CN108383760B - Method for preparing fully-substituted amidine - Google Patents

Method for preparing fully-substituted amidine Download PDF

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CN108383760B
CN108383760B CN201810422338.4A CN201810422338A CN108383760B CN 108383760 B CN108383760 B CN 108383760B CN 201810422338 A CN201810422338 A CN 201810422338A CN 108383760 B CN108383760 B CN 108383760B
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CN108383760A (en
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赵彦伟
陈继君
龙文号
李海燕
万小兵
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Suzhou University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
    • C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J27/00—Catalysts comprising the elements or compounds of halogens, sulfur, selenium, tellurium, phosphorus or nitrogen; Catalysts comprising carbon compounds
    • B01J27/06—Halogens; Compounds thereof
    • B01J27/08—Halides
    • B01J27/122—Halides of copper
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/0215—Sulfur-containing compounds
    • B01J31/0225—Sulfur-containing compounds comprising sulfonic acid groups or the corresponding salts
    • B01J31/0227—Sulfur-containing compounds comprising sulfonic acid groups or the corresponding salts being perfluorinated, i.e. comprising at least one perfluorinated moiety as substructure in case of polyfunctional compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/36—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/16—Radicals substituted by singly bound hetero atoms other than halogen by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/34—Sulfur atoms
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

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Abstract

The invention discloses a method for preparing fully-substituted amidine, which is characterized in that a sulfonamide derivative, a nitrile derivative and a diazo derivative are used as reaction substrates, transition metal is used as a catalyst, and the fully-substituted amidine is prepared by four-component series reaction in an organic solvent. The method used by the invention has the following characteristics: the method has the advantages of more economical reaction, wider substrate universality, easier post-functionalization, avoidance of waste of raw materials, mild reaction conditions, capability of being carried out in the air, less catalyst consumption, simple and convenient post-treatment, and contribution to product purification and large-scale industrial application. Meanwhile, the raw materials such as reactants, catalysts and the like used in the method are cheap and easy to obtain, the reaction composition is reasonable, no ligand is needed, the atom economy is high, the reaction steps are few, the high yield can be obtained by only one-step reaction, the method meets the requirements and directions of modern green chemistry and pharmaceutical chemistry, is suitable for screening high-activity amidine drugs, can well realize gram-level reaction, and is suitable for large-scale industrial production.

Description

Method for preparing fully-substituted amidine
Technical Field
The invention relates to a method for preparing fully-substituted amidine, belonging to the technical field of organic synthesis.
Background
Fully substituted amidines are ubiquitous in natural products and play an important role in the pharmaceutical and agrochemical industries. In addition, fully substituted amidines are also often considered privileged scaffolds in pharmaceutical chemistry for the discovery and optimization of new synthetic drug molecules. The fully substituted amidines are also building blocks for the construction of a variety of heterocyclic compounds. At present, the method for preparing the fully-substituted amidine has the defects of harsh reaction conditions, complex raw material preparation, large raw material consumption, expensive raw materials, narrow substrate range and the like. For example:
(1) yasumaru Hatanaka et al reported a method for preparing fully substituted amidines by condensing sulfonyl azides with thioamides, but the sulfonyl azides and thioamides in the reaction are usually prepared in advance by one-step or multi-step reaction, so that the range of substrates is narrowed and the preparation cost is high (see: Yasumaru Hatanaka;Chem. Commun.2013,49,10242−10244）；
(2) sukbok Chang et al reported the preparation of fully substituted amidines by a three-component reaction of a terminal alkyne, sulfonyl azide and amine, but this reaction only producedNAlkyl-substituted amidines, and the reaction requires the use of a sulfonyl azide with toxicity (see: Sukbok Chang;J. Am. Chem. Soc. 2005,127, 2038−2039）；
therefore, it is necessary to develop a preparation method with abundant raw material sources, high reaction activity, low cost, safety, environmental protection and simple operation to effectively synthesize the fully-substituted amidine compound.
Disclosure of Invention
The invention aims to provide a method for preparing fully-substituted amidine, which has the advantages of abundant sources of reaction raw materials, wide universality of reaction substrates, simple and convenient operation and convenience for later-stage functional synthesis of potential drug molecules.
In order to achieve the purpose of the invention, the technical scheme adopted by the invention is as follows:
a process for preparing a fully substituted amidine characterized by: the fully substituted amidine is prepared by taking a sulfonamide derivative, a nitrile derivative and a diazo derivative as reaction substrates and taking transition metal or a transition metal compound as a catalyst through four-component series reaction in an organic solvent.
The invention also discloses application of copper or a copper compound as a catalyst in preparation of the fully substituted amidine. Preferably, when preparing the fully substituted amidine, a sulfonamide derivative, a nitrile derivative and a diazo derivative are taken as reaction substrates; the copper compound is selected from one of copper iodide, copper chloride and copper trifluoromethanesulfonate. Preferably, when the fully substituted amidine is prepared, the reaction temperature is 60-80 ℃, the reaction time is 0.5-2 hours, and the reaction is carried out in the air.
In the invention, the chemical structure general formula of the sulfonamide derivative is as follows:
Figure 716088DEST_PATH_IMAGE001
in the formula, R1Selected from naphthyl, thienyl, quinolyl, benzyl, cyclopropyl, methyl, n-butyl; or R1The chemical structural general formula is as follows:
Figure 59344DEST_PATH_IMAGE002
in the formula, R2Is methyl, hydrogen, fluorine, chlorine, bromine, iodine, trifluoromethyl, tert-butyl, methoxy, methoxycarbonyl or nitro;
the chemical structural formula of the nitrile derivative is as follows:
Figure 170520DEST_PATH_IMAGE003
in the formula, R3Selected from methyl, chlorine, phenyl; r4Selected from methoxy, phenyl; r5Selected from hydrogen, methyl, acetyl; r5Selected from hydrogen, chlorine, bromine, methoxy, trifluoromethyl;
the chemical structural formula of the diazo derivative is as follows:
Figure 915622DEST_PATH_IMAGE004
in the formula, R7Selected from ethyl, isopropyl, cyclohexyl, tert-butyl, phenyl; r8Selected from fluorine, bromine, trimethylsilyl, methoxymethyl, acetoxy, thienyl, naphthyl; r9Selected from hydrogen, methyl, nitro, cyano; r10Selected from phenyl, methyl, methoxy;
the chemical structural formula of the fully substituted amidine is as follows:
Figure 414736DEST_PATH_IMAGE005
。
in the technical scheme, the reaction temperature of the four-component series reaction is 60-80 ℃, the reaction time is 0.5-2 hours, and preferably the reaction temperature of the four-component series reaction is 80 ℃, and the reaction time is 2 hours; the four-component series reaction is carried out in air.
In the above technical scheme, the transition metal is copper; the organic solvent is acetonitrile.
In the technical scheme, the catalyst is selected from one of copper iodide, copper powder, copper chloride and copper trifluoromethanesulfonate.
In the technical scheme, the dosage of the catalyst is 2 to 5 percent of the molar weight of the sulfonamide compound; the dosage of the nitrile derivative is 20 to 100 times of the molar weight of the sulfonamide compound; the dosage of the diazo derivative is 4 to 6 times of the molar weight of the sulfonamide compound.
Preferably, the amount of the catalyst is 2% by mole of the sulfonamide compound; the amount of the nitrile derivative is 20 times of the molar amount of the sulfonamide compound; the dosage of the diazo derivative is 6 times of the molar weight of the sulfonamide compound.
The invention further discloses the fully substituted amidine prepared by the method for preparing the fully substituted amidine.
The four-component series reaction of the present invention is carried out in air. After the reaction is finished, quenching the product by using saturated sodium sulfite, extracting the product by using ethyl acetate, removing the solvent by using a rotary evaporator, adsorbing the solvent by using silica gel, and finally performing simple column chromatography by using a mixed solvent of ethyl acetate and petroleum ether to obtain the product, namely the fully substituted amidine.
Due to the application of the technical scheme, compared with the prior art, the invention has the following advantages:
1. the invention uses copper trifluoromethanesulfonate as a catalyst to realize four-component series reaction of sulfonamide, nitrile and two-molecule diazo compound to prepare the fully substituted amidine, and compared with the prior art, which has the advantages of pre-preparation of raw materials, large toxicity of the raw materials and harsh conditions, the invention has the advantages of more economical reaction, wider substrate universality, easy obtainment of the raw materials and easier functionalization at the later stage.
2. The method disclosed by the invention avoids the waste of raw materials, has mild reaction conditions, can be carried out in the air, has small catalyst consumption and simple and convenient post-treatment, is beneficial to the purification and large-scale industrial application of products, and is easier to carry out one-step functionalization of commercial medicines.
3. The method has the advantages of cheap and easily obtained raw materials such as reactants, catalysts and the like, reasonable reaction composition, no ligand, high atom economy, less reaction steps, high yield, accordance with the requirements and directions of modern green chemistry and pharmaceutical chemistry, suitability for screening high-activity amidine drugs and suitability for large-scale industrial production, and can be used for preparing the amidine drugs with high activity.
4. The invention realizes the synthesis of the fully-substituted amidine by taking the nitrile derivative as the main raw material, obviously expands the substrate range for synthesizing the fully-substituted amidine, has novel and practical reaction, can synthesize a plurality of fully-substituted amidines which cannot be synthesized by other methods, widens the molecular library of the fully-substituted amidines, and provides a chance for drug screening.
Detailed Description
The invention is further described below with reference to the following examples:
the sulfonamide compound, the nitrile derivative, the diazo compound and the catalyst are all commercial products which can be purchased directly, the sulfonamide can be synthesized by the reaction of the commercial sulfonyl chloride and the commercial hydrazine hydrate, and the diazo compound can be synthesized by the reaction of the commercial alcohol and the commercial p-toluenesulfonyl azide.
Example one
Figure 166661DEST_PATH_IMAGE006
The reaction flask was charged with Compound 1a (0.5 mmol, 85.6 mg), Compound 3a (3 mmol, 316. mu. L), Cu (OTf)2(0.01 mmol, 3.6 mg) and compound 2a (2 m L). The system was heated in air at 80 ℃ for about 2 hours, quenched with saturated sodium sulfite solution, extracted with ethyl acetate (10 m L × 3), the solvent removed with a rotary evaporator, adsorbed on silica gel, and the product 4a was obtained by simple column chromatography, with a yield of 94%.
1H NMR (400 MHz, CDCl3) 7.76–7.74 (m, 2H), 7.25–7.23 (m, 2H), 4.25–4.18 (m, 6H), 4.06 (q,J= 7.1 Hz, 2H), 2.50 (s, 3H), 2.39 (s, 2H), 1.28 (t,J= 7.1 Hz, 3H), 1.16 (t,J= 7.1 Hz, 3H).13C NMR (101 MHz, CDCl3) 167.8,167.6, 166.6, 142.1, 140.3, 128.9, 126.1, 62.0, 61.2, 51.5, 51.2, 21.3, 17.3,13.9, 13.8. HRMS (ESI-TOF): Anal. Calcd. For C17H24N2O6S+Na+: 407.1247, Found:407.1248; IR (neat, cm-1): υ 2985, 1737, 1537, 1020, 683。
Example two
Figure 409423DEST_PATH_IMAGE007
The reaction flask was charged with Compound 1b (0.5 mmol, 78.6 mg), Compound 3a (3 mmol, 316. mu. L), Cu (OTf)2(0.01 mmol, 3.6 mg) and compound 2a (2 m L). The system was then heated in air at 80 ℃ for about 2 hours, quenched with saturated sodium sulfite solution, extracted with ethyl acetate (10 m L × 3), the solvent removed with a rotary evaporator, adsorbed on silica gel, and the product 4b was obtained by simple column chromatography in 87% yield.
1H NMR (400 MHz, CDCl3) 7.89– 7.86 (m, 2H), 7.53–7.43 (m, 3H), 4.2 –4.18 (m, 6H), 4.04 (q,J= 7.1 Hz, 2H), 2.52 (s, 3H), 1.27 (t,J= 7.1 Hz,3H), 1.14 (t,J= 7.1 Hz, 3H).13C NMR (101 MHz, CDCl3) 167.7, 167.5, 166.8,143.0, 131.5, 128.3, 126.0, 62.0, 61.2, 51.6, 51.3, 17.4, 13.9, 13.8. HRMS(ESI-TOF): Anal. Calcd. For C16H22N2O6S+Na+: 393.1091, Found: 393.1093; IR(neat, cm-1): υ 2982, 1744, 1545, 1141, 731, 630。
EXAMPLE III
Figure 212294DEST_PATH_IMAGE008
The reaction flask was charged with Compound 1c (0.5 mmol, 87.6 mg), Compound 3a (3 mmol, 316. mu. L), Cu (OTf)2(0.01 mmol, 3.6 mg) and compound 2a (2 m L). The system was then heated in air at 80 ℃ for about 2 hours, quenched with saturated sodium sulfite solution, extracted with ethyl acetate (10 m L × 3), the solvent removed with a rotary evaporator, adsorbed on silica gel, and the product 4c was obtained by simple column chromatography in 83% yield.
1H NMR (400 MHz, CDCl3) 7.91–7.86 (m, 2H), 7.16–7.10 (m, 2H), 4.26–4.17 (m, 6H), 4.06 (q,J= 7.1 Hz, 2H), 2.53 (s, 3H), 1.29 (t,J= 7.1 Hz,3H), 1.16 (t,J= 7.1 Hz, 3H).13C NMR (101 MHz, CDCl3) 167.7, 167.5, 166.8,164.3 (J= 251 Hz), 139.3 (J= 3 Hz), 128.7 (J= 9 Hz), 115.4 (J= 22 Hz),62.0, 61.3, 51.6, 51.3, 17.5, 13.9, 13.8. HRMS (ESI-TOF): Anal. Calcd. ForC16H21FN2O6S+Na+: 411.0997, Found: 411.1011; IR (neat, cm-1): υ 2975, 1743,1551, 1143, 840, 685。
Example four
Figure 616731DEST_PATH_IMAGE009
1c was replaced with 1d (0.5 mmol, 95.8 mg) based on example three, and the yield was 80% the same as the rest. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.
1H NMR (400 MHz, CDCl3) 7.83–7.80 (m, 2H), 7.45–7.41 (m, 2H), 4.26–4.21 (m, 6H), 4.09–4.03 (q,J= 7.1 Hz, 2H), 2.53 (s, 3H), 1.29 (t,J= 7.1Hz, 3H), 1.16 (t,J= 7.1 Hz, 3H).13C NMR (101 MHz, CDCl3) 167.7, 167.4,166.9, 141.6, 137.8, 128.6, 127.6, 62.0, 61.3, 51.6, 51.4, 17.5, 13.9, 13.8.HRMS (ESI-TOF): Anal. Calcd. For C16H21 35ClN2O6S+Na+: 427.0701, C16H21 37ClN2O6S+Na+: 429.0672, Found: 427.0714, 429.0714; IR (neat, cm-1): υ 2975, 1548, 1205,759, 655。
EXAMPLE five
Figure 855951DEST_PATH_IMAGE010
1c was replaced with 1e (0.5 mmol, 118.1 mg) based on example three, and the yield was 76% the same as the rest. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.
1H NMR (400 MHz, CDCl3) 7.76–7.73 (m, 2H), 7.61–7.58 (m, 2H), 4.26–4.17 (m, 6H), 4.06 (q,J= 7.1 Hz, 2H), 2.53 (s, 3H), 1.29 (t,J= 7.1 Hz,3H), 1.16 (t,J= 7.1 Hz, 3H).13C NMR (101 MHz, CDCl3) 167.7, 167.4, 166.9,142.2, 131.5, 127.8, 126.2, 62.1, 61.3, 51.6, 51.4, 17.6, 13.9, 13.8. HRMS(ESI-TOF): Anal. Calcd. For C16H21 79BrN2O6S+Na+: 471.0196, C16H21 81BrN2O6S+Na+:473.0175, Found: 471.0197, 473.0184; IR (neat, cm-1): υ 2975, 1739, 1548,746, 646。
EXAMPLE six
Figure 902404DEST_PATH_IMAGE011
The yield was 68% as the rest, replacing 1c with 1f (0.5 mmol, 141.6 mg) on the basis of example three. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.
1H NMR (400 MHz, CDCl3) 7.83– 7.79 (m, 2H), 7.61–7.58 (m, 2H), 4.26–4.20 (m, 4H), 4.17 (s, 2H), 4.05 (q,J= 7.1 Hz, 2H), 2.52 (s, 3H), 1.28 (t,J= 7.1 Hz, 3H), 1.16 (t,J= 7.1 Hz, 3H).13C NMR (101 MHz, CDCl3) 167.6,167.4, 166.9, 142.8, 137.5, 127.6, 98.6, 77.32, 61.3, 51.6, 51.3, 17.5, 13.9,13.8. HRMS (ESI-TOF): Anal. Calcd. For C16H21IN2O6S +Na+: 519.0057, Found:519.0071; IR (neat, cm-1): υ 2974, 1546, 1204, 1188, 738, 640。
EXAMPLE seven
Figure 294203DEST_PATH_IMAGE012
1c was replaced with 1g (0.5 mmol, 112.6 mg) based on example three, and the yield was 69% the same. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.
1H NMR (400 MHz, CDCl3) 8.03–8.01 (m, 2H), 7.74–7.72 (m, 2H), 4.27–4.22 (m, 4H), 4.17 (s, 2H), 4.04 (q,J= 7.1 Hz, 2H), 2.56 (s, 3H), 1.29 (t,J= 7.1 Hz, 3H), 1.13 (t,J= 7.1 Hz, 3H).13C NMR (101 MHz, CDCl3) 167.6,167.4, 167.1, 146.5, 133.2 (q,J= 33 Hz), 126.7, 125.5 (q,J= 4 Hz), 123.3(q,J= 271 Hz), 62.1, 61.3, 51.7, 51.5, 17.8, 13.9, 13.8. HRMS (ESI-TOF):Anal. Calcd. For C17H21F3N2O6S +Na+: 461.0965, Found: 461.0954; IR (neat, cm-1):υ 2976, 1549, 1205, 1016, 721, 644。
Example eight
Figure 338382DEST_PATH_IMAGE013
The reaction flask was charged with Compound 1h (0.5 mmol, 106.7 mg), Compound 3a (3 mmol, 316. mu. L), Cu (OTf)2(0.01 mmol, 3.6 mg) and compound 2a (2 m L). The system is heated in air at 80 ℃ for about 2 hours, quenched with saturated sodium sulfite solution, extracted with ethyl acetate (10 m L × 3), the solvent removed with a rotary evaporator, adsorbed on silica gel, and the product obtained is obtained by simple column chromatography for 4 hours in 92% yield.
1H NMR (400 MHz, CDCl3) 7.80– 7.78 (m, 2H), 7.47–7.45 (m, 2H), 4.24–4.19 (m, 6H), 4.03 (q,J= 7.1 Hz, 2H), 2.51 (s, 3H), 1.32 (s, 9H), 1.26 (t,J= 7.1 Hz, 3H), 1.13 (t,J= 7.1 Hz, 3H).13C NMR (101 MHz, CDCl3) 167.7,167.5, 166.6, 154.9, 140.1, 125.8, 125.2, 61.8, 61.0, 51.5, 51.2, 34.7, 30.8,17.2, 13.8, 13.7. HRMS (ESI-TOF): Anal. Calcd. For C20H30N2O6S +Na+: 449.1717,Found: 449.1729; IR (neat, cm-1): υ 2964, 1741, 1547, 1150, 659。
Example nine
Figure 598986DEST_PATH_IMAGE014
The reaction flask was charged with Compound 1i (0.5 mmol, 85.6 mg), Compound 3a (3 mmol, 316. mu. L), Cu (OTf)2(0.01 mmol, 3.6 mg) and compound 2a (2 m L). The system was heated in air at 80 ℃ for about 2 hours, quenched with saturated sodium sulfite solution, extracted with ethyl acetate (10 m L × 3), the solvent removed with a rotary evaporator, adsorbed on silica gel, and the product 4i was obtained by simple column chromatography with a yield of 95%.
1H NMR (400 MHz, CDCl3) 7.81–7.77 (m, 2H), 6.94–6.90 (m, 2H), 4.24–4.19 (m, 6H), 4.06 (q,J= 7.1 Hz, 2H), 3.84 (s, 3H), 2.49 (s, 3H), 1.27 (t,J= 7.1 Hz, 4H), 1.16 (t,J= 7.1 Hz, 3H).13C NMR (101 MHz, CDCl3) 167.8,167.5, 166.5, 161.9, 135.0, 128.0, 113.4, 61.8, 61.1, 55.3, 51.4, 51.1, 17.1,13.8, 13.7. HRMS (ESI-TOF): Anal. Calcd. For C17H24N2O7S +Na+: 423.1196, Found:423.1205; IR (neat, cm-1): υ 2987, 1736, 1186, 1140, 687。
Example ten
Figure 386814DEST_PATH_IMAGE015
A reaction flask was charged with 1j (0.5 mmol, 85.6 mg) of the compound, 3a (3 mmol, 316. mu. L) of the compound, in that order,Cu(OTf)2(0.01 mmol, 3.6 mg) and compound 2a (2 m L). The system was heated in air at 80 ℃ for about 2 hours, quenched with saturated sodium sulfite solution, extracted with ethyl acetate (10 m L × 3), the solvent removed with a rotary evaporator, adsorbed on silica gel, and the product 4j was obtained by simple column chromatography with a yield of 95%.
1H NMR (400 MHz, CDCl3) 8.00–7.98 (m, 1H), 7.41–7.37 (m, 1H), 7.28–7.24 (m, 2H), 4.24–4.19 (m, 6H), 4.02 (q,J= 7.1 Hz, 2H), 2.61 (s, 3H), 2.50(s, 3H), 1.27 (t,J= 7.1 Hz, 3H), 1.13 (t,J= 7.1 Hz, 3H).13C NMR (101 MHz,CDCl3) 167.9, 167.5, 166.9, 140.8, 137.1, 131.8, 131.7, 127.3, 125.3, 61.9,61.2, 51.4, 50.9, 20.0, 17.4, 13.9, 13.8. HRMS (ESI-TOF): Anal. Calcd. ForC17H24N2O6S+Na+: 407.1247, Found: 407.1256; IR (neat, cm-1): υ 2968, 1741,1213, 1025, 630。
EXAMPLE eleven
Figure 429856DEST_PATH_IMAGE016
1j was replaced with 1k (0.5 mmol, 118.1 mg) based on example ten, the rest being equal, the yield being 60%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.
1H NMR (400 MHz, CDCl3) 8.16–8.14 (m, 1H), 7.70–7.68 (m, 1H), 7.44–7.39 (m, 1H), 7.36–7.32 (m, 1H), 4.27–4.21 (m, 6H), 4.03 (q,J= 7.1 Hz, 2H),2.57 (s, 3H), 1.29 (t,J= 7.1 Hz, 3H), 1.12 (t,J= 7.1 Hz, 3H).13C NMR (101MHz, CDCl3) 167.8, 167.4, 167.0, 141.7, 134.8, 132.6, 129.3, 127.0, 120.4,62.0, 61.2, 51.4, 50.9, 18.0, 13.9, 13.8. HRMS (ESI-TOF): Anal. Calcd. ForC16H21 79BrN2O6S+Na+: 471.0196, C16H21 81BrN2O6S+Na+: 373.0175, Found: 471.0198,473.0197; IR (neat, cm-1): υ 2992, 1739, 1209, 1184, 1023, 743。
Example twelve
Figure 644937DEST_PATH_IMAGE017
1j was replaced with 1l (0.5 mmol, 107.6 mg) based on example ten, and the yield was 73% the same as the rest. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.
1H NMR (400 MHz, CDCl3) 8.05–8.02 (m, 1H), 7.56–7.53 (m, 3H), 4.26–4.20 (m, 6H), 4.03 (q,J= 7.1 Hz, 2H), 3.91 (s, 3H), 2.54 (s, 3H), 1.28 (t,J= 7.2 Hz, 3H), 1.12 (t,J= 7.1 Hz, 3H).13C NMR (101 MHz, CDCl3) 168.0,167.8, 167.5, 166.6, 140.8, 131.6, 131.4, 130.1, 128.6, 127.8, 62.0, 61.2,52.6, 51.4, 50.9, 17.7, 13.9, 13.8. HRMS (ESI-TOF): Anal. Calcd. ForC18H24N2O8S+Na+: 451.1146, Found: 451.1145; IR (neat, cm-1): υ 2983, 1740,1188, 1120, 1024, 742, 629。
EXAMPLE thirteen
Figure 999695DEST_PATH_IMAGE018
1j was replaced with 1m (0.5 mmol, 85.6 mg) on the basis of example ten, and the yield was 54% as the rest. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.
1H NMR (400 MHz, CDCl3) 8.72–8.71 (m, 1H), 8.39–8.36 (m, 1H), 8.24–8.21 (m, 1H), 7.72–7.68 (m, 1H), 4.28–4.23 (m, 4H), 4.19 (s, 2H), 4.09 (d,J= 7.1 Hz, 2H), 2.59 (s, 3H), 1.30 (t,J= 7.2 Hz, 3H), 1.16 (t,J= 7.1 Hz,3H).13C NMR (101 MHz, CDCl3) 167.5, 167.4, 167.3, 147.8, 145.1, 131.8,129.8, 126.1, 121.6, 62.2, 61.5, 51.8, 51.5, 17.9, 14.0, 13.9. HRMS (ESI-TOF): Anal. Calcd. For C16H21N3O8S+Na+: 438.0942, Found: 438.0951; IR (neat,cm-1): υ 1745, 1528, 1211, 1183, 1026, 666。
Example fourteen
Figure 981426DEST_PATH_IMAGE019
1j was replaced with 1n (0.5 mmol, 118.1 mg) based on example ten, and the yield was 73% the same as the rest. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.
1H NMR (400 MHz, CDCl3) 8.02–8.01 (m, 1H), 7.83–7.80 (m, 1H), 7.65–7.62 (m, 1H), 7.36–7.32 (m, 1H), 4.27–4.21 (m, 4H), 4.18 (s, 2H), 4.09 (q,J= 7.1 Hz, 2H), 2.54 (s, 3H), 1.29 (t,J= 7.1 Hz, 3H), 1.17 (t,J= 7.1 Hz,3H).13C NMR (101 MHz, CDCl3) 167.6, 167.4, 167.0, 144.9, 134.6, 130.0,129.1, 124.6, 122.2, 62.1, 61.4, 51.7, 51.4, 17.6, 13.9, 13.9. HRMS (ESI-TOF): Anal. Calcd. For C16H21 79BrN2O6S+Na+: 471.0196, C16H21 81BrN2O6S+Na+:473.0175, Found: 471.0188, 473.0187; IR (neat, cm-1): υ 2980, 1542, 1207,1023, 661, 631。
Example fifteen
Figure 738030DEST_PATH_IMAGE020
1j was replaced with 1o (0.5 mmol, 103.7 mg) based on example ten, the remaining is the same, the yield is 89%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.
1H NMR (400 MHz, CDCl3) 8.44 (s, 1H), 7.94–7.85 (m, 4H), 7.60–7.53(m, 2H), 4.23–4.18 (m, 6H), 3.99 (q,J= 7.1 Hz, 2H), 2.56 (s, 3H), 1.25 (t,J= 7.1 Hz, 3H), 1.05 (t,J= 7.1 Hz, 3H).13C NMR (101 MHz, CDCl3) 167.7,167.5, 166.8, 140.0, 134.2, 131.8, 128.9, 128.5, 128.0, 127.5, 126.9, 126.4,122.3, 61.9, 61.2, 51.5, 51.3, 17.4, 13.8, 13.7. HRMS (ESI-TOF): Anal. Calcd.For C20H24N2O6S+Na+: 443.1247, Found: 443.1249; IR (neat, cm-1): υ 2976, 1548,1210, 1020, 678。
Example sixteen
Figure 796116DEST_PATH_IMAGE021
1j was replaced with 1p (0.5 mmol, 81.7 mg) based on example ten, and the yield was 70% the same as the rest. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.
1H NMR (400 MHz, CDCl3) 7.58–7.57 (m, 1H), 7.51–7.49 (m, 1H), 7.02–7.00 (m, 1H), 4.26–4.21 (m, 6H), 4.13 (q,J= 7.2 Hz, 2H), 2.52 (s, 3H), 1.29(t,J= 7.1 Hz, 3H), 1.22 (t,J= 7.1 Hz, 3H).13C NMR (101 MHz, CDCl3)167.7, 167.4, 167.0, 144.5, 130.4, 130.0, 126.5, 62.1, 61.4, 51.6, 51.3,17.3, 13.9, 13.9. HRMS (ESI-TOF): Anal. Calcd. For C14H20N2O6S2+Na+: 399.0655,Found: 399.0666; IR (neat, cm-1): υ 2983, 1741, 1140, 1015, 724, 623。
Example seventeen
Figure 107011DEST_PATH_IMAGE022
The yield was 84% as the rest, except that 1j was replaced with 1q (0.5 mmol, 104.2 mg) on the basis of example ten. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.
1H NMR (400 MHz, CDCl3) 9.05–9.03 (m, 1H), 8.50–8.48 (m, 1H), 8.21–8.18 (m, 1H), 7.99–7.97 (m, 1H), 7.58–7.55 (m, 1H), 7.49–7.45 (m, 1H), 4.25–4.20 (m, 4H), 4.14 (s, 2H), 3.73 (q,J= 7.1 Hz, 2H), 2.75 (s, 3H), 1.27 (t,J= 7.1 Hz, 3H), 0.89 (t,J= 7.1 Hz, 3H).13C NMR (101 MHz, CDCl3) 167.7,167.6, 167.3, 150.7, 143.7, 139.1, 135.9, 132.5, 129.4, 128.5, 124.9, 121.4,61.8, 60.7, 51.2, 50.8, 17.4, 13.9, 13.5. HRMS (ESI-TOF): Anal. Calcd. ForC19H23N3O6S+Na+: 444.1200, Found: 444.1213; IR (neat, cm-1): υ 2995, 1749,1543, 1125, 1020, 678。
EXAMPLE eighteen
Figure 236641DEST_PATH_IMAGE023
The yield was 97% as the rest, except that 1j was replaced with 1r (0.5 mmol, 85.6 mg) on the basis of example ten. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.
1H NMR (400 MHz, CDCl3) 7.41–7.30 (m, 5H), 4.23–4.17 (m, 8H), 4.12(s, 2H), 2.28 (s, 3H), 1.32–1.25 (m, 6H).13C NMR (101 MHz, CDCl3) 167.8,167.4, 167.1, 130.7, 130.0, 128.2, 127.9, 61.8, 61.3, 60.6, 51.1, 50.7, 17.2,14.0, 13.8. HRMS (ESI-TOF): Anal. Calcd. For C17H24N2O6S+Na+: 407.1247, Found:407.1257; IR (neat, cm-1): υ 2980, 1746, 1557, 1189, 1026, 792。
Example nineteen
Figure 503543DEST_PATH_IMAGE024
1j was replaced with 1s (0.5 mmol, 60.6 mg) based on example ten, and the yield was 96% the same. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.
1H NMR (400 MHz, CDCl3) 4.28–4.18 (m, 8H), 2.55–2.48 (m, 4H), 1.33–1.27 (m, 6H), 1.14–1.09 (m, 2H), 0.95–0.90 (m, 2H).13C NMR (101 MHz, CDCl3)167.9, 167.7, 166.2, 61.9, 61.2, 51.3, 51.0, 32.1, 17.5, 13.9, 13.9, 4.9.HRMS(ESI-TOF):Anal.Calcd.For C13H22N2O6S+Na+: 357.1091,Found:357.1078;IR(neat,cm-1): υ2991,1551,1188,1125,1024,723。
Example twenty
Figure 60427DEST_PATH_IMAGE025
The reaction flask was charged with Compound 1t (0.5 mmol, 47.6 mg), Compound 3a (3 mmol, 316. mu. L), Cu (OTf)2(0.01 mmol, 3.6 mg) and compound 2a (2 m L). The system was heated in air at 80 ℃ for about 2 hours, quenched with saturated sodium sulfite solution, extracted with ethyl acetate (10 m L × 3), the solvent removed with a rotary evaporator, adsorbed on silica gel, and the product was obtained by simple column chromatography in 4t with a yield of 95%.
1H NMR (400 MHz, CDCl3) 4.27–4.18 (m, 8H), 2.97 (s, 3H), 2.50 (s,3H), 1.32–1.27 (m, 6H).13C NMR (101 MHz, CDCl3) 167.9, 167.6, 166.3, 61.9,61.2, 51.3, 51.0, 42.9, 17.4, 14.0, 13.9. HRMS (ESI-TOF): Anal. Calcd. ForC11H20N2O6S+Na+: 331.0934, Found: 331.0946; IR (neat, cm-1): υ 2980, 1556,1190, 1021, 844。
Example twenty one
Figure 999564DEST_PATH_IMAGE026
The reaction flask was charged with Compound 1u (0.5 mmol, 68.6 mg), Compound 3a (3 mmol, 316. mu. L), Cu (OTf)2(0.01 mmol, 3.6 mg) and compound 2a (2 m L). The system was heated in air at 80 ℃ for about 2 hours, quenched with saturated sodium sulfite solution, extracted with ethyl acetate (10 m L × 3), the solvent removed with a rotary evaporator, adsorbed on silica gel, and the product was obtained as 4u by simple column chromatography, with a yield of 99%.
1H NMR (400 MHz, CDCl3) 4.27–4.17 (m, 8H), 3.01–2.97 (m, 2H), 2.51(s, 3H), 1.83–1.75 (m, 2H), 1.49–1.39 (m, 2H), 1.32–1.26 (m, 6H), 0.94 (t,J= 7.4 Hz, 3H).13C NMR (101 MHz, CDCl3) 167.9, 167.6, 166.5, 61.9, 61.2,54.6, 51.3, 51.0, 25.5, 21.3, 17.6, 13.94, 13.90, 13.4. HRMS (ESI-TOF): Anal.Calcd. For C14H26N2O6S+Na+: 373.1404, Found: 373.1416; IR (neat, cm-1): υ 2959,1744, 1191, 1126, 892。
Example twenty two
Figure 464043DEST_PATH_IMAGE027
The reaction flask was charged with Compound 1a (0.5 mmol, 85.6 mg), Compound 3a (3 mmol, 316. mu. L), Cu (OTf)2(0.01 mmol, 3.6 mg) and compound 2b (1046 μ L). the system was then heated in air at 80 ℃ for about 2 hours, quenched with saturated sodium sulfite solution, extracted with ethyl acetate (10 m L × 3), the solvent removed with a rotary evaporator, adsorbed on silica gel, and the product 5a was obtained by simple column chromatography in 66% yield.
1H NMR (400 MHz, CDCl3) 7.77–7.75 (m, 2H), 7.25–7.23 (m, 2H), 4.26–4.20 (m, 4H), 4.13 (s, 2H), 4.03 (q,J= 7.2 Hz, 2H), 2.92–2.88 (m, 2H), 2.39(s, 3H), 1.69–1.61 (m, 2H), 1.50–1.41 (m, 2H), 1.29 (t,J= 7.1 Hz, 3H), 1.15(t,J= 7.1 Hz, 3H), 0.94 (t,J= 7.3 Hz, 3H).13C NMR (101 MHz, CDCl3)169.3, 167.9, 167.8, 141.9, 140.7, 128.9, 126.0, 62.0, 61.2, 51.1, 51.0,30.1, 28.5, 22.7, 21.2, 14.0, 13.8, 13.4. HRMS (ESI-TOF): Anal. Calcd. ForC20H30N2O6S+Na+: 449.1717, Found: 449.1710; IR (neat, cm-1): υ 2961, 1538,1145, 1087, 684。
Example twenty three
Figure 54293DEST_PATH_IMAGE028
The yield was 66% with 2b replaced by 2c (894 μ L) on the basis of example twenty-two, the main test data for the products produced are as follows, and the actual synthesis products are in agreement with the theoretical analysis, as can be seen from the analysis.
1H NMR (400 MHz, CDCl3) 7.76–7.74 (m, 2H), 7.25–7.23 (m, 2H), 4.29(s, 2H), 4.24 (q,J= 7.1 Hz, 2H), 4.11 (s, 2H), 4.02 (q,J= 7.1 Hz, 2H),3.67 (t,J= 5.8 Hz, 2H), 3.13–3.06 (m, 2H), 2.39 (s, 3H), 2.27–2.20 (m, 2H),1.29 (t,J= 7.1 Hz, 3H), 1.14 (t,J= 7.1 Hz, 3H).13C NMR (101 MHz, CDCl3)168.0, 167.8, 167.7, 142.1, 140.3, 128.9, 126.0, 62.0, 61.2, 51.3, 51.1,44.4, 29.5, 27.7, 21.3, 14.0, 13.8. HRMS (ESI-TOF): Anal. Calcd. ForC19H27 35ClN2O6S+Na+: 469.1171, C19H27 37ClN2O6S+Na+: 471.1141, Found: 469.1158,471.1127; IR (neat, cm-1): υ 2978, 1736, 1536, 1217, 1139, 685。
Example twenty-four
Figure 578816DEST_PATH_IMAGE029
The yield was 69% with 2b replaced by 2d (1492 μ L) on the basis of twenty-two in the example, the main test data for the products produced are as follows, and the actual synthesis products are in agreement with the theoretical analysis, as can be seen from the analysis.
1H NMR (400 MHz, CDCl3) 7.76–7.74 (m, 2H), 7.30–7.16 (m, 7H), 4.14(q,J= 7.2 Hz, 2H), 4.07 (s, 2H), 4.01 (q,J= 7.1 Hz, 2H), 3.92 (s, 2H),2.87–2.83 (m, 2H), 2.73 (t,J= 7.2 Hz, 2H), 2.38 (s, 3H), 2.03–1.95 (m, 2H),1.23 (t,J= 7.1 Hz, 3H), 1.12 (t,J= 7.1 Hz, 3H).13C NMR (101 MHz, CDCl3)169.1,167.8,167.6,142.0,140.6,140.5,128.9,128.4, 128.3, 126.1, 126.0, 61.9,61.2,51.0,50.7,35.2,29.4,28.1,21.2,13.9,13.8.HRMS(ESI-TOF): Anal. Calcd. ForC25H32N2O6S+Na+: 511.1873, Found: 511.1866; IR (neat, cm-1): υ 2982, 1741,1539, 1140, 685。
Example twenty-five
Figure 739670DEST_PATH_IMAGE030
The yield was 66% by replacing 2b with 2e (909. mu. L) on the basis of twenty-two in example, the main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis by analysis.
1H NMR (400 MHz, CDCl3) 7.77–7.75 (m, 2H), 7.25–7.23 (m, 2H), 4.43(s, 2H), 4.21 (q,J= 7.1 Hz, 2H), 4.14 (s, 2H), 4.02 (q,J= 7.1 Hz, 2H),3.82 (t,J= 5.9 Hz, 2H), 3.31(s, 3H), 3.26 (t,J= 5.9 Hz, 2H), 2.39 (s,3H), 1.29 (t,J= 7.1 Hz, 3H), 1.14 (t,J= 7.1 Hz, 3H).13C NMR (101 MHz,CDCl3) 168.2, 167.8, 167.5, 142.0, 140.6, 128.9, 126.0, 69.9, 61.7, 61.1,58.7, 51.7, 51.6, 31.1, 21.3, 14.0, 13.8. HRMS (ESI-TOF): Anal. Calcd. ForC19H28N2O7S+Na+: 451.1509, Found: 451.1506; IR (neat, cm-1): υ 2918, 1748,1544, 1206, 1186, 686。
Example twenty-six
Figure 476681DEST_PATH_IMAGE031
The yield was 80% with 2b replaced by 2f (1310. mu. L) on the basis of twenty-two in the example, the main test data for the products produced are as follows, and the actual synthesis products are in agreement with the theoretical analysis by analysis.
1H NMR (400 MHz, CDCl3) 7.80–7.78 (m, 2H), 7.31–7.30 (m, 4H), 7.25–7.22 (m, 3H), 4.21 (d,J= 7.1 Hz, 2H), 4.14 (d,J= 5.2 Hz, 4H), 4.03 (q,J= 7.1 Hz, 2H), 3.21–3.17 (m, 2H), 3.06–3.02 (m, 2H), 2.38 (s, 3H), 1.26 (t,J= 7.2 Hz, 3H), 1.15 (t,J= 7.1 Hz, 3H).13C NMR (101 MHz, CDCl3) 168.2,167.8, 167.7, 142.0, 140.5, 139.5, 128.9, 128.6, 128.2, 126.5, 126.0, 62.0,61.2,51.4,51.1,32.6,32.4,21.3,13.9,13.8.HRMS(ESI-TOF): Anal. Calcd. ForC24H30N2O6S+Na+: 497.1717, Found: 497.1705; IR (neat, cm-1): υ 2987, 1736,1537, 1209, 1190, 689。
Example twenty-seven
Figure 449667DEST_PATH_IMAGE032
The yield was 40% by replacing 2b with 2g (898. mu. L) on the basis of twenty-two in example, the main test data for the products produced are as follows, and the actual synthesis products are in agreement with the theoretical analysis by analysis.
1H NMR (400 MHz, CDCl3) 7.77–7.74 (m, 2H), 7.25–7.23 (m, 2H), 4.29–4.20 (m, 4H), 4.02–3.96 (m, 4H), 2.39 (s, 3H), 1.36 (d,J= 7.3 Hz, 6H), 1.29(t,J= 6.8 Hz, 3H), 1.17 (d,J= 6.9 Hz, 1H), 1.11 (t,J= 6.9 Hz, 3H).13CNMR (101 MHz, CDCl3) 172.1, 168.0, 168.0, 141.8, 141.0, 128.8, 126.0, 62.0,61.1, 52.4, 51.5, 31.8, 21.3, 19.4, 18.3, 14.0, 13.8. HRMS (ESI-TOF): Anal.Calcd. For C19H28N2O6S+Na+: 435.1560, Found: 435.1564; IR (neat, cm-1): υ 2978,1744, 1542, 1142, 1086, 675。
Example twenty-eight
Figure 348353DEST_PATH_IMAGE033
The yield was 85% with 2b replaced by 2h (737 μ L) based on example twenty two, the main test data for the prepared product is as follows, and the actual synthesized product is consistent with theoretical analysis by analysis.
1H NMR (400 MHz, CDCl3) 7.77–7.75 (m, 2H), 7.24–7.22 (m, 2H), 4.52–3.91 (m, 8H), 2.38 (s, 3H), 1.93–1.86 (m, 1H), 1.29–1.07 (m, 10H).13C NMR(101 MHz, CDCl3) 168.2, 168.0, 168.0, 141.6, 141.2, 128.7, 125.9, 61.7,61.1, 51.7, 51.0, 21.2, 13.9, 13.8, 8.4, 7.2. HRMS (ESI-TOF): Anal. Calcd.For C19H26N2O6S+Na+: 433.1404, Found: 433.1409; IR (neat, cm-1): υ 2938, 1743,1540, 1147, 681。
Example twenty-nine
Figure 121137DEST_PATH_IMAGE034
The yield was 52% by replacing 2b with 2i (1021. mu. L) on the basis of twenty-two in example, the main test data for the products produced are as follows, and the actual synthesis products are in agreement with the theoretical analysis by analysis.
1H NMR (400 MHz, CDCl3) 7.52–7.50 (m, 2H), 7.46–7.42 (m, 1H), 7.38–7.34 (m, 2H), 7.21–7.19 (m, 2H), 7.14–7.12 (m, 2H), 4.35 (s, 2H), 4.19–4.09(m, 4H), 3.87 (s, 2H), 2.36 (s, 3H), 1.26 (t,J= 7.1 Hz, 3H), 1.19 (t,J=7.1 Hz, 3H).13C NMR (101 MHz, CDCl3) 168.0, 167.7, 167.4, 141.9, 140.1,130.8, 130.3, 128.8, 128.3, 127.2, 126.4, 61.7, 61.5, 52.0, 50.1, 21.3, 14.0,13.9. HRMS (ESI-TOF): Anal. Calcd. For C22H26N2O6S+Na+: 469.1404, Found:469.1397; IR (neat, cm-1): υ 2979, 1743, 1522, 1209, 1144, 731, 661。
Example thirty
Figure 68364DEST_PATH_IMAGE035
The yield was 59% as the same as the remainder, except that 2b was replaced with 2j (1171.5 mg) based on example twenty-two. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.
1H NMR (400 MHz, CDCl3) 7.55–7.53 (m, 2H), 7.18–7.10 (m, 6H), 4.32(s, 2H), 4.17–4.10 (m, 4H), 3.90 (s, 2H), 2.37 (d,J= 4.8 Hz, 6H), 1.24 (t,J= 7.1 Hz, 3H), 1.20 (t,J= 7.1 Hz, 3H).13C NMR (101 MHz, CDCl3) 168.0,167.7, 167.6, 141.8, 140.5, 140.2, 129.0, 128.6, 127.9, 127.0, 126.3, 61.6,61.4, 52.0, 50.1, 21.4, 21.2, 13.9, 13.9. HRMS (ESI-TOF): Anal. Calcd. ForC23H28N2O6S+Na+: 483.1560, Found: 483.1571; IR (neat, cm-1): υ 2980, 1742,1546, 1146, 885, 683。
Example thirty one
Figure 242994DEST_PATH_IMAGE036
The yield was 32% as the rest, with 2b replaced by 2k (1451.6 mg) on the basis of example twenty-two. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.
1H NMR (400 MHz, CDCl3) 7.98–7.96 (m, 2H), 7.57–7.55 (m, 2H), 7.39–7.37 (m, 2H), 7.18–7.16 (m, 2H), 4.34 (s, 2H), 4.19–4.11 (m, 4H), 3.86 (s,2H), 2.63 (s, 3H), 2.38 (s, 3H), 1.25 (t,J= 7.1 Hz, 3H), 1.20 (t,J= 7.1Hz, 3H).13C NMR (101 MHz, CDCl3) 197.2, 167.8, 167.6, 166.1, 142.3, 140.0,138.3, 135.4, 128.9, 128.3, 127.7, 126.4, 62.0, 61.6, 51.9, 50.2, 26.6, 21.4,14.0, 14.0. HRMS (ESI-TOF): Anal. Calcd. For C24H28N2O7S+Na+: 511.1509, Found:511.1495; IR (neat, cm-1): υ 2983, 1741, 1535, 1146, 886, 677。
Example thirty-two
Figure 233952DEST_PATH_IMAGE037
The yield was 61% by replacing 2b with 2l (1154. mu. L) on the basis of twenty-two in example, the main test data for the products produced are as follows, and the actual synthesis products are in agreement with the theoretical analysis by analysis.
1H NMR (400 MHz, CDCl3) 7.73–7.71 (m, 2H), 7.30–7.26 (m, 2H), 7.23–7.17 (m, 5H), 4.42 (s, 2H), 4.18 (s, 2H), 4.09–4.01 (m, 6H), 2.37 (s, 3H),1.20–1.15 (m, 6H).13C NMR (101 MHz, CDCl3) 167.8, 167.5, 166.2, 142.1,140.2, 132.8, 128.9, 128.8, 128.0, 126.9, 126.2, 61.8, 61.3, 51.4, 51.1,36.2, 21.3, 13.9, 13.8. HRMS (ESI-TOF): Anal. Calcd. For C23H28N2O6S+Na+:483.1560, Found: 483.1555; IR (neat, cm-1): υ 2985, 1745, 1543, 1189, 1140,686。
Example thirty-three
Figure 494032DEST_PATH_IMAGE038
The yield was 69% as the rest, replacing 2b with 2m (1515.9 mg) on the basis of example twenty-two. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.
1H NMR (400 MHz, CDCl3) 7.70–7.68 (m, 2H), 7.29–7.23 (m, 2H), 7.20–7.15 (m, 4H), 4.39 (s, 2H), 4.19 (s, 2H), 4.07 (q,J= 7.2 Hz, 4H), 4.02 (s,2H), 2.38 (s, 3H), 1.21–1.16 (m, 6H).13C NMR (101 MHz, CDCl3) 167.8, 167.4,165.8, 142.3, 139.9, 132.9, 131.2, 129.5, 128.92, 128.91, 126.2, 62.0, 61.4,51.4, 51.1, 35.4, 21.3, 13.9, 13.9. HRMS (ESI-TOF): Anal. Calcd. ForC23H27 35ClN2O6S+Na+: 517.1171, C23H27 37ClN2O6S+Na+: 519.1141, Found: 517.1166,519.1140; IR (neat, cm-1): υ 2980, 1737, 1550, 1194, 1146, 1089, 677。
Example thirty-four
Figure 244951DEST_PATH_IMAGE039
The reaction flask was charged with Compound 1a (0.5 mmol, 85.6 mg), Compound 3a (3 mmol, 316. mu. L), Cu (OTf)2(0.01 mmol, 3.6 mg) and compound 2n (1960.4 mg). The system was then heated in air at 80 ℃ for about 2 hours, quenched with saturated sodium sulfite solution, extracted with ethyl acetate (10 m L × 3), the solvent removed with a rotary evaporator, adsorbed on silica gel, and the product was obtained by simple column chromatography in 5m with a yield of 76%.
1H NMR (400 MHz, CDCl3) 7.69–7.67 (m, 2H), 7.41–7.38 (m, 2H), 7.19–7.17 (m, 2H), 7.11–7.09 (m, 2H), 4.36 (s, 2H), 4.19 (s, 2H), 4.06 (q,J= 7.1Hz, 4H), 4.02 (s, 2H), 2.38 (s, 3H), 1.21–1.16 (m, 6H).13C NMR (101 MHz,CDCl3) 167.7, 167.3, 165.6, 142.3, 139.9, 131.8, 131.7, 129.8, 128.9,126.2, 120.9, 61.9, 61.3, 51.3, 51.0, 35.4, 21.3, 13.9, 13.8. HRMS (ESI-TOF):Anal. Calcd. For C23H27 79BrN2O6S+Na+: 561.0665, C23H27 81BrN2O6S+Na+: 563.0645,Found: 561.0676, 563.0630; IR (neat, cm-1): υ 2978, 1737, 1550, 1193, 1146,673。
Example thirty-five
Figure 8507DEST_PATH_IMAGE040
The reaction flask was charged with Compound 1a (0.5 mmol, 85.6 mg), Compound 3a (3 mmol, 316. mu. L), Cu (OTf)2(0.01 mmol, 3.6 mg) and compound 2o (1357 μ L). the system was then heated in air at 80 ℃ for about 2 hours, quenched with saturated sodium sulfite solution, extracted with ethyl acetate (10 m L × 3), the solvent removed by rotary evaporator, adsorbed on silica gel, and the product 5n was obtained by simple column chromatography in 66% yield.
1H NMR (400 MHz, CDCl3) 7.73–7.71 (m, 2H), 7.20–7.18 (m, 2H), 7.14–7.12 (m, 2H), 6.83–6.80 (m, 2H), 4.34 (s, 2H), 4.18 (s, 2H), 4.09–4.03 (m,6H), 3.76 (s, 3H), 2.37 (s, 3H), 1.21–1.16 (m, 6H).13C NMR (101 MHz, CDCl3)167.9, 167.5, 166.6, 158.5, 142.1, 140.2, 129.2, 128.8, 126.2, 124.6, 114.2,61.8, 61.2, 55.1, 51.4, 51.0, 35.4, 21.3, 13.9, 13.9. HRMS (ESI-TOF): Anal.Calcd. For C24H30N2O7S+Na+: 513.1666, Found: 513.1680; IR (neat, cm-1): υ 2986,1743, 1556, 1185, 1143, 684。
Example thirty-six
Figure 514575DEST_PATH_IMAGE041
A reaction flask was charged with Compound 1a (0.5 mmol, 85.6 mg), Compound 3a (3 mmol, 316. mu. L), and Cu (COTf)2(0.01 mmol, 3.6 mg) and compound 2p (1515.9 mg). The system was then heated in air at 80 ℃ for about 2 hours, quenched with saturated sodium sulfite solution, extracted with ethyl acetate (10 m L × 3), the solvent removed with a rotary evaporator, adsorbed on silica gel, and the product was obtained by simple column chromatography in 5o with a yield of 68%.
1H NMR (400 MHz, CDCl3) 7.73–7.71 (m, 2H), 7.38–7.34 (m, 1H), 7.30–7.27 (m, 1H), 7.21–7.15 (m, 4H), 4.46 (s, 2H), 4.21 (s, 2H), 4.11–4.04 (m,4H), 3.94 (s, 2H), 2.36 (s, 3H), 1.19 (t,J= 7.1 Hz, 6H).13C NMR (101 MHz,CDCl3) 167.8, 167.4, 166.0, 142.3, 139.9, 133.2, 130.7, 129.3, 129.2,128.9, 128.5, 127.3, 126.3, 61.9, 61.4, 51.3, 50.8, 33.6, 21.3, 13.9, 13.9.HRMS (ESI-TOF): Anal. Calcd. For C23H27 35ClN2O6S+Na+: 517.1171, C23H27 37ClN2O6S+Na+: 519.1141, Found: 517.1175, 519.1155; IR (neat, cm-1): υ 2989, 1748, 1546,1139, 683。
Example thirty-seven
Figure 917743DEST_PATH_IMAGE042
The reaction flask was charged with Compound 1a (0.5 mmol, 85.6 mg), Compound 3a (3 mmol, 316. mu. L), Cu (OTf)2(0.01 mmol, 3.6 mg) and compound 2q (1560 μ L). The system was heated in air at 80 ℃ for about 2 hours, quenched with saturated sodium sulfite solution, extracted with ethyl acetate (10 m L × 3), the solvent removed with a rotary evaporator, adsorbed on silica gel, and the product 5p was obtained by simple column chromatography, with a yield of 67%.
1H NMR (400 MHz, CDCl3) 7.70–7.68 (m, 2H), 7.51–7.43 (m, 4H), 7.18–7.16 (m, 2H), 4.49 (s, 2H), 4.21 (s, 2H), 4.11–4.04 (m, 4H), 4.02 (s, 2H),2.36 (s, 3H), 1.21–1.17 (m, 6H).13C NMR (101 MHz, CDCl3) 167.8, 167.3,165.3, 142.5, 139.8, 133.9, 131.6 (d,J= 1 Hz), 131.1 (d,J= 32 Hz), 129.5,129.0, 126.3, 124.8 (d,J= 4 Hz), 124.0 (d,J= 4 Hz), 123.8 (d,J= 271Hz), 62.1, 61.5, 51.5, 51.1, 35.7, 21.3, 14.0, 13.9. HRMS (ESI-TOF): Anal.Calcd. For C24H27F3N2O6S+Na+: 551.1434, Found: 551.1438; IR (neat, cm-1): υ2982, 1744, 1541, 1120, 674。
Example thirty-eight
Figure 534669DEST_PATH_IMAGE043
The reaction flask was charged with Compound 1a (0.5 mmol, 85.6 mg), Compound 3a (3 mmol, 316. mu. L), Cu (OTf)2(0.01 mmol, 3.6 mg) and compound 2r (1860.4 mg). The system was heated in air at 80 ℃ for about 2 hours, quenched with saturated sodium sulfite solution, extracted with ethyl acetate (10 m L × 3), the solvent removed with a rotary evaporator, adsorbed on silica gel, and the product 5q was obtained by simple column chromatography in 77% yield.
1H NMR (400 MHz, CDCl3) 7.68–7.66 (m, 2H), 7.36–7.34 (m, 1H), 7.261–7.256 (m, 1H), 7.19–7.17 (m, 2H), 7.11–7.09 (m, 1H), 4.38 (s, 2H), 4.21 (s,2H), 4.13–4.07 (m, 4H), 4.02 (s, 2H), 2.38 (s, 3H), 1.23–1.18 (m, 6H).13C NMR(101 MHz, CDCl3) 167.7, 167.3, 165.1, 142.5, 139.7, 132.9, 132.8, 131.3,130.7, 130.0, 129.0, 127.6, 126.3, 62.2, 61.5, 51.4, 51.2, 34.9, 21.4, 14.0,13.9. HRMS (ESI-TOF): Anal. Calcd. For C23H26 35Cl2N2O6S+H+: 551.0781,C23H26 37Cl2N2O6S+H+: 553.0751, Found: 551.0783, 553.0795; IR (neat, cm-1): υ2982, 1736, 1550, 1144, 1088, 682。
Example thirty-nine
Figure 559257DEST_PATH_IMAGE044
The reaction flask was charged with Compound 1a (0.5 mmol, 85.6 mg), Compound 3a (3 mmol, 316. mu. L), Cu (OTf)2(0.01 mmol, 3.6 mg) and compound 2s (1772.0 mg). The system was then heated in air at 80 ℃ for about 2 hours, quenched with saturated sodium sulfite solution, extracted with ethyl acetate (10 m L × 3), the solvent removed with a rotary evaporator, adsorbed on silica gel, and the product 5r was obtained by simple column chromatography in 39% yield.
1H NMR (400 MHz, CDCl3) 7.72–7.71 (m, 2H), 7.19–7.17 (m, 2H), 6.79–6.73 (m, 3H), 4.36 (s, 2H), 4.20 (s, 2H), 4.11–4.04 (m, 6H), 3.85 (s, 3H),3.82 (s, 3H), 2.37 (s, 3H), 1.22–1.17 (m, 6H).13C NMR (101 MHz, CDCl3)167.9, 167.6, 166.6, 149.2, 147.9, 142.1, 140.2, 128.8, 126.3, 125.0, 120.2,111.31, 111.28, 61.9, 61.3, 55.8, 55.7, 51.4, 51.1, 35.5, 21.3, 13.9, 13.9.HRMS (ESI-TOF): Anal. Calcd. For C25H32N2O8S+Na+: 543.1772, Found: 543.1761; IR(neat, cm-1): υ 2936, 1748, 1538, 1136, 1022, 683。
Example forty
Figure 32964DEST_PATH_IMAGE045
The yield was 59% as the rest, replacing 2b with 2t (1672.1 mg) on the basis of example twenty-two. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.
1H NMR (400 MHz, CDCl3) 7.89–7.85 (m, 2H), 7.73–7.71 (m, 1H), 7.62–7.60 (m, 2H), 7.59–7.50 (m, 2H), 7.31–7.26 (m, 2H), 7.02–7.00 (m, 2H), 4.78(s, 2H), 4.31 (s, 2H), 4.14 (q,J= 7.2 Hz, 2H), 4.05 (q,J= 7.2 Hz, 2H),3.96 (s, 2H), 2.29 (s, 3H), 1.25 (t,J= 7.1 Hz, 3H), 1.13 (t,J= 7.1 Hz,3H).13C NMR (101 MHz, CDCl3) 168.1, 167.6, 167.2, 142.1, 139.8, 133.6,130.9, 128.80, 128.75, 128.2, 127.6, 126.6, 126.4, 125.9, 125.6, 124.9,122.5, 61.9, 61.5, 51.2, 51.1, 32.8, 21.2, 14.0, 13.8. HRMS (ESI-TOF): Anal.Calcd. For C27H30N2O6S+Na+: 533.1717, Found: 533.1725; IR (neat, cm-1): υ 2979,1743, 1537, 1147, 674。
Example forty one
Figure 126691DEST_PATH_IMAGE046
The reaction flask was charged with Compound 1a (0.5 mmol, 85.6 mg), Compound 3b (3 mmol, 384.4 mg), Cu (OTf)2(0.01 mmol, 3.6 mg) and compound 2a (2 m L). The system was heated in air at 80 ℃ for about 2 hours, quenched with saturated sodium sulfite solution, extracted with ethyl acetate (10 m L × 3), the solvent removed with a rotary evaporator, adsorbed on silica gel, and the product 6a was obtained by simple column chromatography in 92% yield.
1H NMR (400 MHz, CDCl3) 7.76–7.74 (m, 2H), 7.25–7.23 (m, 2H), 5.11–5.02 (m, 1H), 4.97–4.88 (m, 1H), 4.16 (d,J= 6.8 Hz, 4H), 2.50 (s, 3H), 2.39(s, 3H), 1.26 (d,J= 6.3 Hz, 6H), 1.14 (d,J= 6.3 Hz, 6H).13C NMR (101 MHz,CDCl3) 167.2, 167.0, 166.6, 141.9, 140.3, 128.8, 126.0, 69.9, 69.0, 51.7,51.4, 21.45, 21.36, 21.2, 17.3. HRMS (ESI-TOF): Anal. Calcd. For C19H28N2O6S+Na+: 435.1560, Found: 435.1561; IR (neat, cm-1): υ 2981, 1737, 1554, 1141,1102, 685。
Example forty two
Figure 344045DEST_PATH_IMAGE047
The yield was 52% as the rest, replacing 3b with 3c (3 mmol, 426.5 mg) on the basis of example forty one. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.
1H NMR (400 MHz, CDCl3) 7.78–7.76 (m, 2H), 7.24–7.22 (m, 2H), 4.08(d,J= 2.1 Hz, 4H), 2.48 (s, 3H), 2.38 (s, 3H), 1.46 (s, 9H), 1.36 (s, 9H).13C NMR (101 MHz, CDCl3) 166.9, 166.63, 166.60, 141.9, 140.4, 128.8, 126.1,83.1, 82.0, 52.4, 52.0, 27.7, 27.6, 21.2, 17.2. HRMS (ESI-TOF): Anal. Calcd.For C21H32N2O6S+Na+: 463.1873, Found: 463.1863; IR (neat, cm-1): υ 2978, 1741,1555, 1227, 1142, 681。
Example forty-three
Figure 957560DEST_PATH_IMAGE048
The yield was 81% as the rest, replacing 3b with 3d (3 mmol, 504.6 mg) on the basis of example forty one. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.
1H NMR (400 MHz, CDCl3) 7.76–7.74 (m, 2H), 7.24–7.22 (m, 2H), 4.86–4.80 (m, 1H), 4.69–4.64 (m, 1H), 4.17 (d,J= 9.1 Hz, 4H), 2.50 (s, 3H), 2.38(s, 3H), 1.85–1.82 (m, 2H), 1.71–1.63 (m, 5H), 1.55–1.23 (m, 13H).13C NMR(101 MHz, CDCl3) 167.1, 166.9, 166.5, 141.9, 140.3, 128.8, 126.0, 74.6,73.7, 51.8, 51.4, 31.14, 31.05, 25.0, 24.8, 23.32, 23.29, 21.2, 17.2. HRMS(ESI-TOF): Anal. Calcd. For C25H36N2O6S+Na+: 515.2186, Found: 515.2190; IR(neat, cm-1): υ 2933, 1739, 1553, 1188, 1145, 687。
Example forty-four
Figure 805431DEST_PATH_IMAGE049
The yield was 99% as the rest, replacing 3b with 3e (3 mmol, 486.5 mg) on the basis of example forty one. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.
1H NMR (400 MHz, CDCl3) 7.79–7.76 (m, 2H), 7.36–7.32 (m, 2H), 7.28–7.14 (m, 6H), 7.09–7.07 (m, 2H), 6.88–6.85 (m, 2H), 4.47 (s, 2H), 4.42 (s,2H), 2.54 (s, 3H), 2.31 (s, 3H).13C NMR (101 MHz, CDCl3) 166.8, 166.5,166.3, 150.0, 149.8, 142.3, 139.9, 129.4, 129.2, 129.0, 126.3, 126.1, 125.9,121.1, 120.9, 51.81, 51.78, 21.2, 17.3. HRMS (ESI-TOF): Anal. Calcd. ForC25H24N2O6S+Na+: 503.1247, Found: 503.1235; IR (neat, cm-1): υ 2924, 1764,1547, 1143, 686。
Example forty-five
Figure 261820DEST_PATH_IMAGE050
The yield was 99% the same as the rest, except that 3f (3 mmol, 396.3 mg) was substituted for 3b based on example forty one. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.
1H NMR (400 MHz, DMSO) 7.67–7.65 (m, 2H), 7.35–7.33 (m, 2H), 4.71–4.69 (m, 1H), 4.62–4.57 (m, 4H), 4.50–4.48 (m, 1H), 4.44–4.42 (m, 1H), 4.36–4.34 (m, 1H), 4.30–4.27 (m, 3H), 4.22–4.20 (m, 1H), 2.43 (s, 3H), 2.37 (s,3H).13C NMR (101 MHz, DMSO) 168.4, 167.9, 167.8, 142.1, 140.6, 129.3,125.8, 82.3 (d,J= 7.7 Hz), 80.6 (d,J= 7.9 Hz), 64.5 (d,J= 18.9 Hz),64.0 (d,J= 19.2 Hz), 51.5, 51.5, 20.9, 17.1. HRMS (ESI-TOF): Anal. Calcd.For C17H22F2N2O6S+Na+: 443.1059, Found: 443.1061; IR (neat, cm-1): υ 2920, 1747,1546, 1184, 1142, 683。
Example forty-six
Figure 144850DEST_PATH_IMAGE051
A reaction flask was charged with Compound 1a (0.5 mmol, 85.6 mg), Compound 3g (3 mmol, 579.0 mg), Cu (OTf)2(0.01 mmol, 3.6 mg) and compound 2a (2 m L). The system was heated in air at 80 ℃ for about 2 hours, quenched with saturated sodium sulfite solution, extracted with ethyl acetate (10 m L × 3), the solvent removed with a rotary evaporator, adsorbed on silica gel, and the product 6f was obtained by simple column chromatography in 88% yield.
1H NMR (400 MHz, CDCl3) 7.74–7.72 (m, 2H), 7.27–7.25 (m, 2H), 4.47(t,J= 5.8 Hz, 2H), 4.29 (s, 2H), 4.25 (t,J= 6.3 Hz, 2H), 4.21 (s, 2H),3.52 (t,J= 5.8 Hz, 2H), 3.31 (t,J= 6.3 Hz, 2H), 2.52 (s, 3H), 2.40 (s,3H).13C NMR (101 MHz, CDCl3) 167.2, 167.1, 166.6, 142.3, 140.0, 129.0,126.0, 64.8, 64.1, 51.4, 51.3, 28.3, 27.9, 21.3, 17.2. HRMS (ESI-TOF): Anal.Calcd. For C17H22 79Br2N2O6S+Na+: 562.9458, C17H22 81Br2N2O6S+Na+: 564.9437, Found:562.9451, 564.9443; IR (neat, cm-1): υ 2957, 1744, 1543, 1143, 1080, 685。
Example forty-seven
Figure 3084DEST_PATH_IMAGE052
A reaction flask was charged with Compound 1a (0.5 mmol, 85.6 mg), Compound 3h (3 mmol, 558.9 mg), Cu (OTf)2(0.01 mmol, 3.6 mg) and compound 2a (2 m L). The system was heated in air at 80 ℃ for about 2 hours, quenched with saturated sodium sulfite solution, extracted with ethyl acetate (10 m L × 3), the solvent removed with a rotary evaporator, adsorbed on silica gel, and the product was obtained in 6g by simple column chromatography, yield 51%.
1H NMR (400 MHz, CDCl3) 7.73–7.71 (m, 2H), 7.20–7.18 (m, 2H), 4.24–4.19 (m, 2H), 4.13 (d,J= 3.5 Hz, 4H), 4.08–4.04 (m, 2H), 2.47 (s, 3H), 2.35(s, 3H), 0.99–0.95 (m, 2H), 0.87–0.82 (m, 2H), 0.01 (s, 9H), -0.02 (s, 9H).13C NMR (101 MHz, CDCl3) 168.0, 167.7, 166.6, 142.0, 140.3, 128.9, 126.2,64.5, 63.6, 51.6, 51.3, 21.3, 17.4, 17.3, 17.1, -1.71. HRMS (ESI-TOF): Anal.Calcd. For C23H40N2O6SSi2+Na+: 551.2038, Found: 551.2045; IR (neat, cm-1): υ2954, 1738, 1555, 1178, 832, 692。
Example forty-eight
Figure 693960DEST_PATH_IMAGE053
The yield was 68% as the rest, replacing 3b with 3i (3 mmol, 474.5 mg) on the basis of example forty one. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.
1H NMR (400 MHz, CDCl3) 7.75–7.73 (m, 2H), 7.26–7.24 (m, 2H), 4.27(t,J= 6.5 Hz, 2H), 4.20 (d,J= 3.4 Hz, 4H), 4.11 (t,J= 6.5 Hz, 2H), 3.42(t,J= 6.0 Hz, 2H), 3.35 (t,J= 6.1 Hz, 2H), 3.31 (s, 3H), 3.29 (s, 3H),2.50 (s, 3H), 2.39 (s, 3H), 1.93–1.87 (m, 2H), 1.81–1.75 (m, 2H).13C NMR (101MHz, CDCl3) 167.8, 167.5, 166.6, 142.1, 140.2, 128.9, 126.1, 68.7, 68.6,63.3, 62.5, 58.5, 58.4, 51.4, 51.1, 28.53, 28.52, 21.2, 17.2. HRMS (ESI-TOF):Anal. Calcd. For C21H32N2O8S +Na+: 495.1772, Found: 495.1785; IR (neat, cm-1):υ 2926, 1741, 1547, 1145, 1081, 684。
Example forty-nine
Figure 637645DEST_PATH_IMAGE054
The yield was 94% as the rest of the same by replacing 3b with 3j (3 mmol, 516.4 mg) based on example forty one. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.
1H NMR (400 MHz, CDCl3) 7.74–7.72 (m, 2H), 7.27–7.25 (m, 2H), 4.38–4.35 (m, 2H), 4.29–4.26 (m, 4H), 4.22 (s, 2H), 4.19–4.17 (m, 4H), 2.50 (s,3H), 2.40 (s, 3H), 2.05 (s, 3H), 2.04 (s, 3H).13C NMR (101 MHz, CDCl3)170.44, 170.42, 167.5, 167.4, 166.7, 142.1, 140.0, 128.8, 125.9, 63.4, 62.8,61.33, 61.31, 51.2, 51.0, 21.1, 20.40, 20.39, 17.0. HRMS (ESI-TOF): Anal.Calcd. For C21H28N2O10S+Na+: 523.1357, Found: 523.1351; IR (neat, cm-1): υ 2921,1735, 1546, 1180, 1145, 685。
Example fifty
Figure 321436DEST_PATH_IMAGE055
The yield was 97% as the rest, replacing 3b with 3k (3 mmol, 528.5 mg) on the basis of example forty one. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.
1H NMR (400 MHz, CDCl3) 7.72–7.70 (m, 2H), 7.32–7.29 (m, 8H), 7.24–7.20 (m, 2H), 7.15–7.13 (m, 2H), 5.14 (s, 2H), 4.98 (s, 2H), 4.21 (s, 4H),2.45 (s, 3H), 2.33 (s, 3H).13C NMR (101 MHz, CDCl3) 167.7, 167.4, 166.7,142.0, 140.1, 134.8, 134.5, 128.9, 128.5, 128.5, 128.4, 128.3, 128.2, 127.9,126.0, 67.5, 66.8, 51.5, 51.3, 21.2, 17.3. HRMS (ESI-TOF): Anal. Calcd. ForC27H28N2O6S+Na+: 531.1560, Found: 531.1566; IR (neat, cm-1): υ 2919, 1747,1558, 1192, 1150, 681。
Example fifty one
Figure 237440DEST_PATH_IMAGE056
The yield was 80% as the rest, replacing 3b with 3l (3 mmol, 570.6 mg) based on example forty one. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.
1H NMR (400 MHz, CDCl3) 7.72–7.70 (m, 2H), 7.21–7.19 (m, 2H), 7.15–7.11 (m, 8H), 5.10 (s, 2H), 4.95 (s, 2H), 4.19 (s, 4H), 2.45 (s, 3H), 2.34–2.31 (m, 9H).13C NMR (101 MHz, CDCl3) 167.7, 167.4, 166.7, 141.9, 140.2,138.4, 138.0, 131.8, 131.5, 129.2, 129.0, 128.9, 128.4, 128.1, 126.0, 67.5,66.8, 51.5, 51.2, 21.2, 20.96, 20.95, 17.3. HRMS (ESI-TOF): Anal. Calcd. ForC29H32N2O6S+Na+: 559.1873, Found: 559.1888; IR (neat, cm-1): υ 2919, 1737,1537, 1196, 1145, 871, 678。
Example fifty two
Figure 895954DEST_PATH_IMAGE057
A reaction flask was charged with Compound 1a (0.5 mmol, 85.6 mg) and Compound 3m (3 mmol, 66 mg) in that order3.5mg）、Cu(OTf)2(0.01 mmol, 3.6 mg) and compound 2a (2 m L). The system was heated in air at 80 ℃ for about 2 hours, quenched with saturated sodium sulfite solution, extracted with ethyl acetate (10 m L × 3), the solvent removed with a rotary evaporator, adsorbed on silica gel, and the product was obtained in 6l by simple column chromatography, with a yield of 99%.
1H NMR (400 MHz, DMSO) 8.24–8.22 (m, 2H), 8.16–8.13 (m, 2H), 7.67–7.65 (m, 2H), 7.61–7.59 (m, 2H), 7.56–7.53 (m, 2H), 7.26–7.24 (m, 2H), 5.34(s, 2H), 5.23 (s, 2H), 4.69 (s, 2H), 4.39 (s, 2H), 2.43 (s, 3H), 2.30 (s,3H).13C NMR (101 MHz, DMSO) 168.3, 167.9, 167.8, 147.2, 147.0, 143.5,143.2, 142.0, 140.4, 129.2, 128.6, 128.0, 125.7, 123.6, 123.4, 79.2, 65.4,64.7, 51.7, 51.6, 20.8, 17.2. HRMS (ESI-TOF): Anal. Calcd. For C27H26N4O10S +Na+: 621.1262, Found: 621.1264; IR (neat, cm-1): υ 3080, 1511, 1343, 1270, 734。
Example fifty three
Figure 264618DEST_PATH_IMAGE058
A reaction flask was charged with Compound 1a (0.5 mmol, 85.6 mg), Compound 3n (3 mmol, 603.6 mg), Cu (OTf)2(0.01 mmol, 3.6 mg) and compound 2a (2 m L). The system was heated in air at 80 ℃ for about 2 hours, quenched with saturated sodium sulfite solution, extracted with ethyl acetate (10 m L × 3), the solvent removed with a rotary evaporator, adsorbed on silica gel, and the product 6m was obtained by simple column chromatography with a yield of 88%.
1H NMR (400 MHz, CDCl3) 7.63–7.61 (m, 2H), 7.58–7.56 (m, 2H), 7.53–7.51 (m, 2H), 7.41–7.39 (m, 2H), 7.31–7.29 (m, 2H), 7.14–7.12 (m, 2H), 5.19(s, 2H), 5.03 (s, 2H), 4.30 (s, 2H), 4.24 (s, 2H), 2.43 (s, 3H), 2.31 (s,3H).13C NMR (101 MHz, CDCl3) 167.4, 167.2, 166.9, 142.3, 140.2, 139.8,139.7, 132.2, 132.1, 129.0, 128.3, 127.8, 125.9, 118.2, 118.1, 112.0, 111.6,66.2, 65.4, 51.6, 51.4, 21.2, 17.2. HRMS (ESI-TOF): Anal. Calcd. ForC29H26N4O6S+Na+: 581.1465, Found: 581.1476; IR (neat, cm-1): υ 3131, 2226,1746, 1625, 1268, 818。
Example fifty four
Figure 627467DEST_PATH_IMAGE059
A reaction flask was charged with Compound 1a (0.5 mmol, 85.6 mg), Compound 3o (3 mmol, 612.6 mg), Cu (OTf)2(0.01 mmol, 3.6 mg) and compound 2a (2 m L). The system was heated in air at 80 ℃ for about 2 hours, quenched with saturated sodium sulfite solution, extracted with ethyl acetate (10 m L × 3), the solvent removed with a rotary evaporator, adsorbed on silica gel, and the product 6n was obtained by simple column chromatography with a yield of 99%.
1H NMR (400 MHz, CDCl3) 7.87–7.83 (m, 4H), 7.81–7.79 (m, 2H), 7.62–7.58 (m, 2H), 7.49–7.45 (m, 4H), 7.24–7.22 (m, 2H), 5.43 (s, 2H), 5.23 (s,2H), 4.49 (s, 4H), 2.61 (s, 3H), 2.33 (s, 3H).13C NMR (101 MHz, CDCl3)191.2, 190.8, 167.5, 167.4, 167.2, 142.1, 140.2, 134.1, 134.0, 133.6, 133.4,129.0, 128.82, 128.79, 127.58, 127.55, 126.2, 77.20, 67.1, 66.4, 51.2, 51.0,21.2, 17.3. HRMS (ESI-TOF): Anal. Calcd. For C29H28N2O8S+Na+: 587.1459, Found:587.1446; IR (neat, cm-1): υ 2936, 1697, 1178, 963, 756, 687。
Example fifty five
Figure 319348DEST_PATH_IMAGE060
A reaction flask was charged with Compound 1a (0.5 mmol, 85.6 mg), Compound 3p (3 mmol, 426.4 mg), Cu (OTf)2(0.01 mmol, 3.6 mg) and compound 2a (2 m L). The system was heated in air at 80 ℃ for about 2 hours, quenched with saturated sodium sulfite solution, extracted with ethyl acetate (10 m L × 3), the solvent removed with a rotary evaporator, adsorbed on silica gel, and the product 6o was obtained by simple column chromatography with a yield of 99%.
1H NMR (400 MHz, CDCl3) 7.66–7.64 (m, 2H), 7.18–7.16 (m, 2H), 4.70(s, 2H), 4.48 (s, 2H), 4.31 (s, 2H), 4.28 (s, 2H), 2.44 (s, 3H), 2.31 (s,3H), 2.05 (s, 3H), 1.98 (s, 3H).13C NMR (101 MHz, CDCl3) 201.0, 199.7,167.2, 167.12, 167.08, 142.2, 139.9, 128.9, 126.0, 69.0, 68.5, 50.9, 50.7,25.7, 25.5, 21.1, 17.1. HRMS (ESI-TOF): Anal. Calcd. For C19H24N2O8S+Na+:463.1146, Found: 463.1140; IR (neat, cm-1): υ 2931, 1729, 1545, 1144, 1081,688。
Example fifty six
Figure 476660DEST_PATH_IMAGE061
A reaction flask was charged with Compound 1a (0.5 mmol, 85.6 mg), Compound 3q (3 mmol, 474.3 mg), Cu (OTf)2(0.01 mmol, 3.6 mg) and compound 2a (2 m L). The system was heated in air at 80 ℃ for about 2 hours, quenched with saturated sodium sulfite solution, extracted with ethyl acetate (10 m L × 3), the solvent removed with a rotary evaporator, adsorbed on silica gel, and the product 6p was obtained by simple column chromatography in 96% yield.
1H NMR (400 MHz, CDCl3) 7.75–7.73 (m, 2H), 7.26–7.24 (m, 2H), 4.70(s, 2H), 4.51 (s, 2H), 4.38 (s, 2H), 4.35 (s, 2H), 3.75 (s, 3H), 3.72 (s,3H), 2.53 (s, 3H), 2.39 (s, 3H).13C NMR (101 MHz, CDCl3) 167.4, 167.30,167.28, 167.2, 166.9, 142.1, 140.0, 128.9, 126.0, 61.2, 60.7, 52.2, 52.0,51.0, 50.7, 21.1, 17.0. HRMS (ESI-TOF): Anal. Calcd. For C19H24N2O10S +Na+:495.1044, Found: 495.1043; IR (neat, cm-1): υ 2957, 1746, 1547, 1167, 1144,1082, 686。
Example fifty seven
Figure 801462DEST_PATH_IMAGE062
A reaction flask was charged with Compound 1a (0.5 mmol, 85.6 mg), Compound 3r (3 mmol, 588.7 mg), Cu (OTf)2(0.01 mmol, 3.6 mg) and compound 2a (2 m L). The system was heated in air at 80 ℃ for about 2 hours, quenched with saturated sodium sulfite solution, extracted with ethyl acetate (10 m L × 3), the solvent removed with a rotary evaporator, adsorbed on silica gel, and the product 6q was obtained by simple column chromatography in 62% yield.
1H NMR (400 MHz, CDCl3) 7.75–7.73 (m, 2H), 7.21–7.19 (m, 2H), 7.15–7.12 (m, 2H), 6.93–6.90 (m, 2H), 6.83–6.82 (m, 1H), 6.78–6.77 (m, 1H), 4.37(t,J= 6.5 Hz, 2H), 4.17 (t,J= 6.8 Hz, 2H), 4.12 (s, 4H), 3.15 (t,J= 6.4Hz, 2H), 2.98 (t,J= 6.8 Hz, 2H), 2.43 (s, 3H), 2.34 (s, 3H).13C NMR (101MHz, CDCl3) 167.6, 167.4, 166.5, 142.1, 140.2, 139.2, 138.9, 128.9, 126.9,126.8, 126.1, 125.7, 125.5, 124.2, 123.9, 65.8, 65.1, 51.4, 51.2, 28.9, 28.8,21.2, 17.3. HRMS (ESI-TOF): Anal. Calcd. For C25H28N2O6S3+Na+: 571.1002, Found:571.1004; IR (neat, cm-1): υ 2958, 1743, 1534, 1171, 1147, 707, 665。
Example fifty eight
Figure 905684DEST_PATH_IMAGE063
A reaction flask was charged with Compound 1a (0.5 mmol, 85.6 mg), Compound 3s (3 mmol, 720.8 mg), Cu (OTf)2(0.01 mmol, 3.6 mg) and compound 2a (2 m L). The system was heated in air at 80 ℃ for about 2 hours, quenched with saturated sodium sulfite solution, extracted with ethyl acetate (10 m L × 3), the solvent removed with a rotary evaporator, adsorbed on silica gel, and the product 6r was obtained by simple column chromatography with a yield of 98%.
1H NMR (400 MHz, CDCl3) 8.06–8.01 (m, 2H), 7.88–7.81 (m, 4H), 7.78–7.76 (m, 2H), 7.57–7.47 (m, 4H), 7.45–7.40 (m, 2H), 7.36–7.34 (m, 1H), 7.30–7.29 (m, 1H), 7.19–7.17 (m, 2H), 4.53 (t,J= 7.0 Hz, 2H), 4.33 (t,J= 7.4Hz, 2H), 4.03 (s, 2H), 3.97 (s, 2H), 3.41 (t,J= 6.9 Hz, 2H), 3.24 (t,J=7.4 Hz, 2H), 2.41 (s, 3H), 2.24 (s, 3H).13C NMR (101 MHz, CDCl3) 167.7,167.3, 166.4, 142.1, 140.2, 133.60, 133.57, 133.0, 132.8, 131.7, 131.6,128.9, 128.7, 128.6, 127.5, 127.3, 127.0, 126.8, 126.1, 126.0, 126.0, 125.52,125.47, 125.3, 125.3, 123.2, 123.1, 65.6, 64.9, 51.2, 51.1, 31.6, 31.6, 21.0,17.1. HRMS (ESI-TOF): Anal. Calcd. For C37H36N2O6S+Na+: 659.2186, Found:659.2173; IR (neat, cm-1): υ 2958, 1742, 1546, 1145, 777, 733。
Example fifty nine
After the reaction flask was charged with compound 1a (0.5 mmol, 85.6 mg), compound 3a (2 mmol, 211 μ L), CuI (0.025 mmol, 4.8 mg) and compound 2a (2 m L) in this order, the system was heated in air at 80 ℃ for about 2 hours, quenched with saturated sodium sulfite solution, extracted with ethyl acetate (10 m L × 3), the solvent was removed with a rotary evaporator, and adsorbed on silica gel, and the product 4a was obtained by simple column chromatography with a yield of 11%, the data for the product tested being as in example one.
The CuI was replaced with Cu (0.025 mmol, 1.6 mg) in 23% yield and the product tested as in example one.
Replacement of CuI with CuCl2(0.025 mmol, 3.4 mg) in 19% yield, the product was tested as in example one.
Replacement of CuI by Cu (OTf)2(0.025 mmol, 9.0 mg) in 37% yield and the data is as in example one.
Replacement of CuI by Cu (OTf)2(0.01 mmol, 3.6 mg), yield 42%, the product was analyzed as in example one, the amount of compound 3a was changed to (3 mmol, 316. mu. L) and yield 78%, the amount of compound 2a was further changed to 1m L and yield 89%, the reaction conditions were changed to 60 ℃ in air for about 2 hours and yield 59%, the reaction conditions were changed to 70 ℃ in air for about 2 hours and yield 74%, and the reaction conditions were changed to 80 ℃ in air for about 0.5 hours and yield 81%.

Claims (6)

1. A process for preparing a fully substituted amidine characterized by: preparing fully substituted amidine by taking a sulfonamide derivative, a nitrile derivative and a diazo derivative as reaction substrates and taking transition metal or a transition metal compound as a catalyst through four-component series reaction in an organic solvent; the transition metal is copper;
wherein, the chemical structure general formula of the sulfonamide derivative is as follows:
Figure 948971DEST_PATH_IMAGE001
in the formula, R1Selected from naphthyl, thienyl, quinolyl, benzyl, cyclopropyl, methyl, n-butyl; or R1The chemical structural general formula is as follows:
Figure 459587DEST_PATH_IMAGE002
in the formula, R2Selected from methyl, hydrogen, fluorine, chlorine, bromine, iodine, trifluoromethyl, tert-butyl, methoxy, methoxycarbonyl and nitro;
the chemical structural formula of the nitrile derivative is as follows:
Figure 973745DEST_PATH_IMAGE004
in the formula, R3Selected from methyl, chlorine, phenyl; r4Selected from methoxy, phenyl; r5Selected from hydrogen, methyl, acetyl; r6Selected from hydrogen, chlorine, bromine, methoxy, trifluoromethyl;
the chemical structural formula of the diazo derivative is as follows:
Figure 103375DEST_PATH_IMAGE005
in the formula, R7Selected from ethyl, isopropyl, cyclohexyl, tert-butyl, phenyl; r8Selected from fluorine, bromine, trimethylsilyl, methoxymethyl, acetoxy, thienyl, naphthyl; r9Selected from hydrogen, methyl, nitro, cyano; r10Selected from phenyl, methyl, methoxy.
2. The process for the preparation of a fully substituted amidine according to claim 1, wherein: the reaction temperature of the four-component series reaction is 60-80 ℃, and the reaction time is 0.5-2 hours; the four-component series reaction is carried out in air.
3. The process for the preparation of a fully substituted amidine according to claim 1, wherein: the organic solvent is acetonitrile.
4. The process for the preparation of a fully substituted amidine according to claim 1, wherein: the catalyst is selected from one of copper iodide, copper powder, copper chloride and copper trifluoromethanesulfonate.
5. The process for the preparation of a fully substituted amidine according to claim 1, wherein: the dosage of the catalyst is 2 to 5 percent of the molar weight of the sulfonamide compound; the dosage of the nitrile derivative is 20 to 100 times of the molar weight of the sulfonamide compound; the dosage of the diazo derivative is 4 to 6 times of the molar weight of the sulfonamide compound.
6. The process for the preparation of a fully substituted amidine according to claim 5, wherein: the amount of the catalyst is 2 percent of the molar weight of the sulfonamide compound; the amount of the nitrile derivative is 20 times of the molar amount of the sulfonamide compound; the dosage of the diazo derivative is 6 times of the molar weight of the sulfonamide compound.
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Title
Highly Efficient One-Pot Synthesis of N-Sulfonylamidines by Cu-Catalyzed Three-Component Coupling of Sulfonyl Azide, Alkyne, and Amine;Imhyuck Bae et al.;《 Journal of the American Society》;20050127;第127卷;第2038-2039页 *
Interception of amide ylides with sulfonamides: synthesis of (E)-N-sulfonyl amidines catalyzed by Zn(OTf)2;Jijun Chen et al.;《Chemical Communications》;20171122;第53卷;第13256--13259页 *
Synthetic Utility of Ammonium Salts in a Cu-Catalyzed Three-Component Reaction as a Facile Coupling Parterner;Jinho Kim et al.;《Journal of the Organic Chemistry》;20081029;第73卷;第9454-9457页 *

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