阅读说明：本技术 一种多取代3-磺酰胺喹啉化合物的合成方法 (Synthesis method of polysubstituted 3-sulfonamide quinoline compound ) 是由 吴祥 赵利萍 谢金明 付延明 朱成峰 李有桂 于 2021-08-31 设计创作，主要内容包括：本发明公开了一种多取代3-磺酰胺喹啉化合物的合成方法,通过金催化叠氮基团对炔基的进攻,形成α-亚胺金卡宾中间体；在α-亚胺中间体的作用下引发1,2-N迁移,从而形成多取代3-磺酰胺喹啉化合物。本发明的合成方法具有高效性以及对底物的普适性强等优点。(The invention discloses a synthesis method of a polysubstituted 3-sulfonamide quinoline compound, which comprises the steps of forming an alpha-imine gold carbene intermediate by attacking alkynyl by gold catalytic azide groups; 1,2-N migration is initiated under the action of an alpha-imine intermediate, so that a multi-substituted 3-sulfonamide quinoline compound is formed. The synthetic method has the advantages of high efficiency, strong universality on substrates and the like.)

1. A method for synthesizing a polysubstituted 3-sulfonamide quinoline compound is characterized by comprising the following steps:

the reaction substrate forms an alpha-imine gold carbene intermediate under the action of a gold catalyst, and a 3-sulfonamide quinoline compound is formed through 1.2-N migration; the reaction scheme is as follows:

in the above general formula:

in the above general formula: r¹Selected from phenyl or substituted phenyl, alkyl or 3-thienyl, wherein the substituent of the substituted phenyl is selected from methyl, methoxy, halogen, trifluoromethyl, tert-butyl or-CO₂Me；R²Selected from methyl, methoxy, 3, 4-methylenedioxy or halogen; r³Is selected from phenyl, substituted phenyl or methyl, wherein the substituent of the substituted phenyl is selected from methyl, methoxy, halogen, trifluoromethyl, tert-butyl or-CO₂Me。

2. The method of synthesis according to claim 1, characterized by the steps of:

adding 0.1mmol of reaction substrate and 0.02mmol of catalyst into a solvent, and reacting at 30-90 ℃ for 72 hours to obtain a target product.

3. The method of synthesis according to claim 2, characterized in that:

the catalyst comprises AuCl and AuCl₃、tBuXPhosAuNTf₂、JohnPhosAuNTf₂、tBuXPhosAuSbF₆、JohnPhosAuSbF₆、ZnI₂、(CH₃COO)₂Cu·H₂O、AuCl₃/AgSbF₆、AuCl₃/AgNTf₂、PtCl₂Indium triflate, copper tetraacetonitrile hexafluorophosphate or palladium acetate/triphenylphosphine catalysts.

4. The method of synthesis according to claim 3, characterized in that:

the catalyst is tBuXPhosAUNTf₂。

5. The method of synthesis according to claim 2, characterized in that:

the solvent comprises 1, 2-dichloroethane, dichloromethane, chloroform, acetonitrile, 1, 4-dioxane, benzene, toluene, acetone, tetrahydrofuran or DMF.

6. The method of synthesis according to claim 5, characterized in that:

the solvent is acetone.

7. The method of synthesis according to claim 2, characterized in that:

the reaction temperature was 75 ℃.

Technical Field

The invention belongs to the field of organic chemistry, and particularly relates to a synthesis method of a polysubstituted 3-sulfonamide quinoline compound.

Background

Homogeneous gold catalysis has the advantages of high catalytic activity, mild reaction conditions, good functional group compatibility and the like, and attacks alkyne and subsequent N through azide₂The elimination of (a) forms an alpha-imine gold carbene intermediate. Quinoline is an important fine chemical raw material and is mainly used for synthesizing medicines, dyes, pesticides and the like. Due to the nitrogen atom on the quinoline ringThe onium ion has a basic nature and can form a stable salt with a strong acid. For example, dibucaine hydrochloride is a very good anesthetic and chloroquine phosphate is a very good antimalarial.

Toste et al (Journal of the American Chemical Society,2005,127(32):11260-11261) first reported alpha-iminogold carbene, which first reported the synthesis of polysubstituted pyrrole compounds with regard to the catalysis of intramolecular nitrogen olefin transfer with a gold catalyst, the synthetic route being as follows:

since 1,2-N migration has been rarely reported, in the first example, 1,2-N migration to gold carbene, highly selective synthesis of polysubstituted indenes by 1, 1-carboalkoxy-ated alkynylamides was reported in 2014 by Davies et al (chem. Eur. J.2014,20, 7262-.

In 2015 Liu et al (chem. Eur. J.2015,21,18571-18575) reported a highly efficient gold catalyzed oxidative ring expansion reaction involving 1,2-N migration.

The above prior art, despite the formation of the final product by gold catalysis followed by 1,2-N migration, however, 1,2-N migration initiated by the α -imine gold carbene intermediate has not been reported. Thus, new gold-catalyzed methods remain highly challenging and are highly desirable for building multi-functionalized structures.

Disclosure of Invention

Because 1,2-N migration initiated by alpha-imine gold carbene has not been reported, the invention aims to provide a method for synthesizing polysubstituted 3-sulfonamide quinoline with high efficiency and good universality on a substrate.

According to the synthesis method of the polysubstituted 3-sulfonamide quinoline compound, a reaction substrate forms an alpha-imine gold carbene intermediate under the action of a gold catalyst, and the 3-sulfonamide quinoline compound is formed through 1.2-N migration.

The reaction scheme is as follows:

in the above general formula: r¹Selected from phenyl or substituted phenyl, alkyl or 3-thienyl, wherein the substituent of the substituted phenyl is selected from methyl, methoxy, halogen, trifluoromethyl, tert-butyl or-CO₂Me；R²Selected from methyl, methoxy, 3, 4-methylenedioxy or halogen; r³Is selected from phenyl, substituted phenyl or methyl, wherein the substituent of the substituted phenyl is selected from methyl, methoxy, halogen, trifluoromethyl, tert-butyl or-CO₂Me。

The method specifically comprises the following steps:

0.1mmol of a reaction substrate and 0.02mmol of a catalyst are added into 3mL of a solvent and reacted at 30-90 ℃ for 72 hours to obtain a target product.

Since different catalysts have a great influence on the yield of the reaction, by reacting AuCl and AuCl₃、tBuXPhosAuNTf₂、 JohnPhosAuNTf₂、tBuXPhosAuSbF₆、JohnPhosAuSbF₆、ZnI₂、(CH3COO)₂Cu·H₂O、 AuCl₃/AgsbF₆、AuCl₃/AgNTf₂、PtCl₂The research on indium trifluoromethanesulfonate, copper tetraacetonitrile hexafluorophosphate and palladium acetate/triphenylphosphine catalyst is carried out, and the preferable catalyst is tBuXPhosAUNTf₂。

Further, through the research on organic solvents of 1, 2-dichloroethane, dichloromethane, trichloromethane, acetonitrile, 1, 4-dioxane, benzene, toluene, acetone, tetrahydrofuran and DMF, acetone is preferably used as a reaction solvent in the invention.

Further, since temperature has a great influence on reaction yield, 75 ℃ is preferred as the optimum reaction temperature in the present invention by screening from 30 to 90 ℃.

In order to verify the universality of the substrate, the invention further provides the reaction of different alkynyl substituents 1a-1q under the catalysis of gold under the optimal conditions, and the reaction route and corresponding products are as follows:

reaction procedure 0.1mmol of 1a-1q and 0.02mmol of catalyst were added to 3mL of an organic solvent and reacted at 75 ℃ for 72 hours. In this reaction, substrates 1a-1q with different substituent groups are all suitable for this reaction to give the corresponding polysubstituted 3-sulfonamide quinoline compounds. The introduction of the electron-donating substituents (1a-f) in the phenyl moiety, yields are relatively high; the benzene ring is provided with an electron-withdrawing group (1g-m), and the yield is medium or more; thiophene containing hetero atoms, long-chain hexyl, tert-butyl and cyclohexyl (1n-1q) can also be reacted.

In addition, the invention also verifies that when the substituent on the phenyl of the substrate azide substituent is changed, the method of the invention also has good applicability.

Reaction procedure 0.1mmol of 1r-1y and 0.02mmol of catalyst were added to 3mL of organic solvent and reacted at 75 ℃ for 72 hours.

It can be seen that the reaction of the present invention proceeds smoothly under optimal conditions and gives moderate to good yields to the corresponding polysubstituted 3-sulfonamide quinoline compounds regardless of the position and electronic nature of the substituents.

To further verify that the synthetic methods of the invention have broad applicability to a variety of substrates, the experiment also investigated the effect of groups attached to sulfonamides on the reaction.

Reaction procedure 0.1mmol of 1z-1e' and 0.02mmol of catalyst were added to 3mL of an organic solvent and reacted at 75 ℃ for 72 hours.

It can be seen that the reaction of the present invention proceeds smoothly under optimum conditions and gives moderate to good yields regardless of the change in the electronic properties of the substituents on the benzene ring attached to the sulfonamide. When the group connected with the sulfamide is methyl, the corresponding polysubstituted 3-sulfamide quinoline compound can be obtained.

Detailed Description

The above-described aspects of the invention are explained in further detail below with reference to specific embodiments, which should not be construed as limiting the subject matter of the invention in any way. All technical solutions realized based on the above contents of the present invention belong to the scope of the present invention. The present invention has been described generally and/or specifically with respect to materials used in testing and testing methods.

Firstly, screening the catalyst, and respectively adding 0.02mmol AuCl and AuCl into a Schlenk tube₃、tBuXPhosAuNTf₂、 JohnPhosAuNTf₂、tBuXPhosAuSbF₆、JohnPhosAuSbF₆、ZnI₂、(CH3COO)₂Cu·H₂O、 AuCl₃/AgsbF₆、AuCl₃/AgNTf₂、PtCl₂Indium trifluoromethanesulfonate, copper tetraacetonitrile hexafluorophosphate and palladium acetate/triphenylphosphine catalyst. Vacuum was applied and nitrogen was purged, 1a 40.2mg dissolved in 3mL of 1, 2-dichloroethane was added to a Schlenk tube at room temperature using a syringe, the tube was sealed, and the mixture was heated to 75 ℃ for reaction for 72 hours. Evaporating the solvent under reduced pressure and passing the residue throughPurifying by silica gel column chromatography, wherein the petroleum ether/ethyl acetate ratio is 10/1-30/1, so as to obtain the white product 2a, and the yield is 18%, 30%, 64%, 56%, 60%, 55%, 15%, 23%, 28%, 36%, 15%, 0 and 0 respectively. tBuXPhosAUNTf can be seen₂Is the optimal catalyst.

In the optimum catalyst tBuXPhosAUNTf₂Under the condition, the reaction solvent is screened. Converting tBuXPhosauNTf₂18mg was added to a Schlenk tube oven dried; vacuum was drawn and nitrogen gas was introduced, 1a 40.2mg dissolved in 3mL of dichloromethane, acetonitrile, 1, 4-dioxane, benzene, toluene, acetone, tetrahydrofuran, DMF, respectively, was added to a Schlenk tube using a syringe at room temperature, the tube was sealed, and the mixture was heated to 75 ℃ for reaction for 72 hours. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography with petroleum ether/ethyl acetate 10/1-30/1 to give white product 2a in 51%, 42%, 51%, 40%, 50%, 80%, 66%, 45% yield, respectively. It can be seen that acetone is the optimal solvent.

The reaction temperature is screened under optimal catalyst and solvent conditions. Converting tBuXPhosauNTf₂18mg was added to a Schlenk tube oven dried; vacuum was applied and nitrogen was purged, 1a 40.2mg dissolved in 3mL of acetone was added to a Schlenk tube at room temperature using a syringe, the tube was sealed, and the mixture was heated to 60 ℃, 75 ℃, and 90 ℃ respectively for reaction for 72 hours. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography with petroleum ether/ethyl acetate 10/1-30/1 to give white product 2a in 80% yield. The yields were 46%, 80%, 64%, respectively. It can be seen that the optimum reaction temperature is 75 ℃.

From the above, it can be seen that the reaction effect is best when tBuXPhosAUNTf2 is used as a catalyst, acetone is used as a solvent, and the reaction temperature is 75 ℃.

Example 1: preparation of Compound 2a

Converting tBuXPhosauNTf₂18mg into the ovenOven dried Schlenk tube. Vacuum was applied and nitrogen was purged, 1a 40.2mg dissolved in 3mL of acetone was added to a Schlenk tube at room temperature using a syringe, the tube was sealed, and the mixture was heated to 75 ℃ for reaction for 72 hours. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography with petroleum ether/ethyl acetate 10/1-30/1 to give white product 2a in 80% yield.

¹H NMR(400MHz,CDCl₃)δ8.47(s,1H),8.03(d,J＝8.3Hz,1H),7.86(dd,J＝8.2,1.4Hz, 1H),7.66(ddd,J＝8.5,6.9,1.5Hz,1H),7.60–7.54(m,1H),7.50(d,J＝8.3Hz,2H),7.47–7.40 (m,3H),7.18(d,J＝8.1Hz,2H),7.14–7.10(m,2H),6.80(s,1H),2.38(s,3H).¹³C NMR(101 MHz,CDCl₃)δ152.17,144.05,143.40,135.53,134.73,128.81,128.38,128.30,128.16,128.13, 127.36,126.67,126.47,126.34,126.09,125.23,20.53.HRMS(ESI)m/z(M+H)⁺calculated for C₂₂H₁₉N₂O₂S:375.1167,observed:375.1174.

Example 2: preparation of Compound 2b

By the method of example 1 using the substrate 1b instead of 1a, a white product 2b was prepared in 84% yield.

¹H NMR(600MHz,CDCl₃)δ8.49(s,1H),8.01(d,J＝8.8Hz,1H),7.87(d,J＝8.1Hz,1H), 7.68–7.62(m,1H),7.59–7.53(m,3H),7.38(td,J＝7.6,1.4Hz,1H),7.31(d,J＝7.6Hz,1H), 7.20(t,J＝7.8Hz,3H),6.75(d,J＝7.3Hz,1H),6.48(s,1H),2.37(s,3H),1.89(s,3H).¹³C NMR (101MHz,CDCl₃)δ152.99,144.83,144.54,136.65,135.78,135.26,131.26,129.85,129.73, 129.14,128.91,128.42,127.72,127.51,127.39,127.25,126.67,124.37,21.58,19.14.HRMS(ESI) m/z(M+H)⁺calculated for C₂₃H₂₁N₂O₂S:389.1324,observed:389.1332.

Example 3: preparation of Compound 2c

By the method of example 1 using the substrate 1c instead of 1a, a white product 2c was prepared in 53% yield.

¹H NMR(600MHz,CDCl₃)δ8.48(s,1H),8.03(d,J＝8.4Hz,1H),7.86(d,J＝7.6Hz,1H), 7.66(t,J＝7.5Hz,1H),7.56(ddd,J＝8.1,6.9,1.2Hz,1H),7.48(d,J＝8.1Hz,2H),7.31(t,J＝ 7.6Hz,1H),7.25(d,J＝7.0Hz,1H),7.18(d,J＝8.1Hz,2H),6.90(d,J＝7.4Hz,1H),6.84(s, 1H),6.81(s,1H),2.37(s,3H),2.34(s,3H).¹³C NMR(101MHz,CDCl₃)δ153.56,145.09,144.34, 139.22,136.44,135.82,130.19,129.82,129.19,129.17,129.15,128.98,128.41,127.70,127.52, 127.32,127.13,126.36,125.22,21.59,21.48.RMS(ESI)m/z(M+H)⁺calculated for C₂₃H₂₁N₂O₂S: 389.1324,observed:389.1332.

Example 4: preparation of Compound 2d

By the method of example 1 using the substrate 1d instead of 1a, a white product 2d was prepared in 91% yield.

¹H NMR(400MHz,CDCl₃)δ8.44(s,1H),8.02(d,J＝8.2Hz,1H),7.85(d,J＝7.8Hz,1H), 7.65(ddd,J＝8.4,6.9,1.5Hz,1H),7.58–7.52(m,3H),7.26–7.21(m,2H),7.19(d,J＝8.1Hz, 2H),7.03(d,J＝8.1Hz,2H),6.83(s,1H),2.43(s,3H),2.38(s,3H).¹³C NMR(101MHz,CDCl₃) δ153.18,145.04,144.44,139.51,135.77,133.57,130.01,129.82,129.17,129.01,128.52,128.31, 127.64,127.45,127.25,127.17,125.61,21.59,21.38.HRMS(ESI)m/z(M+H)⁺calculated for C₂₃H₂₁N₂O₂S:389.1324,observed:389.1332.

Example 5: preparation of Compound 2e

By the method of example 1 using the substrate 1e instead of 1a, the white product 2e was prepared in 85% yield.

¹H NMR(600MHz,CDCl₃)δ8.43(s,1H),8.02(d,J＝8.4Hz,1H),7.84(d,J＝8.1Hz,1H), 7.64(t,J＝7.5Hz,1H),7.55(t,J＝7.9Hz,3H),7.45(d,J＝8.0Hz,2H),7.19(d,J＝8.0Hz,2H), 7.11(d,J＝8.0Hz,2H),6.92(s,1H),2.38(s,3H),1.37(s,9H).¹³C NMR(151MHz,CDCl₃)δ 153.12,152.55,145.05,144.38,135.72,133.56,129.82,129.16,128.99,128.45,128.07,127.60, 127.42,127.23,127.13,126.34,125.61,34.80,31.25,21.59.HRMS(ESI)m/z(M+H)⁺calculated for C₂₆H₂₇N₂O₂S:431.1793,observed:431.1788.

Example 6: preparation of Compound 2f

By the method of example 1 using the substrate 1f instead of 1a, the white product 2f was prepared in 91% yield.

¹H NMR(600MHz,CDCl₃)δ8.42(s,1H),8.01(d,J＝8.4Hz,1H),7.84(d,J＝8.1Hz,1H), 7.64(t,J＝7.7Hz,1H),7.54(d,J＝7.8Hz,3H),7.19(d,J＝8.0Hz,2H),7.10(d,J＝8.3Hz,2H), 6.95(d,J＝8.7Hz,2H),6.85(s,1H),3.87(s,3H),2.37(s,3H).¹³C NMR(101MHz,CDCl₃)δ 159.40,151.82,144.01,143.37,134.78,128.82,128.79,128.07,127.96,127.74,127.51,126.52, 126.38,126.14,126.10,124.61,113.71,54.45,20.54.HRMS(ESI)m/z(M+H)⁺calculated for C₂₃H₂₁N₂O₃S:405.1273,observed:405.1269.

Example 7: preparation of Compound 2g

By the method of example 1 using 1g of the substrate instead of 1a, 2g of a white product was prepared in 83% yield.

¹H NMR(600MHz,CDCl₃)δ8.45(s,1H),8.02(d,J＝8.4Hz,1H),7.87(d,J＝7.5Hz,1H), 7.68(t,J＝7.6Hz,1H),7.58(t,J＝7.8Hz,1H),7.52(d,J＝8.3Hz,2H),7.20(d,J＝8.1Hz,2H), 7.15–7.09(m,4H),6.68(s,1H),2.39(s,3H).¹³C NMR(151MHz,Chloroform-d)δ163.24(d,J＝ 250.2Hz),152.26,145.12,144.54,135.82,132.68(d,J＝3.5Hz),130.52,130.47,129.87,129.34, 129.11,128.26,127.69,127.51,127.07,126.88,116.33(d,J＝21.9Hz),21.58.¹⁹F NMR(564MHz, CDCl₃)δ-111.16.RMS(ESI)m/z(M+H)⁺calculated for C₂₂H₁₈FN₂O₂S:393.1076,observed: 393.1079.

Example 8: preparation of Compound 2h

By the method of example 1, using substrate 1h instead of 1a, a white product 2h was prepared in 62% yield.

¹H NMR(400MHz,CDCl₃)δ8.49(s,1H),8.03(d,J＝8.4Hz,1H),7.89(d,J＝9.5Hz,1H),7.72 –7.65(m,1H),7.62–7.55(m,1H),7.45(d,J＝8.3Hz,2H),7.42–7.37(m,1H),7.18(d,J＝8.1 Hz,2H),7.16–7.11(m,1H),6.96(d,J＝6.3Hz,1H),6.68–6.63(m,1H),2.39(s,3H).¹³C NMR (101MHz,CDCl₃)δ163.03(d,J＝249.0Hz),152.22,145.26,144.67,138.78(d,J＝7.4Hz), 135.68,130.90(d,J＝8.3Hz),129.95,129.56,129.22,128.07,128.00,127.83,127.65(d,J＝5.1 Hz),127.02,123.85,116.41(d,J＝21.2Hz),115.97(d,J＝22.4Hz),21.55.¹⁹F NMR(564MHz, CDCl₃)δ-110.69.RMS(ESI)m/z(M+H)⁺calculated for C₂₂H₁₈FN₂O₂S:393.1076,observed: 393.1079.

Example 9: preparation of Compound 2i

By the method of example 1 using the substrate 1i instead of 1a, a white product 2i was prepared in 67% yield.

¹H NMR(600MHz,DMSO-d₆)δ10.11(s,1H),8.16(s,1H),8.02–7.97(t,2H),7.77(t,J＝ 7.8Hz,1H),7.66–7.60(t,1H),7.38(d,J＝8.1Hz,2H),7.28(t,J＝9.1Hz,1H),7.23(d,J＝7.9 Hz,2H),7.14(d,J＝8.1Hz,2H),2.34(s,3H).¹³C NMR(101MHz,DMSO-d₆)δ161.83(dd,J＝ 245.5,13.4Hz),154.28,145.32,143.09,141.55(t,J＝9.9Hz),137.13,134.53,130.14,129.60, 128.73,128.26,127.68,127.65,127.39,126.42,112.52(dd,J＝19.1,8.2Hz),103.75(t,J＝25.5 Hz),20.93.¹⁹F NMR(377MHz,CDCl₃)δ-105.76.RMS(ESI)m/z(M+H)⁺calculated for C₂₂H₁₈F₂N₂O₂S:411.0979,observed:411.0984.

Example 10: preparation of Compound 2j

By the method of example 1 using substrate 1j instead of 1a, white product 2j was prepared in 63% yield.

¹H NMR(400MHz,CDCl₃)δ8.46(s,1H),8.02(d,J＝8.2Hz,1H),7.87(d,J＝8.7Hz,1H),7.68 (ddd,J＝8.4,6.9,1.5Hz,1H),7.62–7.57(m,1H),7.52(d,J＝8.3Hz,2H),7.42–7.37(m,2H), 7.20(d,J＝8.1Hz,2H),7.10–7.05(m,2H),6.65(s,1H),2.39(s,3H).¹³C NMR(101MHz, CDCl₃)δ152.16,145.24,144.61,135.85,135.69,135.10,129.94,129.92,129.46,129.19,128.20, 127.77,127.62,127.57,127.17,127.11,21.61.HRMS(ESI)m/z(M+H)⁺calculated for C₂₂H₁₈ClN₂O₂S:409.0778,observed:409.0786.

Example 11: preparation of Compound 2k

By the method of example 1 using substrate 1j instead of 1a, white product 2j was prepared in 65% yield.

¹H NMR(600MHz,CDCl₃)δ8.46(s,1H),8.01(d,J＝8.4Hz,1H),7.87(d,J＝8.1Hz,1H),7.68 (t,J＝7.6Hz,1H),7.57(dd,J＝21.4,8.0Hz,3H),7.52(d,J＝8.1Hz,2H),7.20(d,J＝8.1Hz, 2H),7.01(d,J＝8.2Hz,2H),6.63(s,1H),2.39(s,3H).¹³C NMR(101MHz,CDCl₃)δ152.17, 145.24,144.59,135.83,135.55,132.39,130.16,129.90,129.44,129.18,128.12,127.75,127.61, 127.55,127.20,127.08,123.89,21.59.HRMS(ESI)m/z(M+H)⁺calculated for C₂₂H₁₈BrN₂O₂S: 453.0254,observed:453.0275.

Example 12: preparation of Compound 2l

By the method of example 1 using 1l of the substrate instead of 1a, 2l of a white product was prepared in 51% yield.

¹H NMR(600MHz,CDCl₃)δ8.48(s,1H),8.03(d,J＝8.4Hz,1H),7.89(d,J＝8.2Hz,1H),7.71 (t,J＝7.7Hz,1H),7.66(d,J＝7.9Hz,2H),7.61(t,J＝7.6Hz,1H),7.49(d,J＝8.0Hz,2H),7.27 (d,J＝9.2Hz,2H),7.19(d,J＝7.9Hz,2H),6.62(s,1H),2.40(s,3H).¹³C NMR(101MHz,CDCl₃) δ152.13,145.39,144.65,140.41,135.85,131.53,131.20,129.95,129.70,129.25,129.10,128.25, 128.18(q,J＝203.2Hz),128.00,127.87,127.84,127.63,127.06,126.07(q,J＝3.6Hz),21.59.¹⁹F NMR(377MHz,CDCl₃)δ-62.80.RMS(ESI)m/z(M+H)⁺calculated for C₂₃H₁₈F₃N₂O₂S: 443.1041,observed:443.1046.

Example 13: preparation of Compound 2m

By the method of example 1 using the substrate 1m instead of 1a, a white product 2m was prepared in 37% yield.

¹H NMR(600MHz,DMSO-d₆)δ8.50(s,1H),8.09(d,J＝7.9Hz,2H),8.04(d,J＝8.5Hz,1H), 7.89(d,J＝8.2Hz,1H),7.70(t,J＝7.7Hz,1H),7.60(t,J＝7.5Hz,1H),7.48(d,J＝8.1Hz,2H), 7.20(dd,J＝8.2,3.9Hz,4H),3.99(s,3H),2.40(s,3H).¹³C NMR(101MHz,CDCl₃)δ168.81, 166.37,152.35,144.63,141.07,135.74,130.87,130.38,129.93,129.52,129.23,128.64,128.11, 127.83,127.72,127.60,127.50,127.05,52.46,21.59.RMS(ESI)m/z(M+H)⁺calculated for C₂₄H₂₁N₂O₂S:401.1324,observed:401.1328.

Example 14: preparation of Compound 2n

By the method of example 1 using the substrate 1n instead of 1a, a white product 2n was prepared in 40% yield.

¹H NMR(600MHz,CDCl₃)δ8.40(s,1H),8.01(d,J＝8.4Hz,1H),7.83(d,J＝8.1Hz,1H), 7.65(t,J＝7.2Hz,1H),7.58(d,J＝8.1Hz,2H),7.57–7.53(m,1H),7.47(dd,J＝4.9,2.9Hz,1H), 7.28(d,J＝1.7Hz,1H),7.20(d,J＝8.0Hz,2H),7.07(d,J＝4.4Hz,1H),6.92(s,1H),2.37(s, 3H).¹³C NMR(151MHz,CDCl₃)δ148.50,145.12,144.48,137.59,135.87,129.89,129.13, 129.09,128.54,127.71,127.67,127.57,127.42,127.36,127.06,126.03,125.67,21.56.RMS(ESI) m/z(M+H)⁺calculated for C₂₀H₁₇N₂O₂S₂:381.0731,observed:381.0736.

Example 15: preparation of Compound 2o

By the method of example 1 using the substrate 1o instead of 1a, 2o was prepared as a white product in 47% yield.

¹H NMR(600MHz,CDCl₃)δ8.21(s,1H),7.95(d,J＝8.4Hz,1H),7.76(d,J＝8.2Hz,1H), 7.63(dd,J＝14.8,8.0Hz,3H),7.48(t,J＝7.4Hz,1H),7.21(d,J＝8.0Hz,2H),6.86(s,1H),2.66 –2.58(m,2H),2.36(s,3H),1.52(p,J＝7.8Hz,2H),1.28(dt,J＝14.8,7.4Hz,3H),1.24–1.18 (m,3H),0.86(t,J＝7.1Hz,3H).¹³C NMR(151MHz,cdcl₃)δ156.25,145.57,144.35,136.16, 129.87,129.04,128.53,128.51,128.41,127.45,127.10,127.06,126.46,34.12,31.64,29.25,28.27, 22.53,21.52,14.06.HRMS(ESI)m/z(M+H)⁺calculated for C₂₂H₂₇N₂O₂S:383.1793,observed: 383.1798.

Example 16: preparation of Compound 2p

By the method of example 1 using the substrate 1p instead of 1a, a white product 2p was prepared in 40% yield.

¹H NMR(600MHz,CDCl₃)δ8.22(s,1H),7.96(d,J＝8.4Hz,1H),7.77(d,J＝8.2Hz,1H), 7.63(t,J＝7.6Hz,1H),7.60(d,J＝8.1Hz,2H),7.51–7.45(m,1H),7.22(d,J＝8.0Hz,2H),6.80 (s,1H),2.46(tt,J＝11.7,3.4Hz,1H),2.36(s,3H),1.76(d,J＝12.6Hz,2H),1.69(d,J＝11.8Hz, 1H),1.62(q,J＝12.4Hz,2H),1.32(d,J＝13.3Hz,2H),1.30–1.22(m,1H),1.24–1.16(m, 1H).¹³C NMR(101MHz,CDCl₃)δ160.56,146.21,144.29,136.17,130.85,129.86,129.11,128.86, 127.54,127.38,127.16,126.79,126.36,40.48,31.78,26.44,25.77,21.52.RMS(ESI)m/z(M+H)⁺ calculated for C₂₂H₂₅N₂O₂S:381.1637,observed:381.1641.

Example 17: preparation of Compound 2q

By the method of example 1 using the substrate 1q instead of 1a, a white product 2q was prepared in 47% yield.

¹H NMR(600MHz,CDCl₃)δ8.28(s,1H),7.93(d,J＝8.4Hz,1H),7.71(d,J＝8.2Hz,3H),7.62 –7.57(m,1H),7.48(d,J＝7.4Hz,1H),7.21(d,J＝8.0Hz,2H),6.87(s,1H),2.35(s,3H),1.41(s, 9H).¹³C NMR(101MHz,CDCl₃)δ158.84,144.46,144.02,136.19,129.80,129.18,129.15,128.48, 127.43,126.83,126.73,125.99,38.21,29.86,21.56.RMS(ESI)m/z(M+H)⁺calculated for C₂₀H₂₃N₂O₂S:355.1480,observed:355.1485.

Example 18: preparation of Compound 2r

By the method of example 1 using the substrate 1r instead of 1a, a white product 2r was prepared in 71% yield.

¹H NMR(600MHz,CDCl₃)δ8.58(s,1H),7.88(d,J＝8.4Hz,1H),7.57–7.53(m,1H),7.51 (d,J＝8.1Hz,2H),7.44(dt,J＝14.0,6.9Hz,3H),7.39(d,J＝7.0Hz,1H),7.19(d,J＝8.0Hz, 2H),7.15(d,J＝6.5Hz,2H),6.82(s,1H),2.72(s,3H),2.38(s,3H).¹³C NMR(151MHz,CDCl₃) δ152.56,145.34,144.43,136.57,135.66,134.41,129.81,129.35,129.30,128.84,128.40,127.99, 127.68,127.37,127.21,127.10,123.16,21.57,18.82.RMS(ESI)m/z(M+H)⁺calculated for C₂₃H₂₁N₂O₂S:389.1324,observed:389.1329.

Example 19: preparation of Compound 2s

By the method of example 1 using substrate 1s instead of 1a, white product 2s was prepared in 54% yield.

¹H NMR(600MHz,CDCl₃)δ8.38(s,1H),7.92(d,J＝8.5Hz,1H),7.62(s,1H),7.49(d,J＝ 8.2Hz,3H),7.43(dt,J＝14.2,7.0Hz,3H),7.18(d,J＝8.0Hz,2H),7.11(d,J＝6.6Hz,2H),6.76 (s,1H),2.55(s,3H),2.38(s,3H).¹³C NMR(151MHz,CDCl₃)δ152.24,144.33,143.73,137.38, 136.67,135.78,131.49,129.78,129.26,128.83,128.40,128.32,127.74,127.10,126.27,125.69, 21.66,21.55.RMS(ESI)m/z(M+H)⁺calculated for C₂₃H₂₁N₂O₂S:389.1324,observed:389.1329.

Example 20: preparation of Compound 2t

By the method of example 1 using the substrate 1t instead of 1a, the white product 2t was prepared in 79% yield.

¹H NMR(600MHz,CDCl₃)δ8.42(s,1H),7.69(d,J＝8.1Hz,1H),7.51(t,J＝7.6Hz,3H), 7.48–7.43(m,4H),7.21(d,J＝6.7Hz,2H),7.17(d,J＝8.0Hz,2H),6.85(s,1H),2.72(s,3H), 2.37(s,3H).¹³C NMR(151MHz,CDCl₃)δ151.52,144.30,144.27,137.33,137.15,135.80, 129.80,129.17,129.13,129.12,128.69,128.01,127.62,127.14,127.10,126.37,125.43,21.56, 17.82.RMS(ESI)m/z(M+H)⁺calculated for C₂₃H₂₁N₂O₂S:389.1324,observed:389.1329.

Example 21: preparation of Compound 2u

By the method of example 1 using substrate 1u instead of 1a, 2u was prepared as a white product in 59% yield.

¹H NMR(400MHz,CDCl₃)δ8.38(s,1H),7.91(d,J＝9.2Hz,1H),7.49(d,J＝8.2Hz,2H), 7.46–7.38(m,3H),7.30(dd,J＝9.2,2.8Hz,1H),7.18(d,J＝8.0Hz,2H),7.12–7.07(m,3H), 6.77(s,1H),3.96(s,3H),2.38(s,3H).¹³C NMR(101MHz,CDCl₃)δ158.48,150.56,144.41, 141.29,136.67,135.82,130.63,129.85,129.30,129.23,128.93,128.70,128.48,127.10,125.21, 122.16,104.74,55.67,21.60.RMS(ESI)m/z(M+H)⁺calculated for C₂₃H₂₁N₂O₃S:405.1273, observed:405.1278.

Example 22: preparation of Compound 2v

By the method of example 1 using substrate 1v instead of 1a, a white product 2v was prepared in 52% yield.

¹H NMR(400MHz,CDCl₃)δ8.42(s,1H),7.76(d,J＝9.0Hz,1H),7.47–7.35(m,6H),7.24 (dd,J＝9.0,2.6Hz,1H),7.16(d,J＝8.0Hz,2H),7.05(d,J＝6.9Hz,2H),6.69(s,1H),3.91(s, 3H),2.38(s,3H).¹³C NMR(101MHz,CDCl₃)δ160.76,153.75,146.99,144.26,136.84,135.80, 129.79,129.22,128.56,128.30,127.83,127.11,126.46,122.88,120.79,107.09,55.59,21.58.RMS (ESI)m/z(M+H)⁺calculated for C₂₃H₂₁N₂O₃S:405.1273,observed:405.1278.

Example 23: preparation of Compound 2w

By the method of example 1 using substrate 1w instead of 1a, a white product 2w was prepared in 76% yield.

¹H NMR(600MHz,CDCl₃)δ8.31(s,1H),7.40(dt,J＝24.1,7.6Hz,5H),7.30(s,1H),7.16 (d,J＝8.0Hz,2H),7.10(s,1H),7.04(d,J＝7.3Hz,2H),6.67(s,1H),6.11(s,2H),2.38(s,3H). ¹³C NMR(151MHz,CDCl₃)δ150.87,150.71,148.56,144.23,143.49,136.72,135.75,129.74, 129.17,129.07,128.37,127.06,127.01,126.74,124.88,105.60,102.44,101.86,21.55.RMS(ESI) m/z(M+H)⁺calculated for C₂₃H₁₉N₂O₄S:419.1066,observed:419.1071.

Example 24: preparation of Compound 2x

By the method of example 1 using substrate 1x instead of 1a, white product 2x was prepared in 52% yield.

¹H NMR(600MHz,CDCl₃)δ8.38(s,1H),8.01(dd,J＝9.2,5.3Hz,1H),7.54(d,J＝8.1Hz, 2H),7.51–7.39(m,5H),7.21(d,J＝8.0Hz,2H),7.16(d,J＝7.6Hz,2H),6.81(s,1H),2.39(s, 3H).¹³C NMR(151MHz,CDCl₃)δ161.03(d,J＝249.5Hz),152.19,144.59,142.02,136.23, 135.68,131.72(d,J＝9.5Hz),129.89,129.55,129.41,129.22,128.47(d,J＝10.6Hz),128.37, 127.12,124.60(d,J＝5.6Hz),119.27(d,J＝25.9Hz),110.41(d,J＝22.3Hz),21.58.¹⁹F NMR (564MHz,CDCl₃)δ-112.09.RMS(ESI)m/z(M+H)⁺calculated for C₂₂H₁₈FN₂O₂S:393.1073, observed:393.1078.

Example 25: preparation of Compound 2y

By the method of example 1 using the substrate 1y instead of 1a, a white product 2y was prepared in 91% yield.

¹H NMR(600MHz,CDCl₃)δ8.34(s,1H),7.95(d,J＝8.9Hz,1H),7.83(d,J＝2.3Hz,1H), 7.57(dd,J＝8.9,2.3Hz,1H),7.54(d,J＝8.2Hz,2H),7.47(dt,J＝14.3,7.1Hz,3H),7.22(d,J＝ 8.0Hz,2H),7.17(d,J＝6.7Hz,2H),6.83(s,1H),2.39(s,3H).¹³C NMR(151MHz,CDCl₃)δ 153.07,144.62,143.24,136.15,135.64,133.20,130.76,129.93,129.91,129.64,129.43,129.30, 128.34,128.31,127.12,125.96,124.23,21.58.RMS(ESI)m/z(M+H)⁺calculated for C₂₂H₁₈ClN₂O₂S:409.0778,observed:409.0783.

Example 26: preparation of Compound 2z

By the method of example 1 using the substrate 1z instead of 1a, a white product 2z was prepared in 80% yield.

¹H NMR(600MHz,CDCl₃)δ8.50(s,1H),8.03(d,J＝8.4Hz,1H),7.88(d,J＝7.5Hz,1H), 7.68(t,J＝7.6Hz,1H),7.57(dt,J＝22.6,7.5Hz,4H),7.46(t,J＝7.3Hz,1H),7.44–7.38(m, 4H),7.08(d,J＝6.9Hz,2H),6.78(s,1H).¹³C NMR(101MHz,CDCl₃)δ153.34,145.21,138.76, 136.54,133.43,129.43,129.38,129.31,129.28,129.24,128.33,128.19,127.70,127.55,127.44, 127.05,126.74.RMS(ESI)m/z(M+H)⁺calculated for C₂₁H₁₇N₂O₂S:361.1011,observed: 361.1016.

Example 27: preparation of Compound 2a

By the method of example 1 using the substrate 1a 'instead of 1a, a white product 2a' was prepared in 82% yield.

¹H NMR(600MHz,CDCl₃)δ8.46(s,1H),8.05(d,J＝8.4Hz,1H),7.88(d,J＝8.8Hz,1H), 7.69(t,J＝7.8Hz,1H),7.62–7.54(m,3H),7.45(dq,J＝14.1,7.2,6.8Hz,3H),7.15–7.10(m, 2H),7.04(t,J＝8.5Hz,2H),6.85(s,1H).¹³C NMR(101MHz,CDCl₃)δ165.45(d,J＝256.4Hz), 153.53,145.36,136.67,134.86(d,J＝3.0Hz),129.85,129.76,129.48,129.47,129.40,129.30, 128.30,128.02,127.67,127.53,127.38,116.53(d,J＝22.7Hz),77.38,77.06,76.74.¹⁹F NMR(377 MHz,CDCl₃)δ-103.63.RMS(ESI)m/z(M+H)⁺calculated for C₂₁H₁₆FN₂O₂S:379.0917, observed:379.0923.

Example 28: preparation of Compound 2b

By the method of example 1 using the substrate 1b 'instead of 1a, a white product 2b' was prepared in 86% yield.

¹H NMR(600MHz,CDCl₃)δ8.46(s,1H),8.05(d,J＝8.4Hz,1H),7.88(d,J＝8.2Hz,1H), 7.70(t,J＝7.6Hz,1H),7.59(t,J＝7.6Hz,1H),7.46(dq,J＝14.5,7.4,6.8Hz,5H),7.33(d,J＝ 8.5Hz,2H),7.13(d,J＝6.6Hz,2H),6.87(s,1H).¹³C NMR(101MHz,CDCl₃)δ153.55,145.47, 140.04,137.18,136.58,129.59,129.54,129.48,129.41,129.31,128.42,128.27,127.78,127.72, 127.63,127.57.RMS(ESI)m/z(M+H)⁺calculated for C₂₁H₁₆ClN₂O₂S:395.0621,observed: 395.0626.

Example 29: preparation of Compound 2c

By the method of example 1 using the substrate 1c 'instead of 1a, a white product 2c' was prepared in 81% yield.

¹H NMR(600MHz,CDCl₃)δ8.46(s,1H),8.05(d,J＝8.4Hz,1H),7.88(d,J＝8.2Hz,1H), 7.70(t,J＝7.8Hz,1H),7.59(t,J＝7.5Hz,1H),7.51–7.42(m,5H),7.38(d,J＝8.3Hz,2H),7.12 (d,J＝7.8Hz,2H),6.87(s,1H).¹³C NMR(101MHz,CDCl₃)δ153.56,145.47,137.69,136.55, 132.51,129.60,129.46,129.40,129.30,128.54,128.45,128.25,127.86,127.67,127.61,127.56. RMS(ESI)m/z(M+H)⁺calculated for C₂₁H₁₆BrN₂O₂S:439.0116,observed:439.0121.

Example 30: preparation of Compound 2d

By the method of example 1 using the substrate 1d 'instead of 1a, a white product 2d' was prepared in 80% yield.

¹H NMR(600MHz,CDCl₃)δ8.51(s,1H),8.04(d,J＝8.4Hz,1H),7.89(d,J＝8.1Hz,1H), 7.68(t,J＝7.9Hz,1H),7.58(t,J＝7.6Hz,1H),7.50(d,J＝8.4Hz,2H),7.44(d,J＝7.4Hz,1H), 7.40(d,J＝8.0Hz,4H),7.03(d,J＝6.8Hz,2H),6.76(s,1H),1.31(s,9H).¹³C NMR(101MHz, CDCl₃)δ157.41,153.49,145.20,136.63,135.78,129.37,129.31,129.26,129.22,128.39,128.33, 127.78,127.62,127.40,126.99,126.90,126.29,35.24,31.05.RMS(ESI)m/z(M+H)⁺calculated for C₂₅H₂₅N₂O₂S:417.1637,observed:417.1642.

Example 31: preparation of Compound 2e

By the method of example 1 using the substrate 1e 'instead of 1a, a white product 2e' was prepared in 74% yield.

¹H NMR(600MHz,CDCl₃)δ8.37(s,1H),8.10(d,J＝8.4Hz,1H),7.85(d,J＝8.2Hz,1H), 7.69(t,J＝7.0Hz,1H),7.56(ddd,J＝23.5,15.9,6.8Hz,6H),6.78(s,1H),2.93(s,3H).¹³C NMR (151MHz,CDCl₃)δ152.51,145.05,136.77,129.72,129.64,129.25,129.21,128.60,128.59, 128.55,127.69,127.60,127.34,124.62,39.79.RMS(ESI)m/z(M+H)⁺calculated for C₁₆H₁₅N₂O₂S: 299.0854,observed:299.0859。