plays an important role in the reaction (Experiments 11-17). It was found that chloroform was the most effective solvent (Experiment 12), while DMF and DMSO, commonly used solvents for calcium carbide reactions, only obtained 12% and trace products 3a, respectively (Experiments 16 and 17). Further, the dosage of calcium carbide / water was screened (Experiments 18-21), and we found that the yield of calcium carbide / water was higher when the dosage was 5mmol / 6mmol (Experiment 21). By screening the reaction time (Experiments 22-23), it was found that the yield of 3a was as high as 90% when reacted for 12 hours at room temperature (Experiment 21). It can be obtained from the above experiments that the reaction conditions shown in Experiment 21 are the optimal conditions obtained by screening.

[0054] Embodiment 2 to Embodiment 58:

[0055] According to the synthesis method of Example 1 and the reaction conditions of Experiment 21 selected in Example 1, different amine compounds 2 and sulfonyl azide compounds 1 are used to carry out the reaction.

[0056] The N-sulfonyl amidine compounds 3 obtained in Examples 1 to 58 and their yields and stereo configurations are shown in Table 2.

[0057] Table 2

[0058]

[0059]

[0060]

[0061]

[0062]

[0063]

[0064] pass 1 H NMR, 13 The products prepared in Examples 1 to 58 were characterized by C NMR, HRMS, single crystal X-ray diffraction analysis, etc., confirming that the product 3 shown in Table 2 was obtained. The characterization data are as follows (representative spectra are shown in Figure 2-Figure 25 shown).

[0065] Embodiment 1: 1 H NMR (500 MHz, CDCl 3)δ7.80(d,J=8.3Hz,2H),7.23(d,J=8.1Hz,2H),3.68(t,J=5.5Hz,2H),3.44(t,J=5.5Hz,2H),2.47(s,3H),2.38(s,3H),1.70-1.51(m,6H); 13 C NMR (126 MHz, CDCl 3 )δ164.0,141.8,141.6,129.2,126.4,47.7,45.9,26.5,25.3,24.2,21.5,17.9; HRMS(ESI)m / z:[M+H] + Calculate for C 14 H 21 N 2 O 2 S + 281.1318; found 281.1313.

[0066] Embodiment 2: 1 H NMR (500 MHz, CDCl 3 )δ7.78(d,J=8.1Hz,2H),7.24(d,J=7.9Hz,2H),3.73-3.62(m,6H),3.49(t,J=4.8Hz,2H),2.50(s,3H),2.38(s,3H); 13 C NMR (126 MHz, CDCl 3 )δ164.7,142.2,141.0,129.2,126.4,66.4,66.3,46.7,44.7,21.5,17.6.

[0067] Embodiment three: 1 H NMR (500 MHz, CDCl 3 )δ7.76(d,J=8.3Hz,2H),7.23(d,J=7.9Hz,2H),4.00(t,J=5Hz,2H),3.77(t,J=5Hz,2H),2.61(m,4H),2.48(s,3H),2.38(s,3H); 13 C NMR (126 MHz, CDCl 3 )δ164.4,142.2,141.0,129.3,126.3,49.4,47.6,27.9,27.0,21.5,17.9; HRMS(ESI)m / z:[M+H] + Calculate for C 13 H 19 N2 O 2 S 2 + 299.0882; found 299.0876.

[0068] Embodiment 4: 1 H NMR (500 MHz, CDCl 3 )δ7.78(d,J=8.3Hz,2H),7.20(d,J=8.0Hz,2H),3.48(t,J=7.0Hz,2H),3.41(t, J=6.9Hz,2H),2.40(s,3H),2.35(s,3H),1.97-1.90(m,2H),1.87-1.81(m,2H); 13 C NMR (126 MHz, CDCl 3 )δ163.8,141.7,141.4,129.1,126.3,48.5,48.2,25.7,24.4,21.4,19.1; HRMS(ESI)m / z:[M+H] + Calculate for C 13 H 19 N 2 O 2 S + 267.1161; found 267.1156.

[0069] Embodiment five: 1 H NMR (500 MHz, CDCl 3 )δ7.78(d,J=8.3Hz,2H),7.24(d,J=8.0Hz,2H),3.70(t,J=5.4Hz,2H),3.51 -3.45(m,4H),3.41(t,J=5.4Hz,2H),2.52(s,3H),2.38(s,3H),1.44(s,9H); 13 C NMR (126 MHz, CDCl 3 )δ164.8,154.4,142.2,141.0,129.3,126.4,80.7,46.1,44.2,28.4,21.5,17.9; HRMS(ESI)m / z:[M+H] + Calculate for C 18 H 28 N 3 O 4 S + 382.1795; found 382.1786.

[0070] Embodiment six:1 H NMR (500 MHz, CDCl 3 )δ8.14(dd,J=5.2,1.9Hz,1H),7.78(d,J=8.4Hz,2H),7.48-7.44(m,1H),7.22(d,J=8.2Hz,2H),6.63(dd,J=7.1, 4.9Hz,1H),6.57(d,J=8.5Hz,1H),3.87-3.80(m,2H),3.61(s,4H),3.52-3.45(m,2H),2.50(s,3H),2.35(s,3H); 13 C NMR (126 MHz, CDCl 3 )δ164.7,158.5,147.9,142.0,141.0,137.7,129.2,126.3,114.0,107.0,45.9,44.5,44.3,43.9,21.4,17.7; HRMS(ESI)m / z:[M+H] + Calculate for C 18 H 23 N 4 O 2 S + 359.1536; found 359.1528.

[0071] Embodiment seven: 1 H NMR (500 MHz, CDCl 3 )δ7.78(d,J=8.3Hz,2H),7.22(d,J=8.1Hz,2H),3.46(q,J=7.1Hz,2H),3.33(q,J=7 .2Hz,2H),2.46(s,3H),2.37(s,3H),1.17(t,J=7.2Hz,3H),1.10(t,J=7.1Hz,3H); 13 C NMR (126 MHz, CDCl 3 )δ164.6,141.7,141.5,129.1,126.2,44.0,43.8,21.5,17.6,13.8,12.2; HRMS(ESI)m / z:[M+H] + Calculate for C 13 H 21 N 2 O 2 S + 269.1318; found 269.1313.

[0072] Embodiment eight: 1H NMR (500 MHz, CDCl 3 )δ7.77(d,J=8.3Hz,2H),7.21(d,J=8.1Hz,2H),3.37-3.33(m,2H),3.24-3.19(m,2H),2. 47(s,3H),2.36(s,3H),1.62-1.52(m,4H),0.90(t,J=7.4Hz,3H),0.81(t,J=7.4Hz,3H); 13 C NMR (126 MHz, CDCl 3 )δ164.9,141.7,141.6,129.1,126.2,51.5,51.1,22.0,21.5,20.2,17.8,11.4,11.2; HRMS(ESI)m / z:[M+H] + calcdfor C 15 H 25 N 2 O 2 S + 297.1631; found 297.1626.

[0073] Embodiment nine: 1 H NMR (500 MHz, CDCl 3 )δ7.78(d,J=8.2Hz,2H),7.22(d,J=8.0Hz,2H),4.09-3.66(m,2H),2.51(s,3H),2.36(s,3H),1.24(dd,J=31.6,6.8Hz,12H); 13 C NMR (126 MHz, CDCl 3 )δ164.0,141.7,141.6,129.1,126.1,48.1,21.5,20.8,20.0,19.9; HRMS(ESI)m / z:[M+H] + Calculate for C 15 H 25 N 2 O 2 S + 297.1631; found 297.1626.

[0074] Embodiment ten: 1 H NMR (500 MHz, CDCl 3)δ7.73(d,J=8.3Hz,2H),7.16(d,J=8.0Hz,2H),3.37-3.30(m,2H),3.24-3.17(m,2H),2.42(s,3H),2.31(s,3H),1.51-1. 41(m,4H),1.26(dt,J=15.0,7.4Hz,2H),1.17(dq,J=14.8,8.0,7.4Hz,2H),0.86(t,J=7.3Hz,3H),0.78(t,J=7.4Hz,3H); 13 C NMR (126 MHz, CDCl 3 )δ164.6,141.5,141.5,128.9,126.0,49.5,49.1,30.6,28.8,21.3,20.1,19.9,17.6,13.6,13.6; HRMS(ESI)m / z:[M+H] + Calculate for C 17 H 29 N 2 O 2 S + 325.1944; found 325.1939.

[0075] Embodiment eleven: 1 H NMR (500 MHz, CDCl 3 )7.80(d,J=8.3Hz,2H),7.24(d,J=8.0Hz,2H),5.80-5.70(m,2H),5.25(d,J=10.4Hz,1H), 5.19-5.10(m,3H),4.07(d,J=6.1Hz,2H),3.92(d,J=5.0Hz,2H),2.51(s,3H),2.39(s,3H); 13 C NMR (126 MHz, CDCl 3 )δ166.0,142.0,141.3,131.7,131.3,129.2,126.4,118.7,117.9,51.5,50.8,21.5,17.9; HRMS(ESI)m / z:[M+H] + Calculate for C 15 H 21 N 2 O 2 S + 293.1318; found 293.1311.

[0076] Embodiment 12: 1HNMR(500MHz,DMSO-d 6 )δ10.14(s,1H),7.54(d,J=7.9Hz,2H),7.42(t,J=7.8Hz,1H),7.20(d,J=8.0Hz,2H),7.20 - 7.14(m,2H),7.10 - 7.05(m,1H),2.37(s,3H),2.22(s,3H); 13 C NMR(126MHz,DMSO-d 6 )δ165.5,155.5(d,J=248.6Hz),141.2(d,J=183.8Hz),129.2,128.0(d,J=1Hz),127.2,125.8,125.6,124.7(d,J=12.1Hz),124.4(d,J=3.6Hz),115.9(d,J=19.7Hz),20.8,20.0;HRMS(ESI)m / z:[M + H] + calcd for C 15 H 16 FN 2 O 2 S + 307.0911;found 307.0904.

[0077] Example XIII: 1 H NMR(500MHz,DMSO-d 6 )δ10.37(s,1H),7.72(d,J=8.3Hz,2H),7.60(dd,J=9.1,4.9Hz,2H),7.35(d,J=8.1Hz,2H),7.17(t,J=8.8Hz,2H),2.46(s,3H),2.35(s,3H); 13 C NMR(126MHz,DMSO-d 6 )δ163.6,159.0(d,J=243.1Hz),142.0,140.5,134.2(d,J=2.8Hz),129.3,125.9,123.7(d,J=8.3Hz),115.3(d,J=22.5Hz),20.9,20.7;HRMS(ESI)m / z:[M + H] + calcd for C 15 H 16 FN 2 O 2 S + 307.0911;found 307.0906.

[0078] Embodiment 14: 1 H NMR (500 MHz, DMSO-d 6 )δ10.42(s,1H),7.71(d,J=8.2Hz,2H),7.61-7.57(m,2H),7.41-7.34(m,4H),2.45(s,3H),2.36(s,3H); 13 C NMR (126 MHz, DMSO-d 6 )δ163.8,142.1,140.4,136.8,129.4,128.8,128.6,125.9,123.3,20.9,20.8; HRMS(ESI)m / z:[M+H] + Calculate for C 15 H 16 C1N 2 O 2 S + 323.0615; found 323.0611.

[0079] Embodiment 15: 1 H NMR (500 MHz, DMSO-d 6 )δ10.47(s,1H),7.88(dd,J=6.9,2.6Hz,1H),7.73(d,J=8.3Hz,2H),7.49-7.46(m,1H),7.40-7.35(m,3H),2.47(s,3H),2.36(s,3H). 13 C NMR (126 MHz, DMSO-d 6 )δ163.6,154.1(d,J=245.5Hz),142.1,140.3,135.0(d,J=3.2Hz),129.4,125.8,123.4,122 .0(d,J=7.3Hz),119.1(d,J=18.5Hz),117.0(d,J=22.1Hz),20.9,20.7; HRMS(ESI)m / z:[M+H] + Calculate for C 15 H 15 CIF 2 O 2 S + 341.0521; found 341.0517.

[0080] Embodiment 16: 1 H NMR (500 MHz, DMSO-d 6)δ10.52(s,1H),7.95(d,J=2.4Hz,1H),7.73(d,J=8.3Hz,2H),7.56(d,J=8.8Hz,1 H),7.46(dd,J=8.8,2.5Hz,1H),7.36(d,J=8.0Hz,2H),2.47(s,3H),2.36(s,3H); 13 C NMR (126 MHz, DMSO-d 6 )δ163.8,142.3,140.2,137.9,130.9,130.6,129.5,126.6,125.9,123.0,121.5,20.9,20.9; HRMS(ESI)m / z:[M+H] + calcdfor C 15 H 15 Cl 2 N 2 O 2 S + 357.0225; found 357.0221.

[0081] Embodiment 17: 1 H NMR (500 MHz, CDCl 3 )δ9.77(s,1H),8.19(d,J=39.7Hz,2H),7.85(d,J=8.3Hz,2H),7.64(t,J=7.9 Hz,1H),7.27(d,J=8.0Hz,2H),7.09-7.02(m,1H),2.60(s,3H),2.39(s,3H); 13 C NMR (126 MHz, CDCl 3 )δ163.4,150.9,147.4,142.8,138.7,129.4,126.6,120.8,116.5,21.8,21.5; HRMS(ESI)m / z:[M+H] + Calculate for C 14 H 16 N 3 O 2 S + 290.0957; found 290.0952.

[0082] Embodiment 18: 1 H NMR (500 MHz, DMSO-d 6)δ9.16(t,J=5.5Hz,1H),8.29(d,J=2.5Hz,1H),7.70(dd,J=8.2,2.5Hz,1H),7.58(d,J=8.3Hz,2H ),7.46(d,J=8.2Hz,1H),7.30(d,J=7.9Hz,2H),4.37(d,J=5.5Hz,2H),2.36(s,3H),2.26(s,3H); 13 C NMR (126 MHz, DMSO-d 6 )δ165.7,149.3,149.0,141.6,140.9,139.2,132.7,129.1,125.7,123.9,41.5,20.9,19.8; HRMS(ESI)m / z:[M+H] + Calculate for C 15 H 17 C1N 3 O 2 S + 338.0724; found 338.0717.

[0083] Embodiment 19: 1 HNMR (500MHz, CDCl 3 )δ7.76-7.71(d,J=8.5Hz,2H),7.22(d,J=8.0Hz,2H),6.15(s,1H),2.37(s,3H),2.28(s,3H),1.30(s,9H); 13 C NMR (126 MHz, CDCl 3 )δ164.6,142.0,141.1,129.2,126.1,53.6,28.3,22.0,21.5; HRMS(ESI)m / z:[M+H] + calcdfor C 13 H 21 N 2 O 2 S + 269.1318; found 269.1312.

[0084] Embodiment 20: 1 H NMR (500 MHz, CDCl 3 )δ7.91(d,J=7.7Hz,2H),7.47-7.41(m,3H),3.68(t,J=6.5Hz,2H),3.43(t,J=7.5Hz,2H),2.47(s,3H),1.65-1.53(m,6H); 13C NMR (126 MHz, CDCl 3 )δ164.0,144.3,131.3,128.6,126.3,47.7,45.9,26.4,25.3,24.1,17.9; HRMS(ESI)m / z:[M+H] + Calculate for C 13 H 19 N 2 O 2 S + 267.1161; found 267.1157.

[0085] Embodiment 21: 1 H NMR (500 MHz, CDCl 3 )δ8.01(d,J=8.4Hz,2H),7.73(d,J=8.4Hz,2H),3.65(t,J=5.4Hz,2H),3.47(t,J=5.4Hz,2H),2.52(s,3H),1.67-1.52(m,6H); 13 C NMR (126 MHz, CDCl 3 )δ163.9,148.2,132.5,126.9,117.8,114.9,47.9,46.1,26.4,25.3,23.9,18.3; HRMS(ESI)m / z:[M+H] + Calculate for C 14 H 18 N 3 O 2 S + 292.1114; found 292.1109.

[0086] Embodiment 22: 1 H NMR (500 MHz, CDCl 3 )δ7.75(s,1H),7.55(d,J=2.9Hz,2H),3.64(t,J=3.9Hz,2H),3.42(t,J=3.9Hz,2H),2.45(s,3H),2.39(s,3H),1.64-1.49(m,6H); 13 CNMR (126MHz, CDCl 3 )δ163.9,143.3,138.5,132.5,128.3,128.3,125.1,47.7,45.9,26.4,25.2,24.0,23.0,17.9; HRMS(ESI)m / z:[M+H] + Calculate for C14 H 20 Bn 2 O 2 S + 359.0423; found 359.0416.

[0087] Embodiment 23: 1 H NMR (500 MHz, CDCl 3 )δ7.80(2H,d,J=8.9Hz,2H),6.88(d,J=8.9Hz,2H),3.79(s,3H),3.65(t,J=6.0Hz,2H),3.40(t,J=5.5Hz,2H),2.42(s,3H),1.64-1.47(m,6H); 13 C NMR (126 MHz, CDCl 3 )δ163.8,161.8,136.4,128.1,113.6,55.5,47.6,45.8,26.4,25.2,24.0,17.6; HRMS(ESI)m / z:[M+H] + Calculate for C 14 H 21 N 2 O 3 S + 297.1267; found 297.1261.

[0088] Embodiment 24: 1 H NMR (500 MHz, CDCl 3 )δ7.55(dd,J=3.7,1.4Hz,1H),7.43(dd,J=5.0,1.5Hz,1H),6.97(dd,J=5.1,3.6Hz ,1H),3.73(t,J=5.6Hz,2H),3.45(t,J=5.6Hz,2H),2.47(s,3H),1.67-1.55(m,6H); 13 C NMR (126 MHz, CDCl 3 )δ163.9,146.1,129.9,129.5,126.7,47.8,46.2,26.5,25.4,24.0,17.7; HRMS(ESI)m / z:[M+H] + Calculate for C 11 H 17 N 2 O 2 S 2 + 273.0725; found 273.0722.

[0089] Embodiment 25: 1 H NMR (500 MHz, CDCl 3 )δ8.23(s,1H),7.60(d,J=5.8Hz,1H),7.49(t,J=5.8Hz,1H),7.23(d,J=8.2Hz,1H),4.38(d,J=5.8Hz,2H),2.88(s,3H),2.32(s,3H); 13 C NMR (126 MHz, CDCl 3 )δ165.7,150.5,149.4,139.1,131.9,124.3,43.1,42.3,20.6; HRMS(ESI)m / z:[M+H] + Calculate for C 9 H 13 C1N 3 O 2 S + 262.0411; found 262.0408.

[0090] Embodiment 26: 1 HNMR (500MHz, CDCl 3 )δ8.19(s,1H),7.44(dd,J=8.2,2.5Hz,1H),7.30-7.25(m,5H),7.22(d,J=8.2Hz,2H),4.31(d,J=5.7Hz,2H),4.19(s,2H),2.11(s,3H); 13 C NMR (126 MHz, CDCl 3 )δ166.4,150.6,149.2,138.9,131.8,130.8,130.0,128.5,124.3,60.7,42.2,20.6; HRMS(ESI)m / z:[M+H] + Calculate for C 15 H 17 C1N 3 O 2 S + 338.0724; found 338.0720.

[0091] Embodiment 27: 1 H NMR (500 MHz, CDCl 3)δ8.31(d,J=2.4Hz,1H),7.65(dd,J=8.3,2.5Hz,1H),7.29(d,J=8.2Hz,1H),7.12(t,J=5.7Hz,1 H),4.45(d,J=5.7Hz,2H),2.99-2.92(m,4H),2.37(s,3H),1.61-1.57(m,4H),1.47-1.43(m,2H); 13 C NMR (126 MHz, CDCl 3 )δ166.4,150.6,149.3,138.7,132.3,124.3,60.5,47.6,42.4,25.1,23.7,20.7,14.2; HRMS(ESI)m / z:[M+H] + Calculate for C 13 H 20 C1N 4 O 2 S + 331.0990; found 331.0986.

[0092] Embodiment 28: 1 H NMR (500 MHz, CDCl 3 )δ7.88-7.82(m,2H),7.46-7.41(m,3H),6.23(s,1H),2.28(s,3H),1.30(s,9H); 13 C NMR (126 MHz, CDCl 3 )δ164.7,143.7,131.5,128.6,126.0,53.6,28.2,21.9; HRMS(ESI)m / z:[M+H] + Calculate for C 12 H 19 N 2 O 2 S + 255.1161; found 255.1158.

[0093] Embodiment 29: 1 H NMR (500 MHz, DMSO-d 6)δ8.41(s,1H),8.18(s,1H),8.13(d,J=7.1Hz,1H),8.07(d,J=8.7Hz,1H),8.00(d,J= 7.2Hz,1H),7.79(dd,J=8.7,1.9Hz,1H),7.68-7.61(m,2H),2.27(s,3H),1.28(s,9H); 13 C NMR (126 MHz, DMSO-d 6 )δ164.4,141.2,133.7,131.7,129.1,128.8,128.2,127.7,127.3,125.3,122.3,52.5,27.7,20.7; HRMS(ESI)m / z:[M+H] + Calculate for C 16 H 21 N 2 O 2 S + 305.1318; found 305.1313.

[0094] Embodiment 30: 1 HNMR (500MHz, CDCl 3 )δ7.74(s,1H),7.59(d,J=8.3Hz,1H),7.53(d,J=8.3Hz,1H),6.03(s,1H),2.42(s,3H),2.32(s,3H),1.31(s,9H); 13 C NMR (126 MHz, CDCl 3 )δ164.6,143.0,138.7,132.7,128.6,128.2,125.0,53.8,28.3,23.1,22.3; HRMS(ESI)m / z:[M+H] + Calculate for C 13 H 20 Bn 2 O 2 S + 347.0423; found 347.0418.

[0095] Embodiment 31: 1 H NMR (500 MHz, CDCl 3 )δ7.46-7.41(m,2H),6.96-6.91(m,1H),6.72(s,1H),2.24(s,3H),1.29(s,9H); 13 C NMR (126 MHz, CDCl3 )δ165.1,145.3,130.1,129.4,126.6,53.7,28.0,21.4; HRMS(ESI)m / z:[M+H] + Calculate for C 10 H 17 N 2 O 2 S 2 + 261.0726; found 261.0721.

[0096] Embodiment 32: 1 H NMR (500 MHz, CDCl 3 )δ8.07(s,0.07H),7.70(d,J=8.3Hz,2.17H),7.23(s,1H),7.20(d,J=8.1Hz,2.14H),2.91 (d,J=4.7Hz,0.24H),2.74(d,J=4.7Hz,3H),2.34(s,3.25H),2.20(s,3H),2.03(s,0.25H); 13 C NMR (126 MHz, CDCl 3 )δ167.0,142.3,140.5,129.3,126.2,28.7,21.4,20.4.

[0097] Embodiment 33: 1 H NMR (500 MHz, CDCl 3 )δ8.06(s,0.24H),7.76(d,J=8.1Hz,2.46H),7.23(d,J=8.0Hz,2.50H),6.42(s,1H),3.32-3.27(m,2.56H), 2.39(s,0.72H),2.38(s,3H),2.30(s,3H),2.07(s,0.7H),1.24(t,J=7.2Hz,0.72H),1.10(t,J=7.3Hz,3H); 13 C NMR (126 MHz, CDCl 3 )δ166.0,165.8,143.0,142.2,140.9,139.6,129.5,129.3,126.4,39.4,37.1,21.6,21.5,21.1,21.0,15.0,13.7; HRMS(ESI)m / z:[M+H] + Calculate for C 11 H 17 N 2 O2 S + 241.1005; found 241.1000.

[0098] Embodiment 34: 1 H NMR (500 MHz, CDCl 3 )δ8.00(s,0.16H),7.75(d,J=8.3Hz,2.33H),7.23(d,J=8.0Hz,2.34H),6.35(s,1H),4.14-4.07(m,1H),3.72-3.68(m ,0.18H),2.39(s,0.52H),2.38(s,3H),2.27(s,3H),2.09(s,0.52H),1.23(d,J=6.5Hz,1.04H),1.11(d,J=6.7Hz,6H); 13 C NMR (126 MHz, CDCl 3 )δ164.9,164.9,142.9,142.1,141.0,139.7,129.4,129.3,126.4,126.3,46.7,43.9,23.5,23.4,21.8,21.6.21.5,21.2,20.9.

[0099] Embodiment 35: 1 H NMR (500 MHz, CDCl 3 )δ8.10(s,0.16H),7.71(d,J=8.2Hz,2.33H),7.21(d,J=8.0Hz,2.33H),6.93(d,J=6.0Hz,1H),3.20-3.16(m,2.32H),2.37(s,0.53H) ,2.36(s,3H),2.24(s,3H),2.05(s,0.5H),1.62-1.56(m,0.37H),1.51-1.44(m,2H),0.93(t,J=7.4Hz,0.54H),0.82(t,J=7.4Hz,3H); 13 C NMR (126 MHz, CDCl 3 )δ166.3,143.0,142.1,140.8,139.5,129.4,129.2,126.2,46.1,43.8,22.9,21.6,21.5,21.4,21.0,20.7,11.4,11.1; HRMS(ESI)m / z:[M+H] + Calculate for C 12 H 19 N 2 O2 S + 255.1161; found 255.1157.

[0100] Embodiment 36: 1 HNMR (500MHz, CDCl 3 )δ8.07(s,0.15H),7.72(d,J=8.0Hz,2.27H),7.21(d,J=8.0Hz,2.31H),6.93(t,J=5.6Hz,1H),3.21(d,J=5.2Hz,2.31H),2.36(s,3H),2.24(s,3 H),2.05(s,0.53H),1.56-1.50(m,0.39H),1.45-1.39(m,2H),1.22(dt, J=14.8,7.5Hz,2.6H),0.91(t,J=7.3Hz,0.52H),0.81(t,J=7.4Hz,3H); 13 C NMR (126 MHz, CDCl 3 )δ166.2,143.0,142.1,140.8,139.5,129.4,129.2,126.2,44.2,41.8,31.6 ,30.3,21.5,21.4,21.0,20.7,20.0,19.7,13.7,13.6; HRMS(ESI)m / z:[M+H] + Calculate for C 13 H 21 N 2 O 2 S + 269.1318; found 269.1313.

[0101] Embodiment 37: 1 H NMR (500 MHz, CDCl 3 )δ8.03(s,0.09H),7.68(d,J=8.3Hz,2.2H),7.21(d,J=8.0Hz,1H),7.17( d,J=8.1Hz,2.17H),3.19-3.15(m,2.24H),2.33(s,3.3H),2.20(s,3H),2 .00(s,0.28H),1.51-1.48(m,0.21H),1.43-1.36(m,2H),1.27-1.21(m,0 .61H),1.19-1.08(m,6H),0.84(t,J=6.9Hz,0.3H),0.79(t,J=6.9Hz,3H); 13C NMR (126 MHz, CDCl 3 )δ166.3,166.2,142.9,142.0,140.7,139.3,129.3,129.1,126.1,126.1,44.4,42.0,31.3,31. 1,29.4,28.1,26.4,26.1,22.4,22.3,21.4,21.3,20.8,20.5,13.9,13.8; HRMS(ESI)m / z:[M+H] + Calculate for C 15 H 25 N 2 O 2 S + 297.1631; found 297.1626.

[0102] Embodiment 38: 1 H NMR (500 MHz, CDCl 3 )δ8.11(s,0.19H),7.76-7.73(m,2.44H),7.25-7.21(m,2.46H),6.44(d,J=7.9Hz,1H),3.84-3.77(m,1H),3.37-3.32(m,0.23H),2. 38(s,0.6H),2.37(s,3H),2.25(s,3H),2.07(s,0.6H),1.87-1.82(d,J=8.8Hz,2.43H),1.67-1.61(m,2.37H),1.35-0.13(m,7.12H); 13 C NMR (126 MHz, CDCl 3 )δ165.0,164.9,142.9,142.0,141.0,139.7,129.4,129.2,126.3,126.3 ,53.3,50.7,33.4,31.9,25.4,25.0,24.7,24.3,21.5,21.5,21.1,20.8.

[0103] Embodiment 39: 1 H NMR (500 MHz, CDCl 3)δ8.14(s,0.19H),7.74(d,J=8.3Hz,2H),7.66(d,J=8.3Hz,0.36H)7.23(d,J=7.9Hz,2.35H),7.04(d,J=7.9Hz,0.39H),7.01-6.97(m,2H),6.82(d,J=8.6Hz,0.39H),6.76(d,J=8.6Hz,2H),6.70(t,J=5.6Hz,1H),3.77(s,0.56H),3.74(s,3H),3.48-3.42(m,2.35H),2.78(t,J=7.4Hz,0.38H),2.72(t,J=7.4Hz,2H),2.39(s,0.52H),2.38(s,3H),2.27(s,3H),1.89(s,0.54H); 13 C NMR(126MHz,CDCl 3 )δ166.2,166.0,158.8,158.3,142.9,142.2,140.8,139.4,130.4,129.8,129.6,129.4,129.3,129.0,126.3,126.3,114.4,114.0,55.3,55.3,46.0,43.4,35.0,33.5,21.5,21.5,20.9;HRMS(ESI)m / z:[M+H] + calcd for C 18 H 23 N 2 O 3 S + 347.1423;found 347.1418.

[0104] Example 40: 1 H NMR(500MHz,CDCl 3 )δ9.75(s,0.43H),8.55(s,1H),7.85(d,J=7.9Hz,1H),7.77(d,J=8.1Hz,2H),7.52(d,J=7.9Hz,2H),7.39(t,J=7.6Hz,1H),7.35-7.28(m,1.49H),7.22(d,J=8.0Hz,2H),7.18(t,J=7.8Hz,2H),7.10(d,J=7.6Hz,1H),7.06(t,J=7.4Hz,1H),2.48(s,3H),2.41(s,1.55H),2.38(s,3H),2.01(s,1.57H); 13 C NMR(126MHz,CDCl3 )δ165.7,163.9,143.3,142.5,140.2,139.1,137.5,136.5,129.7,129. 5,129.3,128.7,128.2,126.4,126.3,126.2,125.4,122.0,21.6,21.5.

[0105] Embodiment 41: 1 H NMR (500 MHz, CDCl 3 )δ9.91(s,1H),8.34(s,0.11H),7.94(d,J=8.0Hz,2H),7.91-7.86(m,2.2H),7 .81-7.78(m,1.1H),7.67(d,J=8.0Hz,0.18H),7.58-7.52(m,2.33H),7.47(t, J=7.8Hz,1H),7.32(dd,J=11.4,7.6Hz,3H),7.21(d,J=8.5Hz,0.08H),7.06(d ,J=7.5Hz,0.3H),2.72(s,0.36H),2.44(s,3H),2.30(s,0.36H),1.90(s,3H); 13 C NMR (126 MHz, CDCl 3 )δ166.6,143.3,139.3,134.4,132.8,129.9,129.6,129.2,128.6,127.7,127.1,126.7,125.4,125.1,121.9,21.6,21.4; HRMS(ESI)m / z:[M+H] + calcdfor C 19 H 19 N 2 O 2 S + 339.1161; found 339.1156.

[0106] Embodiment 42: 1 H NMR (500 MHz, CDCl 3)δ9.66(s,0.66H),8.40(s,1H),7.85(d,J = 8.0Hz,1.42H),7.77(d,J = 8.2Hz,2H),7.39(d,J = 8.4Hz,2H),7.29(d,J = 8.0Hz,1.41H),7.22(d,J = 8.0Hz,2H),7.18(d,J = 7.9Hz,1.53H),6.98(d,J = 8.1Hz,3.51H),2.48(s,3H),2.41(s,2H),2.38(s,3H),2.35(s,2H),2.25(s,3H),1.99(s,2H); 13 C NMR(126MHz,CDCl 3 )δ165.9,163.6,143.2,142.4,140.4,139.3,138.3,135.1,135.0,134.0,130.3,129.5,129.3,129.2,126.5,126.4,126.2,122.0,21.7,21.6,21.5,21.1,20.9.

[0107] Example Forty - three: 1 H NMR(500MHz,CDCl 3 )δ8.62(s,0.5H),8.24(d,J = 8.0Hz,1H),7.88(d,J = 7.9Hz,1H),7.84(d,J = 7.9Hz,2H),7.71(s,1H),7.30 - 7.23(m,3.55H),7.09(d,J = 7.9Hz,0.53H),7.05(t,J = 7.6Hz,1H),6.95(t,J = 7.2Hz,1H),6.89 - 6.82(m,2H),3.84(s,3H),3.82(s,1.57H),2.62(s,3H),2.39(s,4.57H),2.00(s,1.55H); 13 C NMR(126MHz,CDCl 3 )δ166.2,162.4,153.8,148.8,142.9,142.4,140.4,139.6,129.3,127.3,126.9,126.5,125.6,125.2,121.7,120.9,111.8,110.1,55.9,22.7,21.5;HRMS(ESI)m / z:[M + H] + calcd for C 16 H 19 N 2 O 3 S+ 319.1110; found 319.1106.

[0108] Embodiment 44: 1 HNMR (500MHz, CDCl 3 )δ8.46(s,0.16H),7.77(d,J=8.2Hz,0.34H),7.70(d,J=8.2Hz,2H),7.36-7.18(m,8.2H),6.64(t,J=5.7Hz,1H) ,4.44(d,J=5.5Hz,0.33H),4.42(d,J=5.5Hz,2H),2.42(s,0.51H,),2.40(s,3H),2.34(s,3H),2.08(s,0.52H); 13 C NMR (126 MHz, CDCl 3 )δ166.5,165.8,143.1,142.3,140.6,139.4,136.7,135.8,129.5,129.3,128.8 ,128.3,128.3,127.8,126.9,126.5,126.4,48.1,46.1,21.6,21.5,21.2,21.0.

[0109] Embodiment 45: 1 H NMR (500 MHz, CDCl 3 )δ8.47(s,0.1H),7.77(d,J=8.5Hz,0.21H),7.65(d,J=8.5Hz,2H),7.28( d,J=7.0Hz,0.25H),7.22(d,J=8.5Hz,2H),7.20(t,J=1.6Hz,1H),7.18-7 .14(m,2.19H),7.11-7.06(m,2.2H),4.44(d,J=5.7Hz,0.22H),4.37(d,J =5.7Hz,2H),2.43(s,0.33H),2.40(s,3H),2.32(s,3H),2.07(s,0.32H); 13 C NMR (126 MHz, CDCl 3)δ166.6,166.2,143.4,142.4,140.3,139.0,138.0,135.2,134.4,130.6,129.9,129.6,129.4,128.6,12 8.2,127.8,126.9,126.5,126.4,126.3,124.9,47.5,45.3,21.6,21.5,21.2,20.9; HRMS(ESI)m / z:[M+H] + Calculate for C 16 H 18 C1N 2 O 2 S + 337.0772; found 337.0766.

[0110] Embodiment 46: 1 H NMR (500 MHz, CDCl 3 )δ7.86(d,J=8.2Hz,1.34H),7.78(d,J=8.2Hz,2H),7.38(t,J=7.3Hz,1.39H),7.33-7.26(m,5.33H),7.23(d,J=8.0Hz,2H),7.21-7.18(m,2 H),7.12(d,J=7.2Hz,1.42H),4.72(s,2H),4.59(s,1.42H),3.07(s,2H),3.01(s,3H),2.57(s,2H),2.56(s,3H),2.41(s,2H),2.39(s,3H); 13 C NMR (126 MHz, CDCl 3 )δ166.3,166.2,142.0,141.9,141.2,141.2,135.8,135.1,129.3,129.2,129.2,128.8,128.2,128. 2,127.9,126.4,126.4,126.3,54.7,53.8,37.6,36.6,21.5,21.5,18.3,17.9; HRMS(ESI)m / z:[M+H] + Calculate for C 17 H 21 N 2 O 2 S + 317.1318; found 317.1312.

[0111] Embodiment 47: 1 H NMR (500 MHz, CDCl3 ) δ 7.82 (d, J = 8.2 Hz, 1.4H), 7.71 (d, J = 8.3 Hz, 2H), 7.32 (dd, J = 8.2, 6.5 Hz, 1.51H), 7.29 - 7.22 (m, 5.15H), 7.18 - 7.16 (m, 3.39H), 7.10 (d, J = 6.9 Hz, 1.54H), 4.67 (s, 2H), 4.54 (s, 1.42H), 3.52 (q, J = 7.1 Hz, 1.46H), 3.34 (q, J = 7.2 Hz, 2H), 2.55 (s, 3H), 2.46 (s, 2H), 2.36 (s, 2H), 2.33 (s, 3H), 1.12 (d, J = 7.2 Hz, 3H), 1.10 - 1.08 (m, 2H); 13 C NMR (126 MHz, CDCl 3 ) δ 165.6, 165.4, 141.7, 141.6, 141.2, 141.0, 136.1, 135.2, 129.0, 128.9, 128.4, 127.8, 127.7, 127.4, 126.0, 126.0, 52.0, 51.0, 44.5, 43.5, 21.2, 21.2, 17.9, 17.3, 13.2, 11.7; HRMS (ESI) m / z: [M + H] + calcd for C 18 H 23 N 2 O 2 S + 331.1474; found 331.1468.

[0112] Example Forty - Eight: 1 H NMR (500 MHz, CDCl 3 ) δ 7.85 (d, J = 8.3 Hz, 2H), 7.49 (d, J = 8.2 Hz, 1.35H), 7.34 (t, J = 7.6 Hz, 2H), 7.29 - 7.25 (m, 3H), 7.24 - 7.20 (d, J = 7.4 Hz, 2H), 7.13 (t, J = 7.5 Hz, 3.36H), 7.08 (d, J = 8.0 Hz, 1.36H), 5.07 (m, 1H), 4.64 (s, 1.37H), 4.54 (s, 2H), 4.29 (m, 0.7H), 2.69 (s, 2H), 2.42 (s, 3H), 2.41 (s, 3H), 2.33 (s, 2H), 1.19 (d, J = 6.6 Hz, 4H), 1.10 (d, J = 6.8 Hz, 6H); 13 C NMR (126 MHz, CDCl3 ) δ 166.8, 165.3, 141.9, 141.6, 141.3, 141.0, 137.7, 136.7, 129.5, 129.1, 129.0, 128.9, 128.3, 127.5, 126.7, 126.7, 126.4, 126.2, 126.1, 125.5, 50.1, 48.7, 47.1, 46.5, 21.4, 21.4, 21.2, 19.7, 19.1, 18.1; HRMS(ESI) m / z: [M+H] + calcd for C 19 H 25 N 2 O 2 S + 345.1631; found 345.1626.

[0113] Example 49: 1 H NMR (500 MHz, CDCl 3 ) δ 7.82 (1H, d, J = 8.3 Hz, 1H), 7.75 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.0 Hz, 1H), 7.21 (d, J = 7.9 Hz, 2H), 7.15 (dd, J = 8.5, 5.5 Hz, 2H), 7.08 (dd, J = 8.6, 5.4 Hz, 1H), 7.03 (t, J = 8.6 Hz, 1H), 6.94 (t, J = 8.7 Hz, 2H), 4.65 (s, 2H), 4.54 (s, 1H), 3.02 (s, 1.5H), 2.98 (s, 3H), 2.54 (s, 1.5H), 2.51 (s, 3H), 2.38 (s, 1.52H), 2.37 (s, 3H); 13 C NMR (126 MHz, CDCl 3 ) δ 166.1, 166.1, 162.5 (d, J = 248.2 Hz), 162.4 (d, J = 246.8 Hz), 142.1, 142.0, 141.1, 141.1, 131.7 (d, J = 3.2 Hz), 130.9 (d, J = 3.2 Hz), 130.0 (d, J = 8.2 Hz), 129.2, 129.2, 128.1 (d, J = 8.1 Hz), 126.3, 126.3, 116.2 (d, J = 21.7 Hz), 115.6 (d, J = 21.6 Hz), 54.0, 53.1, 37.4, 36.6, 21.5, 21.4, 18.2, 17.9; HRMS(ESI) m / z: [M+H] + calcd for C 17 H20 FN 2 O 2 S + 335.1214; found 335.1217.

[0114] Embodiment 50: 1 H NMR (500 MHz, CDCl 3 )δ7.84(d,J=8.4Hz,1H),7.74(d,J=8.3Hz,2H),7.49(d,J=8.4Hz,1H),7.39(d,J=8.4Hz,2H),7.26(t,J=4.0Hz,1H),7.21(s,2H),7.05(d, J=8.4Hz,2H),6.99(d,J=8.4Hz,1H),4.64(s,2H),4.53(s,1H),3.03(s,1.52H),3.01(s,3H),2.55(s,4.5H),2.40(s,1.51H),2.39(s,3H); 13 C NMR (126 MHz, CDCl 3 )δ166.2,166.2,142.2,142.1,141.1,141.1,135.0,134.2,132.5,131.9,129.9,129.3,129.3,128. 1,126.4,126.4,122.2,121.9,54.2,53.3,37.6,36.8,21.6,21.5,18.3,18.0; HRMS(ESI)m / z:[M+H] + Calculate for C 17 H 20 Bn 2 O 2 S + 395.0423; found 395.0418.

[0115] Embodiment 51: 1 HNMR (500MHz, CDCl 3 )δ7.95-7.90(m,3.46H),7.87-7.79(m,6H),7.59-7.39(m,5.94H),7.28(d,J=7.5Hz,2H),7.21(d,J=8.0Hz,2H),7.11(d,J =5.9Hz,0.74H),5.19(s,2H),5.05(s,1H),3.17(s,2H),2.89(s,3H),2.60(s,3H),2.53(s,2H),2.42(s,2H),2.37(s,3H);13 C NMR (126 MHz, CDCl 3 )δ167.0,166.0,142.1,142.0,141.3,134.0,133.9,131.7,131.3,130.4,130.0,129.3,129.2,129.0,128.9,128.7,127.3,126.9,1 26.8,126.5,126.4,126.2,125.7,125.3,123.6,122.5,121.8,52.8,51.5,38.2,35.6,21.6,21.5,18.5,17.8; HRMS(ESI)m / z:[M+H] + Calculate for C 21 H 23 N 2 O 2 S + 367.1474; found 367.1469.

[0116] Embodiment 52: 1 H NMR (500 MHz, CDCl 3 )δ7.79(d,J=8.2Hz,1.35H),7.74(d,J=8.3Hz,2H),7.20(d,J=8.1Hz,1.34H),7. 18(d,J=8.0Hz,2H),7.10(s,2H),6.99(d,J=8.6Hz,1.39H),6.83(d,J=8.6Hz,1.3 9H),6.76(d,J=8.6Hz,2H),4.59(s,2H),4.46(s,1.37H),3.73(s,2H),3.72(s,3H ),2.98(s,2H),2.92(s,3H),2.50(s,2H),2.45(s,3H),2.34(s,2H),2.33(s,3H); 13 C NMR (126 MHz, CDCl 3 )δ165.9,165.8,159.3,159.1,141.8,141.7,141.1,129.5,129.0,129.0,127.7,127.6,126.8,126 .1,114.4,113.9,55.2,55.1,54.0,52.9,37.2,36.2,21.3,21.3,18.0,17.7; HRMS(ESI)m / z:[M+H] + Calculate for C 18 H 23 N 2 O3 S + 347.1423; found 347.1417.

[0117] Embodiment 53: 1 H NMR (500 MHz, CDCl 3 )δ7.82(t,J=8.4Hz,3.37H),7.26-7.08(m,10H),4.77(s,2H),4.60(s,1.32H),3.88(t,J=6.0Hz,1.3H),3.67(t,J= 5.9Hz,2H),2.90(t,J=5.9Hz,2H),2.84(t,J=6.1Hz,1.33H),2.57(s,2H),2.54(s,3H),2.39(s,3H),2.38(s,2H).; 13 C NMR (126 MHz, CDCl 3 )δ164.9,142.0,141.9,141.2,141.1,134.8,133.8,132.4,131.7,129.2,129.2,128.4,128.0,127.5,127.0,126.9, 126.7,126.6,126.3,126.3,126.1,48.2,47.1,44.4,43.2,29.1,28.1,21.4,21.4,18.3,18.1; HRMS(ESI)m / z:[M+H] + Calculate for C 18 H 21 N 2 O 2 S + 329.1318; found 329.1312.

[0118] Embodiment 54: 1 H NMR (500 MHz, CDCl 3 )δ7.85(d,J=7.9Hz,2H),7.80(d,J=7.9Hz,1.34H),7.29-7.19(m,8.68H),7.11(d,J=7.3Hz,1.41H),7.06(d,J=7.3Hz,2H),3. 67(t,J=7.5Hz,2H),3.58(t,J=7.2Hz,1.39H),3.04(s,2H),2.92(s,3H),2.48(s,3H),2.42(s,3H),2.41(s,2H),2.25(s,2H); 13 C NMR (126 MHz, CDCl 3)δ165.7,165.3,141.8,141.8,141.4,141.3,138.4,137.3,129.1,129.1,128.9,128.8,128.6,128.6, 127.1,126.5,126.3,126.2,53.2,53.0,37.9,37.3,34.6,32.8,21.4,18.3,17.1; HRMS(ESI)m / z:[M+H] + calcdfor C 18 H 23 N 2 O 2 S + 331.1474; found 331.1469.

[0119] Embodiment 55: 1 H NMR (500 MHz, CDCl 3 )δ8.26(s,0.11H),7.36-7.28(m,5.75H),6.80-6.60(m,1H),4.44(d,J=5.1Hz,2.37H),2.90(s,3.51H),2.38(s,3H),2.11(s,0.34H); 13 C NMR (126 MHz, CDCl 3 )δ166.4,165.2,136.7,135.8,129.2,128.8,128.3,128.2,127.9,126.9,48.0,45.9,43.1,42.2,20.9,14.2; HRMS(ESI)m / z:[M+H] + Calculate for C 10 H 15 N 2 O 2 S + 227.0848; found 227.0847.

[0120] Embodiment 56: 1 H NMR (500 MHz, CDCl 3 )δ8.31(s,0.18H),7.41-7.25(m,6.17H),6.45(t,J=5.7Hz,1H),4.46(d,J=5.5Hz,2.41H),2.5 3-2.47(m,1.21H),2.39(s,3H),2.13(s,0.51H),1.18-1.07(m,2.47H),0.99-0.87(m,2.47H); 13C NMR (126 MHz, CDCl 3 )δ166.3,165.1,136.9,135.9,129.3,128.8,128.3,128.3,127.9,126.9,48.0,46.0,32.4,31.7,21.2,5.3; HRMS(ESI)m / z:[M+H] + Calculate for C 12 H 17 N 2 O 2 S + 253.1005; found 253.1000.

[0121] Embodiment 57: 1 H NMR (500 MHz, CDCl 3 )δ8.28(s,0.17H),7.43-7.23(m,12.43H),6.30(t,J=5.6Hz,1H),4.40(d,J=5.6Hz,2H ),4.23(s,0.4H),4.20(s,2H),4.16(d,J=5.6Hz,0.4H),2.13(s,3H),1.98(s,0.51H); 13 C NMR (126 MHz, CDCl 3 )δ167.6,165.9,136.7,135.6,131.0,130.5,130.0,129.1,128.9,128.5,128.4 ,128.3,128.2,128.0,126.7,60.8,60.3,47.7,46.0,21.0; HRMS(ESI)m / z:[M+H] + Calculate for C 16 H 19 N 2 O 2 S + 303.1161; found 303.1158.

[0122] Embodiment 58: 1 H NMR (500 MHz, CDCl 3 )δ7.37-7.23(m,6.2H),6.86-6.77(m,1H),4.45(d,J=5.5Hz,2.38H),2.96(t,J=5.5 Hz,4.78H),2.41(s,0.61H),2.37(s,3H),1.68-1.55(m,6H),1.52-1.39(m,1.27H); 13C NMR (126 MHz, CDCl 3 )δ165.9,164.5,137.3,136.2,129.1,128.6,128.1,127.8,127.5,126.8,47. 8,47.5,45.6,45.3,25.1,25.0,23.8,23.7,21.0,20.7; HRMS(ESI)m / z:[M+H] + Calculate for C 14 H 22 N 3 O 2 S + 296.1427; found 296.1424.

[0123] Table 2 shows that sulfonyl azide has high reaction yields with secondary fatty amines (Examples 1 to 11) and tert-butylamine (Example 19); and has medium reaction yields with primary amines (including halogenated aromatic amines, 2-pyridylamine and 3-pyridylbenzylamine) (Example 12-Example 18). The products of Examples 1 to 19 are highly selective and single, wherein the products of Examples 1 to 18 are mainly E-type (E / Z>99:1), and the products of Example 19 are mainly Z-type (Z / E>99:1). The exact structures of the products of Examples 1, 12 and 17 are clearly determined by single crystal X-ray diffraction analysis. Further, it is found from Examples 1, 20 to 31 that the substituent R on the sulfonyl group has no effect on the product configuration; the reaction reagent amine is the same, and the product configuration is the same (E / Z>99:1).

[0124] It is also found from Table 2 that in Examples 32 to 54, the products are a mixture of Z- or E-isomers, and the mixed products are not easy to separate. The effect of the type of amine on the product configuration is as follows: primary aliphatic amines, primary aromatic amines, and primary benzylamines give products with good yields that are mainly in the Z form (Examples 32 to 40, and Examples 42 to 45); surprisingly, primary naphthylamines give products that are mainly in the E form (Example 41), and their exact structure is clearly determined by single crystal X-ray diffraction analysis; secondary benzylamines and secondary aliphatic amines give products that are mainly in the E form (Examples 46 to 54). Further, different sulfonyl azides react with benzylamine and calcium carbide to obtain products that are mainly in the Z form (Examples 55 to 58), which have the same main configuration as Example 44 (E / Z=1:6) and a close E / Z ratio, indicating that the substituent R on the sulfonyl group has no significant effect on the product configuration; the reaction reagent amines are the same, and the main configuration of the products is the same and the E / Z ratio is close.

[0125] Embodiment 59, 60:

[0126] The synthesized product 3 (0.5 mmol, 1 equiv), m-chloroperbenzoic acid (0.75 mmol, 1.5 equiv), and iodobenzene (0.1 mmol, 0.2 equiv) were dissolved in hexafluoroisopropanol (1 mL) and stirred at room temperature for 12 hours. A saturated sodium bicarbonate aqueous solution (5 mL) was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (10 mL×3). The combined organic phases were washed with saturated brine (5 mL×2), and the organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was separated by column chromatography using petroleum ether and ethyl acetate (v / v=2:1) ​​as eluents to obtain 2-methylbenzimidazole compound 4; the synthetic route is as follows:

[0127]

[0128] Wherein: R is an alkyl group, an aryl group or a heterocyclic ring;

[0129] pass 1 H NMR, 13 The products synthesized in Examples 59 and 60 were characterized by C NMR, confirming that products 4a and 4b were obtained. The characterization data are as follows (representative spectra are shown in Figure 26-Figure 27 shown):

[0130] Embodiment 59 (4a): 1 H NMR (500 MHz, CDCl 3 )δ8.04-7.99(m,1H),7.82-7.78(m,2H),7.64-7.60(m,1H),7.33(qd,J=7.3,1.5Hz,2H),7.28(d,J=8.1Hz,3H),2.81(s,3H),2.38(s,3H); 13 C NMR (126 MHz, CDCl 3 )δ151.5,146.1,142.1,135.6,133.4,130.4,126.9,124.8,124.7,119.8,113.6,21.7,17.0.

[0131] Embodiment 60 (4b): 1 HNMR (500MHz, CDCl 3 )δ8.05(s,1H),7.81(d,J=8.0Hz,2H),7.53(d,J=8.5Hz,1H),7.31(d,J=8.2Hz,2H),7.28(d,J=8.4Hz,1H),2.78(s,3H),2.39(s,3H); 13 C NMR (126 MHz, CDCl 3)δ152.1,146.4,140.5,135.2,133.8,130.6,130.5,126.9,125.3,120.4,113.8,21.7,16.8.

[0132] Therefore, the synthesized N-sulfonylamidine compound 3 can be converted into the 2-methylbenzimidazole compound 4.

[0133] What is disclosed above is only a preferred embodiment of the present invention, which certainly cannot be used to limit the scope of rights of the present invention. A person skilled in the art can understand that all or part of the processes of the above embodiments and equivalent changes made according to the claims of the present invention still fall within the scope of the present invention.

Claims

1. A method for synthesizing N-sulfonyl amidine compounds using copper-catalyzed calcium carbide as an acetylene source, characterized in that: The following steps are involved: S1: dissolving a sulfonyl azide compound 1, an amine compound 2, calcium carbide, an initiator, and a copper catalyst in a solvent for a one-pot reaction to obtain a mixture containing an N-sulfonyl amidine compound 3; S2: Extracting, washing, drying, concentrating, and column chromatography the mixture containing N-sulfonyl amidine compound 3 to obtain a pure product of N-sulfonyl amidine compound 3. The synthetic route is as follows: Wherein: R is an alkyl group, an aryl group or a heterocyclic ring; R 1 is alkyl, aryl or heteroaryl; R 2 is H or alkyl.

2. The method for synthesizing N-sulfonyl amidine compounds using copper-catalyzed calcium carbide as an acetylene source as claimed in claim 1, characterized in that: In the step S1, the initiator is water.

3. The method for synthesizing N-sulfonyl amidine compounds using copper-catalyzed calcium carbide as an acetylene source as claimed in claim 1, characterized in that: In the step S1, the copper catalyst is one of CuI, CuBr, Cu(OAc)2, Cu(OTf)2, Cu(acac)2, CuSCN, Cu(MeCN)4BF4, and Cu(ClO4)2·6H2O.

4. The method for synthesizing N-sulfonyl amidine compounds using copper-catalyzed calcium carbide as an acetylene source as claimed in claim 3, characterized in that: The copper catalyst is Cu(MeCN)4BF4.

5. The method for synthesizing N-sulfonyl amidine compounds using copper-catalyzed calcium carbide as an acetylene source as claimed in claim 1, characterized in that: In the step S1, the solvent is THF or 1,2-dichloroethane or CHCl3 or Ethanol or Acetone or 1,4-dioxane or DMF or DMSO.

6. The method for synthesizing N-sulfonyl amidine compounds using copper-catalyzed calcium carbide as an acetylene source as claimed in claim 5, characterized in that: The solvent is CHCl3.

7. The method for synthesizing N-sulfonyl amidine compounds using copper-catalyzed calcium carbide as an acetylene source as claimed in claim 1, characterized in that: In the step S1, the reaction temperature is room temperature and the reaction time is 6 h-24 h.

8. The method for synthesizing N-sulfonyl amidine compounds using copper-catalyzed calcium carbide as an acetylene source as claimed in claim 1, characterized in that: In the step S1, the volume of the solvent is 1-10 mL / mmol based on the amount of the sulfonyl azide compound, and the molar ratio of the sulfonyl azide compound to the initiator is 1:1-20.

9. The method for synthesizing N-sulfonyl amidine compounds using copper-catalyzed calcium carbide as an acetylene source as claimed in claim 1, characterized in that: In the step S1, the molar ratio of the sulfonyl azide compound to the calcium carbide is 1:1-10, and the molar ratio of the sulfonyl azide compound to the amine compound is 1:0.5-5.

10. The use of the N-sulfonyl amidine compound synthesized as claimed in claim 1, characterized in that: The N-sulfonyl amidine compound is converted into a 2-methylbenzimidazole compound in the presence of a meta-chloroperoxybenzoic acid oxidant.

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