S-alkyl isothiourea compounds and methods for their preparation

Abstract

The application discloses a method for preparing S-alkyl isothiourea under visible light irradiation, and a structural formula of the S-alkyl isothiourea is shown in formula 1. The preparation method comprises the following steps: adding secondary amine, aryl isothiocyanate, aryl alpha-diazo ester and cyclic ether as reaction raw materials into a reactor, adding an organic solvent, and stirring and reacting at room temperature under visible light irradiation for 3 hours. After the reaction is completed, the reactants are concentrated under reduced pressure, and the target product S-alkyl isothiourea is obtained through column chromatography separation. According to the application, secondary amine, aryl isothiocyanate, aryl alpha-diazo ester and cyclic ether are reacted under the promotion of visible light, and a series of S-alkyl isothiourea is efficiently synthesized in one-step operation. The process of the application is completed at room temperature under the condition that no heating and any metal catalyst, base, ligand and other additives are needed, and clean visible light energy is used as a reaction energy source. The process of the application has the advantages of simple operation, mild reaction condition, high efficiency, low energy consumption, high safety and small pollution.

Description

Technical Field

[0001] This invention relates to the field of organic synthetic chemistry, and more particularly to an S-alkyl isothiourea compound and its preparation method. Background Technology

[0002] The information disclosed in the background section of this invention is intended only to enhance the understanding of the overall background of the invention and is not necessarily to be regarded as an admission or in any way implying that such information constitutes prior art known to those skilled in the art.

[0003] S-alkylisothioureas have significant applications in synthetic chemistry and medicinal chemistry. Compounds containing this structure possess a wide range of biological and pharmaceutical activities, such as antiviral, antibacterial, anticancer, and insecticidal activities. The classic method for synthesizing S-alkylisothioureas involves two steps: the addition reaction of an amine with an aryl isothiocyanate to synthesize thiourea, followed by the alkylation of the thiourea with a haloalkane under alkaline or microwave-assisted conditions to generate S-alkylisothiourea (Tetrahedron. 1997, 53, 5291-5304; Org. Lett. 2005, 7, 2429-2431; J. Org. Chem. 2004, 69 1571-1580). This traditional method requires a large amount of additives and additional steps to purify the thiourea. In recent years, chemists have also developed other synthetic methods, such as copper-catalyzed coupling reactions of thioureas with aryl halides or arylboronic acids (Tetrahedron Lett. 2018, 59, 3165-3170; Synthesis. 2017, 49, 5211−5216; Eur. J. Org. Chem. 2022, e202200707), base-promoted alkylation reactions of aryl thioureas with tetraalkylammonium salts (J. Org. Chem. 2022, 87, 9675−9687), and cuprous iodide-catalyzed three-component reactions of thiosulfonates, isonitriles, and aromatic (heteroaromatic) amines (Angew. Chem. Int. Ed. 2014, 53, ...). The methods described above, including K₂CO₃-catalyzed three-component reactions of N,N-dibromoarylsulfonamides, isonitriles, and thiols (J. Org. Chem. 2021, 86, 17581−17593), and the three-component reaction of cuprous iodide-catalyzed thiourea, olefins, and Togni trifluoromethyl reagent II to synthesize trifluoromethyl-substituted isothioureas (Org. Lett. 2022, 24, 7157−7162), while effective, still have some drawbacks, such as the use of metal catalysts or large amounts of additives, and relatively harsh reaction conditions. Therefore, the development of a simple, convenient, and mild method for synthesizing S-alkyl isothioureas remains highly desirable. Summary of the Invention

[0004] This invention provides a method for preparing S-alkylisothioureas. This method utilizes simple and readily available reaction materials, without any additives, and uses clean light energy as the energy source to synthesize a series of S-alkylisothioureas at room temperature. To achieve the above objective, the technical solution of this invention is as follows.

[0005] In a first aspect of the present invention, an S-alkylisothiourea is disclosed, the structural formula of which is shown in Formula 1:

[0006]

[0007] Formula 1.

[0008] In Equation 1 above, the substituent R 1 R 2 It is an alkyl or cycloalkyl group. Substituent R 3 The aryl group is substituted in any way. Substituent R 4 It can be alkyl, methoxy, halogen, cyano, nitro, or ester group. Substituent R 5 It is a 1-8 carbon alkyl, benzyl, isopropyl, isobutyl or allyl.

[0009] In a second aspect of the present invention, a method for preparing the above-mentioned S-alkylisothiourea is disclosed, comprising the steps of: using secondary amine, aryl isothiocyanate, aryl α-diazo ester and cyclic ether as reactants, reacting in an organic solvent at room temperature under visible light irradiation for 3 hours, and then separating the target product S-alkylisothiourea by column chromatography after the reaction is completed.

[0010] Furthermore, the structural formula of the secondary amine is shown in Formula 2:

[0011]

[0012] Formula 3.

[0013] Furthermore, the structural formula of the aryl isothiocyanate is shown in Formula 3:

[0014]

[0015] Formula 3.

[0016] Furthermore, the structural formula of the aryl α-diazo ester is shown in Formula 4:

[0017]

[0018] Formula 4.

[0019] In Equation 2 above, the substituent R 1 R 2 Including any type of alkyl or cycloalkyl.

[0020] In Equation 3 above, the substituent R 3 For any of the aryl groups.

[0021] In Equation 4 above, the substituent R 4 This includes any one of the following: alkyl, methoxy, halogen, cyano, nitro, ester, etc. Substituent R 5 It includes any one of 1-8 carbon alkyl, benzyl, isopropyl, isobutyl, allyl, etc.

[0022] Furthermore, the structural formula of the cyclic ether is shown in Formula 5:

[0023]

[0024] Formula 5.

[0025] Furthermore, the cyclic ether includes any one of tetrahydrofuran, tetrahydropyran, 2,5-dihydrofuran, etc.

[0026] Furthermore, the molar ratio of the secondary amine, aryl isocyanate, aryl α-diazo ester, and cyclic ether is 1:1~3:1~3:1~3:24~120 in sequence.

[0027] Furthermore, the reaction is carried out in an organic solvent, such as toluene, ethyl acetate, 1,2-dichloroethane, acetone, acetonitrile, or dichloromethane.

[0028] Furthermore, the visible light source includes at least one of blue light, white light, violet light, and green light. Preferably, the visible light power is 3-10W, and the irradiation time is 3 hours.

[0029] Further, after the reaction is completed, the reaction solution is concentrated by vacuum concentration at a pressure of 0.09 MPa to obtain a crude product free of organic solvents; the separation is performed by column chromatography; preferably, the column chromatography is performed by washing with a mixed eluent of petroleum ether and ethyl acetate, wherein the volume ratio of petroleum ether to ethyl acetate is 10:1 to 5:1.

[0030] Compared with the prior art, the present invention has the following beneficial effects:

[0031] This invention utilizes visible light to promote the one-step synthesis of a series of S-alkyl isothioureas from a four-component reaction of secondary amines, aryl isocyanates, aryl α-diazo esters, and cyclic ethers. This process uses clean visible light energy as the reaction fuel, and the synthesis of S-alkyl isothioureas is completed at room temperature without heating or the use of any metal catalysts, bases, ligands, or other additives. The process of this invention has the advantages of simple operation, mild reaction conditions, high efficiency, low energy consumption, high safety, and low pollution. Detailed Implementation

[0032] The following description further sets forth specific details of the invention to provide a thorough understanding of it. The terminology used in this specification is for illustrative purposes only and is not intended to limit the scope of the invention.

[0033] Unless otherwise defined, all technical and scientific terms used in this invention have the same meaning as understood by one of ordinary skill in the art. Unless otherwise specified, all pharmaceuticals or reagents used in this invention are used in accordance with the product instructions or conventional methods in the relevant field. The process of this invention will now be further described with reference to specific embodiments.

[0034] Example 1

[0035] A method for preparing isothiourea, referring to route 1, includes the following steps:

[0036]

[0037] Route 1.

[0038] At room temperature, α-diazo ester 1a (0.2 mmol), phenyl isothiocyanate 2a (0.2 mmol), morpholine 3a (0.1 mmol), tetrahydrofuran 4a (12 mmol), and toluene (1 mL) were added sequentially to a 20 mL reaction tube and mixed thoroughly. The mixture was then stirred for 3 h under a 3W blue LED lamp. The reaction was monitored by TLC until completion. The mixture was then concentrated under vacuum (0.09 MPa) until solvent-free to obtain a crude product. The crude product was then washed with a mixture of petroleum ether and ethyl acetate in a volume ratio of 5:1 and subjected to rapid silica gel column chromatography to obtain product 5aa, a yellow oily substance, in a yield of 41.1 mg (93%).

[0039] The NMR results of product 5aa in this embodiment are as follows: 1 H NMR (500 MHz, CDCl3) d 7.42 – 7.40(m, 2H), 7.37 – 7.33 (m, 3H), 7.23 (t, J = 7.8 Hz, 2H), 6.98 (t, J = 7.4 Hz, 1H), 6.86 (d, J = 7.6 Hz, 2H), 4.81 (s, 1H), 3.73 – 3.70 (m, 4H), 3.69 (s, 3H), 3.63– 3.60 (m, 4H), 3.46 – 3.42 (m, 1H), 3.35 – 3.31 (m, 1H), 2.42 – 2.39 (m,2H), 1.56 – 1.53 (m, 4H). 13 C NMR (125 MHz, CDCl3) d171.3, 155.3, 149.7, 136.5,128.71, 128.7, 128.6, 127.1, 122.4, 121.4, 81.0, 69.0, 66.8, 52.2, 48.8,32.1, 28.5, 26.7. ESI HRMS: calculated for C 24 H 30 N₂O₄S [M+H] + 443.2006, found 443.2056.

[0040] Example 2

[0041] A method for preparing isothiourea, referring to route 2, includes the following steps:

[0042]

[0043] Route 2.

[0044] At room temperature, α-diazo ester 1a (0.3 mmol), phenyl isothiocyanate 2a (0.3 mmol), morpholine 3a (0.1 mmol), tetrahydrofuran 4a (2.4 mmol), and toluene (1 ml) were added sequentially to a 20 mL reaction tube and mixed thoroughly. The mixture was then stirred for 3 h under a 3W blue LED lamp. The reaction was monitored by TLC until completion. The mixture was then concentrated under vacuum (0.09 MPa) until solvent-free to obtain a crude product. The crude product was then washed with a mixture of petroleum ether and ethyl acetate in a volume ratio of 5:1 and subjected to rapid silica gel column chromatography to obtain product 5aa, a yellow oily substance, in a yield of 30.1 mg (68%).

[0045] The NMR results of product 5aa in this embodiment are as follows: 1 H NMR (500 MHz, CDCl3) d 7.42 – 7.40(m, 2H), 7.37 – 7.33 (m, 3H), 7.23 (t, J = 7.8 Hz, 2H), 6.98 (t, J = 7.4 Hz, 1H), 6.86 (d, J= 7.6 Hz, 2H), 4.81 (s, 1H), 3.73 – 3.70 (m, 4H), 3.69 (s, 3H), 3.63– 3.60 (m, 4H), 3.46 – 3.42 (m, 1H), 3.35 – 3.31 (m, 1H), 2.42 – 2.39 (m,2H), 1.56 – 1.53 (m, 4H). 13 C NMR (125 MHz, CDCl3) d 171.3, 155.3, 149.7, 136.5,128.71, 128.7, 128.6, 127.1, 122.4, 121.4, 81.0, 69.0, 66.8, 52.2, 48.8,32.1, 28.5, 26.7. ESI HRMS: calculated for C 24 H 30 N₂O₄S [M+H] + 443.2006, found 443.2056.

[0046] Example 3

[0047] A method for preparing isothiourea, referring to route 3, includes the following steps:

[0048]

[0049] Route 3.

[0050] At room temperature, α-diazo ester 1a (0.2 mmol), phenyl isothiocyanate 2a (0.2 mmol), morpholine 3a (0.1 mmol), tetrahydrofuran 4a (12 mmol), and toluene (1 ml) were added sequentially to a 20 mL reaction tube and mixed thoroughly. The mixture was then stirred for 3 h under a 3W purple LED lamp. The reaction was monitored by TLC until completion. The mixture was then concentrated under vacuum (0.09 MPa) until solvent-free to obtain a crude product. The crude product was then washed with a mixture of petroleum ether and ethyl acetate in a volume ratio of 5:1 and subjected to rapid silica gel column chromatography to obtain product 5aa, a yellow oily substance, in a yield of 36.2 mg (82%).

[0051] The NMR results of product 5aa in this embodiment are as follows: 1 H NMR (500 MHz, CDCl3) d 7.42 – 7.40(m, 2H), 7.37 – 7.33 (m, 3H), 7.23 (t, J= 7.8 Hz, 2H), 6.98 (t, J = 7.4 Hz, 1H), 6.86 (d, J = 7.6 Hz, 2H), 4.81 (s, 1H), 3.73 – 3.70 (m, 4H), 3.69 (s, 3H), 3.63– 3.60 (m, 4H), 3.46 – 3.42 (m, 1H), 3.35 – 3.31 (m, 1H), 2.42 – 2.39 (m,2H), 1.56 – 1.53 (m, 4H). 13 C NMR (125 MHz, CDCl3) d 171.3, 155.3, 149.7, 136.5,128.71, 128.7, 128.6, 127.1, 122.4, 121.4, 81.0, 69.0, 66.8, 52.2, 48.8,32.1, 28.5, 26.7. ESI HRMS: calculated for C 24 H 30 N₂O₄S [M+H] + 443.2006, found 443.2056.

[0052] Example 4

[0053] A method for preparing isothiourea, referring to route 4, includes the following steps:

[0054]

[0055] Route 4.

[0056] At room temperature, α-diazo ester 1a (0.2 mmol), phenyl isothiocyanate 2a (0.2 mmol), morpholine 3a (0.1 mmol), tetrahydrofuran 4a (12 mmol), and toluene (1 ml) were added sequentially to a 20 mL reaction tube and mixed thoroughly. The mixture was then stirred for 3 h under a 3W green LED lamp. The reaction was monitored by TLC until completion. The mixture was then concentrated under vacuum (0.09 MPa) until solvent-free to obtain a crude product. The crude product was then washed with a mixture of petroleum ether and ethyl acetate in a volume ratio of 5:1 and subjected to rapid silica gel column chromatography to obtain product 5aa, a yellow oily substance, in a yield of 31.8 mg (72%).

[0057] The NMR results of product 5aa in this embodiment are as follows: 1 H NMR (500 MHz, CDCl3) d7.42 – 7.40(m, 2H), 7.37 – 7.33 (m, 3H), 7.23 (t, J = 7.8 Hz, 2H), 6.98 (t, J = 7.4 Hz, 1H), 6.86 (d, J = 7.6 Hz, 2H), 4.81 (s, 1H), 3.73 – 3.70 (m, 4H), 3.69 (s, 3H), 3.63– 3.60 (m, 4H), 3.46 – 3.42 (m, 1H), 3.35 – 3.31 (m, 1H), 2.42 – 2.39 (m,2H), 1.56 – 1.53 (m, 4H). 13 C NMR (125 MHz, CDCl3) d 171.3, 155.3, 149.7, 136.5,128.71, 128.7, 128.6, 127.1, 122.4, 121.4, 81.0, 69.0, 66.8, 52.2, 48.8,32.1, 28.5, 26.7. ESI HRMS: calculated for C 24 H 30 N₂O₄S [M+H] + 443.2006, found 443.2056.

[0058] Example 5

[0059] A method for preparing isothiourea, referring to route 5, includes the following steps:

[0060]

[0061] Route 5.

[0062] At room temperature, α-diazo ester 1a (0.2 mmol), phenyl isothiocyanate 2a (0.2 mmol), morpholine 3a (0.1 mmol), tetrahydrofuran 4a (12 mmol), and toluene (1 ml) were added sequentially to a 20 mL reaction tube and mixed thoroughly. The mixture was then stirred for 3 h under a 3W white LED lamp. The reaction was monitored by TLC until completion. The mixture was then concentrated under vacuum (0.09 MPa) until solvent-free to obtain a crude product. The crude product was then washed with a mixture of petroleum ether and ethyl acetate in a volume ratio of 5:1 and subjected to rapid silica gel column chromatography to obtain product 5aa, a yellow oily substance, in a yield of 39.3 mg (93%).

[0063] The NMR results of product 5aa in this embodiment are as follows: 1 H NMR (500 MHz, CDCl3) d 7.42 – 7.40(m, 2H), 7.37 – 7.33 (m, 3H), 7.23 (t, J = 7.8 Hz, 2H), 6.98 (t, J = 7.4 Hz, 1H), 6.86 (d, J = 7.6 Hz, 2H), 4.81 (s, 1H), 3.73 – 3.70 (m, 4H), 3.69 (s, 3H), 3.63– 3.60 (m, 4H), 3.46 – 3.42 (m, 1H), 3.35 – 3.31 (m, 1H), 2.42 – 2.39 (m,2H), 1.56 – 1.53 (m, 4H). 13 C NMR (125 MHz, CDCl3) d 171.3, 155.3, 149.7, 136.5,128.71, 128.7, 128.6, 127.1, 122.4, 121.4, 81.0, 69.0, 66.8, 52.2, 48.8,32.1, 28.5, 26.7. ESI HRMS: calculated for C 24 H 30 N₂O₄S [M+H] + 443.2006, found 443.2056.

[0064] Example 6

[0065] A method for preparing isothiourea, referring to route 6, includes the following steps:

[0066]

[0067] Route 6.

[0068] At room temperature, α-diazo ester 1a (0.2 mmol), phenyl isothiocyanate 2a (0.2 mmol), morpholine 3a (0.1 mmol), tetrahydrofuran 4a (12 mmol), and ethyl acetate (1 ml) were added sequentially to a 20 mL reaction tube and mixed thoroughly. The mixture was then stirred for 3 h under a 3 W blue LED lamp. The reaction was monitored by TLC until completion. The mixture was then concentrated under vacuum (0.09 MPa) until solvent-free to obtain a crude product. The crude product was then washed with a mixture of petroleum ether and ethyl acetate in a volume ratio of 5:1 and subjected to rapid silica gel column chromatography to obtain product 5aa, a yellow oily substance, in a yield of 39.3 mg (89%).

[0069] The NMR results of product 5aa in this embodiment are as follows: 1 H NMR (500 MHz, CDCl3) d 7.42 – 7.40(m, 2H), 7.37 – 7.33 (m, 3H), 7.23 (t, J = 7.8 Hz, 2H), 6.98 (t, J = 7.4 Hz, 1H), 6.86 (d, J = 7.6 Hz, 2H), 4.81 (s, 1H), 3.73 – 3.70 (m, 4H), 3.69 (s, 3H), 3.63– 3.60 (m, 4H), 3.46 – 3.42 (m, 1H), 3.35 – 3.31 (m, 1H), 2.42 – 2.39 (m,2H), 1.56 – 1.53 (m, 4H). 13 C NMR (125 MHz, CDCl3) d 171.3, 155.3, 149.7, 136.5,128.71, 128.7, 128.6, 127.1, 122.4, 121.4, 81.0, 69.0, 66.8, 52.2, 48.8,32.1, 28.5, 26.7. ESI HRMS: calculated for C 24 H 30 N₂O₄S [M+H] + 443.2006, found 443.2056.

[0070] Example 7

[0071] A method for preparing isothiourea, referring to route 7, includes the following steps:

[0072]

[0073] Route 7.

[0074] At room temperature, α-diazo ester 1a (0.2 mmol), phenyl isothiocyanate 2a (0.2 mmol), morpholine 3a (0.1 mmol), tetrahydrofuran 4a (12 mmol), and dichloromethane (1 ml) were added sequentially to a 20 mL reaction tube and mixed thoroughly. The mixture was then stirred for 3 h under a 3 W blue LED lamp. The reaction was monitored by TLC until completion. The mixture was then concentrated under vacuum (0.09 MPa) until solvent-free to obtain a crude product. The crude product was then washed with a mixture of petroleum ether and ethyl acetate in a volume ratio of 5:1 and subjected to rapid silica gel column chromatography to obtain product 5aa, a yellow oily substance, in a yield of 37.6 mg (85%).

[0075] The NMR results of product 5aa in this embodiment are as follows: 1 H NMR (500 MHz, CDCl3) d 7.42 – 7.40(m, 2H), 7.37 – 7.33 (m, 3H), 7.23 (t, J = 7.8 Hz, 2H), 6.98 (t, J = 7.4 Hz, 1H), 6.86 (d, J = 7.6 Hz, 2H), 4.81 (s, 1H), 3.73 – 3.70 (m, 4H), 3.69 (s, 3H), 3.63– 3.60 (m, 4H), 3.46 – 3.42 (m, 1H), 3.35 – 3.31 (m, 1H), 2.42 – 2.39 (m,2H), 1.56 – 1.53 (m, 4H). 13 C NMR (125 MHz, CDCl3) d 171.3, 155.3, 149.7, 136.5,128.71, 128.7, 128.6, 127.1, 122.4, 121.4, 81.0, 69.0, 66.8, 52.2, 48.8,32.1, 28.5, 26.7. ESI HRMS: calculated for C 24 H 30 N₂O₄S [M+H] + 443.2006, found 443.2056.

[0076] Example 8

[0077] A method for preparing isothiourea, referring to route 8, includes the following steps:

[0078]

[0079] Route 8.

[0080] At room temperature, α-diazo ester 1a (0.2 mmol), phenyl isothiocyanate 2a (0.2 mmol), morpholine 3a (0.1 mmol), tetrahydrofuran 4a (12 mmol), and 1,2-dichloroethane (1 ml) were added sequentially to a 20 mL reaction tube and mixed thoroughly. The mixture was then stirred for 3 h under a 3 W blue LED lamp. The reaction was monitored by TLC until completion. The mixture was then concentrated under vacuum (0.09 MPa) until solvent-free to obtain the crude product. The crude product was then washed with a mixture of petroleum ether and ethyl acetate in a volume ratio of 5:1 and subjected to rapid silica gel column chromatography to obtain product 5aa, a yellow oil, in 32.7 mg, with a yield of 74%.

[0081] The NMR results of product 5aa in this embodiment are as follows: 1 H NMR (500 MHz, CDCl3) d 7.42 – 7.40(m, 2H), 7.37 – 7.33 (m, 3H), 7.23 (t, J = 7.8 Hz, 2H), 6.98 (t, J = 7.4 Hz, 1H), 6.86 (d, J = 7.6 Hz, 2H), 4.81 (s, 1H), 3.73 – 3.70 (m, 4H), 3.69 (s, 3H), 3.63– 3.60 (m, 4H), 3.46 – 3.42 (m, 1H), 3.35 – 3.31 (m, 1H), 2.42 – 2.39 (m,2H), 1.56 – 1.53 (m, 4H). 13 C NMR (125 MHz, CDCl3) d 171.3, 155.3, 149.7, 136.5,128.71, 128.7, 128.6, 127.1, 122.4, 121.4, 81.0, 69.0, 66.8, 52.2, 48.8,32.1, 28.5, 26.7. ESI HRMS: calculated for C 24 H 30 N₂O₄S [M+H] +443.2006, found 443.2056.

[0082] Example 9

[0083] A method for preparing isothiourea, referring to route 9, includes the following steps:

[0084]

[0085] Route 9.

[0086] At room temperature, α-diazo ester 1a (0.2 mmol), phenyl isothiocyanate 2a (0.2 mmol), morpholine 3a (0.1 mmol), tetrahydrofuran 4a (12 mmol), and acetonitrile (1 ml) were added sequentially to a 20 mL reaction tube and mixed thoroughly. The mixture was then stirred for 3 h under a 3 W blue LED lamp. The reaction was monitored by TLC until completion. The mixture was then concentrated under vacuum (0.09 MPa) until solvent-free to obtain a crude product. The crude product was then washed with a mixture of petroleum ether and ethyl acetate in a volume ratio of 5:1 and subjected to rapid silica gel column chromatography to obtain product 5aa, a yellow oily substance, in a yield of 33.6 mg (76%).

[0087] The NMR results of product 5aa in this embodiment are as follows: 1 H NMR (500 MHz, CDCl3) d 7.42 – 7.40(m, 2H), 7.37 – 7.33 (m, 3H), 7.23 (t, J = 7.8 Hz, 2H), 6.98 (t, J = 7.4 Hz, 1H), 6.86 (d, J = 7.6 Hz, 2H), 4.81 (s, 1H), 3.73 – 3.70 (m, 4H), 3.69 (s, 3H), 3.63– 3.60 (m, 4H), 3.46 – 3.42 (m, 1H), 3.35 – 3.31 (m, 1H), 2.42 – 2.39 (m,2H), 1.56 – 1.53 (m, 4H). 13 C NMR (125 MHz, CDCl3) d171.3, 155.3, 149.7, 136.5,128.71, 128.7, 128.6, 127.1, 122.4, 121.4, 81.0, 69.0, 66.8, 52.2, 48.8,32.1, 28.5, 26.7. ESI HRMS: calculated for C 24 H 30 N₂O₄S [M+H] + 443.2006, found 443.2056.

[0088] Example 10

[0089] A method for preparing isothiourea, referring to route 10, includes the following steps:

[0090]

[0091] Route 10.

[0092] At room temperature, α-diazo ester 1a (0.2 mmol), phenyl isothiocyanate 2a (0.2 mmol), morpholine 3a (0.1 mmol), tetrahydrofuran 4a (12 mmol), and toluene (1 ml) were added sequentially to a 20 mL reaction tube and mixed thoroughly. The mixture was then stirred for 3 h under a 10 W blue LED lamp. The reaction was monitored by TLC until completion. The mixture was then concentrated under vacuum (0.09 MPa) until solvent-free to obtain a crude product. The crude product was then washed with a mixture of petroleum ether and ethyl acetate in a volume ratio of 5:1 and subjected to rapid silica gel column chromatography to obtain product 5aa, a yellow oily substance, in a yield of 40.6 mg (92%).

[0093] The NMR results of product 5aa in this embodiment are as follows: 1 H NMR (500 MHz, CDCl3) d 7.42 – 7.40(m, 2H), 7.37 – 7.33 (m, 3H), 7.23 (t, J = 7.8 Hz, 2H), 6.98 (t, J = 7.4 Hz, 1H), 6.86 (d, J= 7.6 Hz, 2H), 4.81 (s, 1H), 3.73 – 3.70 (m, 4H), 3.69 (s, 3H), 3.63– 3.60 (m, 4H), 3.46 – 3.42 (m, 1H), 3.35 – 3.31 (m, 1H), 2.42 – 2.39 (m,2H), 1.56 – 1.53 (m, 4H). 13 C NMR (125 MHz, CDCl3) d 171.3, 155.3, 149.7, 136.5,128.71, 128.7, 128.6, 127.1, 122.4, 121.4, 81.0, 69.0, 66.8, 52.2, 48.8,32.1, 28.5, 26.7. ESI HRMS: calculated for C 24 H 30 N₂O₄S [M+H] + 443.2006, found 443.2056.

[0094] Example 11

[0095] A method for preparing isothiourea, referring to route 11, includes the following steps:

[0096]

[0097] Route 11.

[0098] At room temperature, α-diazo ester 1b (0.2 mmol), phenyl isothiocyanate 2a (0.2 mmol), morpholine 3a (0.1 mmol), tetrahydrofuran 4a (12 mmol), and toluene (1 ml) were added sequentially to a 20 mL reaction tube. The mixture was thoroughly mixed and stirred for 3 h under a 3W blue LED lamp. The reaction was monitored by TLC until complete. The mixture was then concentrated under vacuum (0.08 MPa) until solvent-free to obtain a crude product. The crude product was then washed with a mixture of petroleum ether and ethyl acetate (4:1 v / v) as eluent, followed by rapid silica gel column chromatography to obtain product 5ab, a yellow oil, in 21.4 mg (47% yield). The product of this example is shown in the figure.

[0099] The NMR results of product 5ab in this embodiment are as follows: 1 H NMR (500 MHz, CDCl3) d 7.29 (d, J = 8.0Hz, 2H), 7.23 (t, J= 7.8 Hz, 2H), 7.16 (d, J = 7.9 Hz, 2H), 6.97 (t, J = 7.4 Hz,1H), 6.86 – 6.85 (m, 2H), 4.77 (s, 1H), 3.74 – 3.70 (m, 4H), 3.69 (s, 3H),3.63 – 3.60 (m, 4H), 3.44 – 3.40 (m, 1H), 3.34 – 3.30 (m, 1H), 2.43 – 2.39 (m, 2H), 2.34 (s, 3H), 1.55 – 1.52 (m, 4H). 13 C NMR (125 MHz, CDCl3) d 171.4,155.3, 149.7, 138.6, 133.6, 129.3, 128.7, 127.1, 122.4, 121.4, 80.9, 68.9,66.8, 52.2, 48.8, 32.2, 28.5 26.7, 21.2. ESI HRMS: calculated for C 25 H 32 N₂O₄S[M+H] + 457.2161, found 457.2190.

[0100] Example 12

[0101] A method for preparing isothiourea, referring to route 12, includes the following steps:

[0102]

[0103] Route 12.

[0104] At room temperature, α-diazo ester 1c (0.2 mmol), phenyl isothiocyanate 2a (0.2 mmol), morpholine 3a (0.1 mmol), tetrahydrofuran 4a (12 mmol), and toluene (1 ml) were added sequentially to a 20 mL reaction tube and mixed thoroughly. The mixture was then stirred for 3 h under a 3W blue LED lamp. The reaction was monitored by TLC until completion. The mixture was then concentrated under vacuum (0.09 MPa) until solvent-free to obtain a crude product. The crude product was then washed with a mixture of petroleum ether and ethyl acetate in a volume ratio of 5:1 and subjected to rapid silica gel column chromatography to obtain the product 5ac of this example, which was a yellow oily substance of 47.3 mg, with a yield of 95%.

[0105] The NMR results of the product 5ac in this embodiment are as follows:1 H NMR (500 MHz, CDCl3) d 7.37 (d, J = 8.4Hz, 2H), 7.33 (d, J = 8.4 Hz, 2H), 7.23 (t, J = 7.8 Hz, 2H), 6.98 (t, J = 7.4 Hz, 1H), 6.86 (d, J = 7.4 Hz, 2H), 4.78 (s, 1H), 3.74 – 3.71 (m, 4H), 3.70 (s, 3H), 3.63 – 3.60 (m, 4H), 3.45 – 3.41 (m, 1H), 3.35 – 3.31 (m, 1H), 2.43 – 2.39 (m, 2H), 1.56 – 1.55 (m, 4H), 1.31 (s, 9H). 13 C NMR (125 MHz, CDCl3) d 171.5,155.3, 151.7, 149.7, 133.4, 128.7, 126.8, 125.6, 122.4, 121.4, 80.9, 69.0,66.8, 52.2, 48.8, 34.6, 32.2, 31.3, 28.5, 26.7. ESI HRMS: calculated for C 28 H 38 N₂O₄S [M+H] + 499.2631, found 499.2669.

[0106] Example 13

[0107] A method for preparing isothiourea, referring to route 13, includes the following steps:

[0108]

[0109] Route 13.

[0110] At room temperature, α-diazo ester 1d (0.2 mmol), phenyl isothiocyanate 2a (0.2 mmol), morpholine 3a (0.1 mmol), tetrahydrofuran 4a (12 mmol), and toluene (1 ml) were added sequentially to a 20 mL reaction tube. The mixture was thoroughly mixed and stirred for 3 h under a 3W blue LED lamp. The reaction was monitored by TLC until complete. The mixture was then concentrated under vacuum (0.09 MPa) until solvent-free to obtain a crude product. The crude product was then washed with a mixture of petroleum ether and ethyl acetate (5:1 v / v) as eluent, followed by rapid silica gel column chromatography to obtain product 5ad, a yellow oil, in a yield of 46.3 mg (98%). The product of this example is shown in the figure.

[0111] The NMR results of the product 5ad in this embodiment are as follows: 1 H NMR (500 MHz, CDCl3) d 7.28 – 7.26(m, 1H), 7.25 – 7.21 (m, 2H), 6.99 – 6.96 (m, 3H), 6.88 – 6.85 (m, 3H), 4.78(s, 1H), 3.80 (s, 3H), 3.73 – 3.70 (m, 4H), 3.70 (s, 3H), 3.63 – 3.60 (m,4H), 3.45 – 3.41 (m, 1H), 3.36 – 3.31 (m, 1H), 2.42 – 2.39 (m, 2H), 1.57 –1.53 (m, 4H). 13 C NMR (125 MHz, CDCl3) d 171.2, 159.8, 155.2, 149.7, 138.0,129.6, 128.7, 122.4, 121.4, 119.5, 114.3, 112.5 80.9, 69.0, 66.8, 55.3, 52.3,48.8, 32.1, 28.4, 26.7.ESI HRMS: calculated for C 25 H 33 N₂O₅S [M+H] + 473.2110, found 473.2142.

[0112] Example 14

[0113] A method for preparing isothiourea, referring to route 14, includes the following steps:

[0114]

[0115] Route 14.

[0116] At room temperature, α-diazo ester 1e (0.2 mmol), phenyl isothiocyanate 2a (0.2 mmol), morpholine 3a (0.1 mmol), tetrahydrofuran 4a (12 mmol), and toluene (1 ml) were added sequentially to a 20 mL reaction tube and mixed thoroughly. The mixture was then stirred for 3 h under a 3W blue LED lamp. The reaction was monitored by TLC until completion. The mixture was then concentrated under vacuum (0.09 MPa) until solvent-free to obtain a crude product. The crude product was then washed with a mixture of petroleum ether and ethyl acetate in a volume ratio of 5:1 and subjected to rapid silica gel column chromatography to obtain product 5ae, a yellow oily substance of 44.9 mg, with a yield of 97%.

[0117] The NMR results of the product 5ae in this embodiment are as follows: 1 H NMR (500 MHz, CDCl3) d 7.42 (s, 1H),7.32 – 7.29 (m, 3H), 7.24 (t, J = 7.8 Hz, 2H), 6.98 (t, J = 7.4 Hz, 1H), 6.87 –6.85 (m, 2H), 4.77 (s, 1H), 3.74 – 3.71 (m, 4H), 3.71 (s, 3H), 3.64 – 3.61(m, 4H), 3.47 – 3,43 (m 1H), 3.35 – 3.31 (m, 1H), 2.44 – 2.39 (m, 2H), 1.57 –1.55 (m, 4H). 13 C NMR (125 MHz, CDCl3) d 170.7, 155.2, 149.7, 138.5, 134.6,129.9, 128.9, 128.7, 127.2, 125.2, 122.4, 121.4, 80.3, 69.3, 66.8, 52.4,48.8, 32.1, 28.4, 26.7. ESI HRMS: calculated for C 24 H 29 ClN2O4S [M+H] + 477.1615, found 477.1656.

[0118] Example 15

[0119] A method for preparing isothiourea, referring to route 15, includes the following steps:

[0120]

[0121] Route 15.

[0122] At room temperature, α-diazo ester 1f (0.2 mmol), phenyl isothiocyanate 2a (0.2 mmol), morpholine 3a (0.1 mmol), tetrahydrofuran 4a (12 mmol), and toluene (1 ml) were added sequentially to a 20 mL reaction tube. The mixture was thoroughly mixed and stirred for 3 h under a 3W blue LED lamp. The reaction was monitored by TLC until complete. The mixture was then concentrated under vacuum (0.09 MPa) until solvent-free to obtain a crude product. The crude product was then washed with a mixture of petroleum ether and ethyl acetate (5:1 v / v) as eluent, followed by rapid silica gel column chromatography to obtain product 5af, a yellow oily substance, at a yield of 48.4 mg (93%). The product of this example is shown in the figure.

[0123] The NMR results of product 5af in this embodiment are as follows: 1 H NMR (500 MHz, CDCl3) d 7.49 (d, J = 8.0Hz, 2H), 7.29 (d, J = 8.2 Hz, 2H), 7.23 (t, J = 7.5 Hz, 2H), 7.00 – 6.97 (m, 1H), 6.86 (d, J = 8.2 Hz, 2H), 4.76 (s, 1H), 3.74 – 3.70 (m,, 4H), 3.69 (s, 3H), 3.64 – 3.60 (m, 4H), 3.46 – 3.42 (m, 1H), 3.33- 3.30 (m, 1H), 2.44 – 2.39 (m,2H), 1.56 – 1.54 (m, 4H). 13 C NMR (125 MHz, CDCl3) d 170.8, 155.2, 149.7, 135.6,131.8, 128.7, 128.7, 122.8, 122.4, 121.4, 80.4, 69.2, 66.8, 52.4, 48.8, 32.1,28.4, 26.7. ESI HRMS: calculated for C 24 H 29 BrN2O4S [M+H]+ 521.1110, found 521.1143.

[0124] Example 16

[0125] A method for preparing isothiourea, referring to route 16, includes the following steps:

[0126]

[0127] Route 16.

[0128] At room temperature, 5 ag (0.2 mmol) of α-diazo ester, 2a (0.2 mmol) of phenyl isothiocyanate, 3a (0.1 mmol) of morpholine, 4a (12 mmol) of tetrahydrofuran, and 1 ml of toluene were added sequentially to a 20 mL reaction tube. The mixture was stirred for 3 h under a 3W blue LED lamp. The reaction was monitored by TLC until the reaction was complete. The mixture was then concentrated under vacuum (0.09 MPa) until solvent-free to obtain a crude product. The crude product was then washed with a mixture of petroleum ether and ethyl acetate in a volume ratio of 5:1 and subjected to rapid silica gel column chromatography to obtain 5 ag of the product of this example, which was 37.3 mg of a yellow oil, with a yield of 81%.

[0129] The NMR results of the 5ag product in this embodiment are as follows: 1 H NMR (500 MHz, CDCl3) d 7.40 – 7.37(m, 2H), 7.23 (t, J = 7.8 Hz, 2H), 7.04 (t, J = 8.6 Hz, 2H), 6.98 (t, J = 7.4 Hz, 1H), 6.86 (d, J = 7.4 Hz, 2H), 4.78 (s, 1H), 3.74 – 3.71 (m, 4H), 3.70 (s, 3H), 3.63 – 3.60 (m, 4H), 3.46 – 3.42 (m, 1H), 3.34 – 3.30 (m, 1H), 2.44 – 2.40 (m, 2H), 1.56 – 1.55 (m, 4H). 13 C NMR (125 MHz, CDCl3) d 171.1, 162.9 (d, J = 245.9Hz), 155.2, 149.7, 132.4 (d, J = 3.2 Hz), 128.9 (d,J = 8.2 Hz), 128.7, 122.4,121.4, 115.6 (d, J = 21.5 Hz), 80.3, 69.1, 66.8, 52.3, 48.8, 32.1, 28.4, 26.7.ESI HRMS: calculated for C 24 H 29 FN2O4S [M+H] + 461.1910, found 461.1945.

[0130] Example 17

[0131] A method for preparing isothiourea, referring to route 17, includes the following steps:

[0132]

[0133] Route 17.

[0134] At room temperature, α-diazo ester 1h (0.2 mmol), phenyl isothiocyanate 2a (0.2 mmol), morpholine 3a (0.1 mmol), tetrahydrofuran 4a (12 mmol), and toluene (1 ml) were added sequentially to a 20 mL reaction tube. The mixture was thoroughly mixed and stirred for 3 h under a 3W blue LED lamp. The reaction was monitored by TLC until complete. The mixture was then concentrated under vacuum (0.08 MPa) until solvent-free to obtain a crude product. The crude product was then washed with a mixture of petroleum ether and ethyl acetate (5:1 v / v) as eluent, followed by rapid silica gel column chromatography to obtain the product of this example, 5 Ah, which was a yellow oily substance of 41.4 mg, with a yield of 90%. The product of this example is shown in the figure.

[0135] The NMR results of the 5ah product in this embodiment are as follows: 1 H NMR (500 MHz, CDCl3) d 7.34 – 7.30(m, 1H), 7.23 (t, J = 7.7 Hz, 2H), 7.19 (d, J = 7.7 Hz, 1H), 7.17 – 7.13 (m, 1H), 7.02 (td, J = 8.4, 2.5 Hz, 1H), 6.98 (t, J = 7.4 Hz, 1H), 6.86 (d, J= 7.5 Hz, 2H),4.80 (s, 1H), 3.74 – 3.71 (m, 4H), 3.71 (s, 3H), 3.64 – 3.61 (m, 4H), 3.47 –3.43 (m, 1H), 3.36 – 3.32 (m, 1H), 2.45 – 2.39 (m, 2H), 1.59 – 1.54 (m, 4H). 13 C NMR (125 MHz, CDCl3) d 170.8, 162.9 (d, J = 245.3 Hz), 155.2, 149.7, 139.0(d, J = 7.2 Hz), 130.1 (d, J = 8.1 Hz), 128.7, 122.7 (d, J = 2.9 Hz), 122.4, 121.4,115.6 (d, J = 21.0 Hz), 114.0 (d, J = 22.4 Hz), 80.4, 69.3, 66.8, 52.4, 48.8,32.1, 28.4, 26.7. ESI HRMS: calculated for C 24 H 29 FN2O4S [M+H] + 461.1910, found 461.1966.

[0136] Example 18

[0137] A method for preparing isothiourea, referring to route 18, includes the following steps:

[0138]

[0139] Route 18.

[0140] At room temperature, α-diazo ester 1i (0.2 mmol), phenyl isothiocyanate 2a (0.2 mmol), morpholine 3a (0.1 mmol), tetrahydrofuran 4a (12 mmol), and toluene (1 ml) were added sequentially to a 20 mL reaction tube and mixed thoroughly. The mixture was then stirred for 3 h under a 3W blue LED lamp. The reaction was monitored by TLC until completion. The mixture was then concentrated under vacuum (0.09 MPa) until solvent-free to obtain a crude product. The crude product was then washed with a mixture of petroleum ether and ethyl acetate in a volume ratio of 5:1 and subjected to rapid silica gel column chromatography to obtain product 5ai, which was a yellow oily substance of 21.2 mg, with a yield of 46%.

[0141] The NMR results of product 5ai in this embodiment are as follows: 1 H NMR (500 MHz, CDCl3) d 7.45 – 7.41(m, 1H), 7.34 – 7.30 (m, 1H), 7.24 – 7.21 (m, 2H), 7.17 – 7.14 (m, 1H), 7.09– 7.06 (m, 1H), 6.97 (t, J = 7.4 Hz, 1H), 6.86 – 6.84 (m, 2H), 5.16 (s, 1H), 3.73 – 3.71 (m, 7H), 3.63 – 3.60 (m, 4H), 3.52 – 3.48 (m, 1H), 3.37 – 3.33(m, 1H), 2.42 – 2.39 (m, 2H), 1.56 – 1.51 (m, 4H). 13 C NMR (125 MHz, CDCl3) d 170.7, 160.4 (d, J = 246.5 Hz), 155.2, 149.7, 130.4 (d, J = 8.3 Hz), 128.7, 128.7(d, J = 3.3 Hz), 124.5 (d, J = 3.6 Hz), 124.0 (d, J = 14.1 Hz), 122.4, 121.4, 115.6(d, J = 21.7 Hz), 73.9 (d, J= 3.0 Hz), 69.4, 66.8, 52.4, 48.8, 32.1, 28.4, 26.7.ESI HRMS: calculated for C 24 H 29 FN2O4S [M+H] + 461.1910, found 461.1958.

[0142] Example 19

[0143] A method for preparing isothiourea, referring to route 19, includes the following steps:

[0144]

[0145] Route 19.

[0146] At room temperature, α-diazo ester 1j (0.2 mmol), phenyl isothiocyanate 2a (0.2 mmol), morpholine 3a (0.1 mmol), tetrahydrofuran 4a (12 mmol), and toluene (1 ml) were added sequentially to a 20 mL reaction tube and mixed thoroughly. The mixture was then stirred for 3 h under a 3 W blue LED lamp. The reaction was monitored by TLC until completion. The mixture was then concentrated under vacuum (0.08 MPa) until solvent-free to obtain a crude product. The crude product was then washed with a mixture of petroleum ether and ethyl acetate in a volume ratio of 5:1 and subjected to rapid silica gel column chromatography to obtain product 5aj, a yellow oily substance of 22.8 mg, with a yield of 60%.

[0147] The NMR results of product 5aj in this embodiment are as follows: 1 H NMR (500 MHz, CDCl3) d 7.48 – 7.46(m, 1H), 7.40 – 7.38 (m, 1H), 7.29 – 7.27 (m, 2H), 7.23 (t, J = 7.8 Hz, 2H), 6.97 (t, J = 7.4 Hz, 1H), 6.85 (d, J = 7.4 Hz, 2H), 5.30 (s, 1H), 3.73 – 3.71 (m,7H), 3.63 – 3.60 (m, 4H), 3.52 – 3.49 (m, 1H), 3.37 – 3.34 (m, 1H), 2.41 –2.38 (m, 2H), 1.56 – 1.52 (m, 4H). 13 C NMR (125 MHz, CDCl3) d 170.7, 155.2,149.7, 134.6, 133.7, 129.9, 129.6, 128.7 (2C), 127.3, 122.4, 121.4, 77.2,69.5, 66.8, 52.3, 48.8, 32.1, 28.4, 26.7.ESI HRMS: calculated for C 24 H 29 ClN2O4S[M+H] + 477.1615, found 477.1656.

[0148] Example 20

[0149] A method for preparing isothiourea, referring to route 20, includes the following steps:

[0150]

[0151] Route 20.

[0152] At room temperature, α-diazo ester 1k (0.2 mmol), phenyl isothiocyanate 2a (0.2 mmol), morpholine 3a (0.1 mmol), tetrahydrofuran 4a (12 mmol), and toluene (1 ml) were added sequentially to a 20 mL reaction tube and mixed thoroughly. The mixture was then stirred for 3 h under a 3 W blue LED lamp. The reaction was monitored by TLC until completion. The mixture was then concentrated under vacuum (0.09 MPa) until solvent-free to obtain a crude product. The crude product was then washed with a mixture of petroleum ether and ethyl acetate in a volume ratio of 3:1 and subjected to rapid silica gel column chromatography to obtain the product 5ak of this example, which was a yellow oily substance of 38.0 mg, with a yield of 76%.

[0153] The NMR results of the product 5ak in this embodiment are as follows: 1 H NMR (500 MHz, CDCl3) d 8.03 (d, J = 8.1Hz, 2H), 7.50 (d, J = 8.2 Hz, 2H), 7.23 (t, J = 7.6 Hz, 2H), 6.98 (t, J = 7.4 Hz, 1H), 6.86 (d, J= 8.2 Hz, 2H), 4.86 (s, 1H), 3.92 (s, 3H), 3.74 – 3.71 (m, 4H), 3.70 (s, 3H), 3.63 – 3.60 (m, 4H), 3.50 – 3.45 (m, 1H), 3.36 – 3.32 (m, 1H), 2.44 – 2.40 (m, 2H), 1.58 – 1.54 (m, 4H). 13 C NMR (125 MHz, CDCl3) d 170.7,166.6, 155.1, 149.7, 141.4, 130.4, 129.9, 128.7, 127.0, 122.4, 121.4, 80.6,69.4, 66.8, 52.4, 52.2, 48.7, 32.1, 28.4, 26.7. ESI HRMS: calculated for C 26 H 32 N₂O₆S [M+H] + 501.2059 was found as 501.2092.

[0154] Example 21

[0155] A method for preparing isothiourea, referring to route 21, includes the following steps:

[0156]

[0157] Route 21.

[0158] At room temperature, α-diazo ester 1l (0.2 mmol), phenyl isothiocyanate 2a (0.2 mmol), morpholine 3a (0.1 mmol), tetrahydrofuran 4a (12 mmol), and toluene (1 ml) were added sequentially to a 20 mL reaction tube and mixed thoroughly. The mixture was then stirred for 3 h under a 3 W blue LED lamp. The reaction was monitored by TLC until completion. The mixture was then concentrated under vacuum (0.08 MPa) until solvent-free to obtain a crude product. The crude product was then washed with a mixture of petroleum ether and ethyl acetate in a volume ratio of 3:1 and subjected to rapid silica gel column chromatography to obtain 5a1 of the product of this example, which was 33.6 mg of a yellow oil, with a yield of 72%.

[0159] The NMR results of product 5al in this embodiment are as follows: 1 H NMR (500 MHz, CDCl3) d 7.65 (d, J= 8.1Hz, 2H), 7.54 (d, J = 8.2 Hz, 2H), 7.24 (t, J = 7.7 Hz, 2H), 7.00 - 6.97 (m, 1H), 6.86 (d, J = 7.5 Hz, 2H), 4.85 (s, 1H), 3.75 – 3.72 (m, 4H), 3.71 (s, 3H), 3.64 – 3.61 (m,4H), 3.51 – 3.48 (m, 1H), 3.35 – 3.33 (m, 1H), 2.45 – 2.41 (m, 2H),1.58-1.55 (m, 4H). 13 C NMR (125 MHz, CDCl3) d 170.3, 155.1, 149.6, 141.6, 132.4,128.7, 127.6, 122.4, 121.4, 118.5, 112.6, 80.3, 69.6, 66.8, 52.6, 48.8, 32.0,28.4, 26.6. ESI HRMS: calculated for C 25 H 29 N3O4S [M+H] + 468.1957, found 468.1988.

[0160] Example 22

[0161] A method for preparing isothiourea, referring to route 22, includes the following steps:

[0162]

[0163] Route 22.

[0164] At room temperature, α-diazo ester 1m (0.2 mmol), phenyl isothiocyanate 2a (0.2 mmol), morpholine 3a (0.1 mmol), tetrahydrofuran 4a (12 mmol), and toluene (1 ml) were added sequentially to a 20 mL reaction tube. The mixture was stirred for 3 h under a 3W blue LED lamp. The reaction was monitored by TLC until completion. The mixture was concentrated under vacuum (0.09 MPa) until solvent-free to obtain a crude product. The crude product was then washed with a mixture of petroleum ether and ethyl acetate in a volume ratio of 5:1 and subjected to rapid silica gel column chromatography to obtain the product 5am, which was a yellow oily substance of 34.1 mg, with a yield of 68%.

[0165] The NMR results of the product at 5am in this embodiment are as follows: 1 H NMR (500 MHz, CDCl3) d 8.21 (d, J = 8.8Hz, 2H), 7.62 (d, J = 8.7 Hz, 2H), 7.24 (t, J = 7.8 Hz, 2H), 6.98 (t, J = 7.4 Hz,1H), 6.88 – 6.86 (m, 2H), 4.88 (s, 1H), 4.21 – 4.15 (m, 2H), 3.75 – 3.70 (m,4H), 3.66 – 3.61 (m, 4H), 3.54 – 3.51 (m, 1H), 3.38 – 3.35 (m, 1H), 2.47 –2.41 (m, 2H), 1.61 – 1.56 (m, 4H), 1.22 (t, J = 7.1 Hz, 3H). 13 C NMR (125 MHz, CDCl3) d 169.7, 155.1, 149.6, 148.0, 143.7, 128.7, 127.7, 123.7, 122.4, 121.4,80.2, 69.6, 66.8, 61.7, 48.8, 32.1, 28.4, 26.7, 14.1. ESI HRMS: calculated for C 23 H 31 N3O6S [M+H] + 502.2012, found 502.2032.

[0166] Example 23

[0167] A method for preparing isothiourea, referring to route 23, includes the following steps:

[0168]

[0169] Route 23.

[0170] At room temperature, α-diazo ester 1o (0.2 mmol), phenyl isothiocyanate 2a (0.2 mmol), morpholine 3a (0.1 mmol), tetrahydrofuran 4a (12 mmol), and toluene (1 ml) were added sequentially to a 20 mL reaction tube and mixed thoroughly. The mixture was then stirred for 3 h under a 3W blue LED lamp. The reaction was monitored by TLC until completion. The mixture was then concentrated under vacuum (0.09 MPa) until solvent-free to obtain a crude product. The crude product was then washed with a mixture of petroleum ether and ethyl acetate in a volume ratio of 7:1 and subjected to rapid silica gel column chromatography to obtain product 5ao, which was a yellow oily substance of 45.6 mg, with a yield of 97%.

[0171] The NMR results of product 5ao in this embodiment are as follows: 1 H NMR (500 MHz, CDCl3) d 7.41 (d, J = 7.7Hz, 2H), 7.36 – 7.30 (m, 3H), 7.23 (t, J = 7.3 Hz, 2H), 6.99 – 6.96 (m 1H), 6.86 (d, J = 8.1 Hz, 2H), 5.06 – 4.99 (m, 1H), 4.75 (s, 1H), 3.74 – 3.69 (m,4H), 3.64 – 3.59 (m, 4H), 3.46 – 3.45 (m, 1H), 3.35 – 3.32 (m, 1H), 2.42 –2.40 (m, 2H), 1.56 (s, 4H), 1.23 (d, J = 6.2 Hz, 3H), 1.10 (d, J = 6.2 Hz, 3H). 13 CNMR (125 MHz, CDCl3) d 170.4, 155.3, 149.7, 136.8, 128.7, 128.5 (2C), 127.0,122.4, 121.4, 81.2, 69.0, 68.7, 66.8, 48.8, 32.2, 28.5, 26.8, 21.8, 21.5. ESIHRMS: calculated for C 26 H 34 N₂O₄S [M+H] + 471.2318, found 471.2358.

[0172] Example 24

[0173] A method for preparing isothiourea, referring to route 24, includes the following steps:

[0174]

[0175] Route 24.

[0176] At room temperature, α-diazo ester 1p (0.2 mmol), phenyl isothiocyanate 2a (0.2 mmol), morpholine 3a (0.1 mmol), tetrahydrofuran 4a (12 mmol), and toluene (1 ml) were added sequentially to a 20 mL reaction tube and mixed thoroughly. The mixture was then stirred for 3 h under a 3 W blue LED lamp. The reaction was monitored by TLC until completion. The mixture was then concentrated under vacuum (0.09 MPa) until solvent-free to obtain the crude product. The crude product was then washed with a mixture of petroleum ether and ethyl acetate in a volume ratio of 5:1 and subjected to rapid silica gel column chromatography to obtain the product 5ap of this example, which was a yellow oily substance of 49.7 mg, with a yield of 96%.

[0177] The NMR results of the product 5ap in this embodiment are as follows: 1 H NMR (500 MHz, CDCl3) d 7.42 – 7.40(m, 2H), 7.34 – 7.29 (m 6H), 7.24 – 7.19 (m, 4H), 6.97 (t, J = 7.3 Hz, 1H),6.86 – 6.85 (m, 2H), 5.17 – 5.09 (m, 2H), 4.85 – 4.84 (m, 1H), 3.73 – 3.68(m, 4H), 3.61 – 3.60 (m, 4H), 3.45 – 3.44 (m, 1H), 3.34 – 3.33 (m, 1H), 2.43 – 2.36 (m, 2H), 1.55 – 1.54 (m, 4H). 13 C NMR (125 MHz, CDCl3) d 170.7, 155.2,149.7, 136.5, 135.5, 128.7 (2C), 128.6, 128.5, 128.3, 128.0, 127.2, 122.4,121.4, 81.1, 69.1, 66.8, 66.7, 48.8, 32.2, 28.5, 26.7. ESI HRMS: calculated for C 30 H 35N₂O₄S [M+H] + 519.2318, found 519.2379.

[0178] Example 25

[0179] A method for preparing isothiourea, referring to route 25, includes the following steps:

[0180]

[0181] Route 25.

[0182] At room temperature, α-diazo ester 1r (0.2 mmol), phenyl isothiocyanate 2a (0.2 mmol), morpholine 3a (0.1 mmol), tetrahydrofuran 4a (12 mmol), and toluene (1 ml) were added sequentially to a 20 mL reaction tube and mixed thoroughly. The mixture was then stirred for 3 h under a 3W blue LED lamp. The reaction was monitored by TLC until completion. The mixture was then concentrated under vacuum (0.09 MPa) until solvent-free to obtain a crude product. The crude product was then washed with a mixture of petroleum ether and ethyl acetate in a volume ratio of 7:1 and subjected to rapid silica gel column chromatography to obtain product 5ar, a yellow oily substance of 44.3 mg, with a yield of 89%.

[0183] The NMR results of the product 5ar in this embodiment are as follows: 1 H NMR (500 MHz, CDCl3) d 7.41 (d, J = 6.8Hz, 2H), 7.36 – 7.31 (m, 3H), 7.23 (t, J = 7.7 Hz, 2H), 6.97 (t, J = 7.4 Hz, 1H), 6.86 (d, J = 8.2 Hz, 2H), 4.78 (s, 1H), 4.14 – 4.11 (m, 2H), 3.73 – 3.70 (m,4H), 3.63 – 3.59 (m, 4H), 3.46 – 3.44 (m, 1H), 3.35 – 3.32 (m, 1H), 2.45 –2.38 (m, 2H), 1.59 – 1.50 (m, 5H), 1.47 – 1.43 (m, 2H), 0.85 – 0.82 (m, 6H). 13 C NMR (125 MHz, CDCl3) d170.9, 155.2, 149.7, 136.7, 128.7, 128.6, 128.5,127.1, 122.4, 121.4, 81.1, 69.0, 66.8, 63.8, 48.8, 37.2, 32.2, 28.5, 26.7,25.0, 22.4, 22.3. ESI HRMS: calculated for C 28 H 38 N₂O₄S [M+H] + 499.2631, found 499.2684.

[0184] Example 26

[0185] A method for preparing isothiourea, referring to route 26, includes the following steps:

[0186]

[0187] Route 26.

[0188] At room temperature, α-diazo ester 1a (0.2 mmol), 4-methylphenyl isothiocyanate 2b (0.2 mmol), morpholine 3a (0.1 mmol), tetrahydrofuran 4a (12 mmol), and toluene (1 ml) were added sequentially to a 20 mL reaction tube. The mixture was stirred for 3 h under a 3 W blue LED lamp. The reaction was monitored by TLC until the reaction was complete. The mixture was then concentrated under vacuum (0.08 MPa) until solvent-free to obtain the crude product. The crude product was then washed with a mixture of petroleum ether and ethyl acetate in a volume ratio of 5:1 and subjected to rapid silica gel column chromatography to obtain the product 5ba, which was a yellow oily substance of 42.9 mg, with a yield of 94%.

[0189] The NMR results of the product 5ba in this embodiment are as follows: 1 H NMR (500 MHz, CDCl3) d 7.42 – 7.40(m, 2H), 7.38 – 7.33 (m, 3H), 7.04 (d, J = 8.2 Hz, 2H), 6.75 (d, J= 8.2 Hz, 2H),4.81 (s, 1H), 3.73 – 3.69 (m, 7H),3.61 – 3.58 (m, 4H), 3.46 – 3.43 (m, 1H),3.36 – 3.32 (m, 1H), 2.46 – 2.41 (m, 2H), 2.29 (s, 3H), 1.59 – 1.55 (m, 4H). 13 C NMR (125 MHz, CDCl3) d 171.3, 155.2, 147.1, 136.5, 131.7, 129.3, 128.7,128.6, 127.1, 121.2, 81.1, 69.1, 66.8, 52.2, 48.8, 32.2, 28.5, 26.7, 20.9.ESI HRMS: calculated for C 25 H 33 N₂O₄S [M+H] + 457.2161, found 457.2197.

[0190] Example 27

[0191] A method for preparing isothiourea, referring to route 27, includes the following steps:

[0192]

[0193] Route 27.

[0194] At room temperature, α-diazo ester 1a (0.2 mmol), 4-ethylphenyl isothiocyanate 2c (0.2 mmol), morpholine 3a (0.1 mmol), tetrahydrofuran 4a (12 mmol), and toluene (1 ml) were added sequentially to a 20 mL reaction tube. The mixture was thoroughly mixed and stirred for 3 h under a 3W blue LED lamp. The reaction was monitored by TLC until complete. The mixture was then concentrated under vacuum (0.09 MPa) until solvent-free to obtain a crude product. The crude product was then washed with a mixture of petroleum ether and ethyl acetate (5:1 v / v) as eluent, followed by rapid silica gel column chromatography to obtain product 5ca, a yellow oil, at a yield of 45.6 mg (97%). The product of this example is shown in the figure.

[0195] The NMR results of the product 5ca in this embodiment are as follows: 1 H NMR (500 MHz, CDCl3) d 7.42 – 7.41(m, 2H), 7.38 – 7.33 (m, 3H), 7.07 (d,J = 8.2 Hz, 2H), 6.78 (d, J = 8.2 Hz, 2H),4.81 (s, 1H), 3.73 – 3.70 (m, 4H), 3.70 (s, 3H), 3.62 – 3.58 (m, 4H), 3.47 –3.43 (m, 1H), 3.36 – 3.32 (m, 1H), 2.62 – 2.57 (m, 2H), 2.45 – 2.38 (m, 2H), 1.58 – 1.54 (m, 4H), 1.21 (t, J = 7.6 Hz, 3H). 13 C NMR (125 MHz, CDCl3) d 171.3,155.1, 147.2, 138.2, 136.5, 128.7, 128.6, 128.1, 127.1, 121.2, 81.1, 69.1,66.8, 52.2, 48.8, 32.2, 28.5, 28.3, 26.7, 15.7. ESI HRMS: calculated for C 26 H 35 N₂O₄S [M+H] + 471.2318, found 471.2366.

[0196] Example 28

[0197] A method for preparing isothiourea, referring to route 28, includes the following steps:

[0198]

[0199] Route 28.

[0200] At room temperature, α-diazo ester 1a (0.2 mmol), 3,5-dimethylphenyl isothiocyanate 2d (0.2 mmol), morpholine 3a (0.1 mmol), tetrahydrofuran 4a (12 mmol), and toluene (1 ml) were added sequentially to a 20 mL reaction tube. The mixture was stirred for 3 h under a 3 W blue LED lamp. The reaction was monitored by TLC until completion. The mixture was concentrated under vacuum (0.09 MPa) until solvent-free to obtain the crude product. The crude product was then washed with a mixture of petroleum ether and ethyl acetate in a volume ratio of 5:1 and subjected to rapid silica gel column chromatography to obtain product 5da, a yellow oil containing 46.1 mg, with a yield of 98%.

[0201] The NMR results of the product 5da in this embodiment are as follows: 1 H NMR (500 MHz, CDCl3) d 7.42 – 7.40(m, 2H), 7.37 – 7.32 (m, 3H), 6.63 (s, 1H), 6.48 (s, 2H), 4.81 (s, 1H), 3.72– 3.70 (m, 4H), 3.69 (s, 3H), 3.59 – 3.56 (m, 4H), 3.47 – 3.44 (m, 1H), 3.37 – 3.33 (m, 1H), 2.50 – 2.45 (m, 2H), 2.25 (s, 6H), 1.59 – 1.57 (m, 4H). 13 C NMR (125 MHz, CDCl3) d 171.3, 154.9, 149.6, 138.1, 136.6, 128.7, 128.6, 127.1,124.1, 119.1, 81.1, 69.1, 66.8, 52.2, 48.8, 32.2, 28.5, 26.8, 21.3. ESI HRMS:calculated for C 26 H 35 N₂O₄S [M+H] + 471.2318, found 471.2343.

[0202] Example 29

[0203] A method for preparing isothiourea, referring to route 29, includes the following steps:

[0204]

[0205] Route 29.

[0206] At room temperature, α-diazo ester 1a (0.2 mmol), 3-methoxyphenyl isothiocyanate 2e (0.2 mmol), morpholine 3a (0.1 mmol), tetrahydrofuran 4a (12 mmol), and toluene (1 ml) were added sequentially to a 20 mL reaction tube. The mixture was stirred for 3 h under a 3 W blue LED lamp. The reaction was monitored by TLC until completion. The mixture was concentrated under vacuum (0.09 MPa) until solvent-free to obtain a crude product. The crude product was then washed with a mixture of petroleum ether and ethyl acetate in a volume ratio of 5:1 and subjected to rapid silica gel column chromatography to obtain product 5ea, a yellow oily substance of 40.1 mg, with a yield of 85%.

[0207] The NMR results of product 5ea in this embodiment are as follows: 1 H NMR (500 MHz, CDCl3) d 7.42 – 7.40(m, 2H), 7.37 – 7.33 (m, 3H), 7.13 (t, J = 8.0 Hz, 1H), 6.56 – 6.54 (m, 1H), 6.47 – 6.43 (m, 2H), 4.81 (s, 1H), 3.76 (s, 3H), 3.73 – 3.70 (m, 4H), 3.70 (s, 3H), 3.62 – 3.59 (m, 4H), 3.47 – 3.43 (m, 1H), 3.37 – 3.33 (m, 1H), 2.48 – 2.43 (m, 2H), 1.58 – 1.57 (m, 4H). 13 C NMR (125 MHz, CDCl3) d 171.3, 160.1,155.3, 151.0, 136.5, 129.4, 128.7, 128.6, 127.1, 114.0, 108.2, 106.9, 81.0,69.0, 66.8, 55.2, 52.2, 48.8, 32.1, 28.5, 26.7. ESI HRMS: calculated forC 25 H 33 N₂O₅S [M+H] + 473.2110, found 473.2140.

[0208] Example 30

[0209] A method for preparing isothiourea, referring to route 30, includes the following steps:

[0210]

[0211] Route 30.

[0212] At room temperature, α-diazo ester 1a (0.2 mmol), 2-methoxyphenyl isothiocyanate 2f (0.2 mmol), morpholine 3a (0.1 mmol), tetrahydrofuran 4a (12 mmol), and toluene (1 ml) were added sequentially to a 20 mL reaction tube. The mixture was stirred for 3 h under a 3W blue LED lamp. The reaction was monitored by TLC until the reaction was complete. The mixture was then concentrated under vacuum (0.09 MPa) until solvent-free to obtain the crude product. The crude product was then washed with a mixture of petroleum ether and ethyl acetate in a volume ratio of 3:1 and subjected to rapid silica gel column chromatography to obtain product 5fa, a yellow oily substance, in a yield of 43.9 mg (93%).

[0213] The NMR results of the product 5fa in this embodiment are as follows: 1 H NMR (500 MHz, CDCl3) d 7.41 (d, J = 6.5Hz, 2H), 7.37 - 7.32 (m, 3H), 6.99 - 6.95 (m, 1H), 6.87 - 6.82 (m, 2H), 6.77- 6.75 (m, 1H), 4.80 (s, 1H), 3.76 (s, 3H), 3.74 – 3.70 (m, 4H), 3.69 (s,3H), 3.65 – 3.61 (m, 4H), 3.47 – 3.42 (m, 1H), 3.35 – 3.31 (m, 1H), 2.51 –2.46 (m, 2H), 1.56 – 1.55 (m, 4H). 13 C NMR (125 MHz, CDCl3) d 171.3, 156.9,150.8, 139.4, 136.5, 128.7, 128.6, 127.1, 123.3, 122.1, 120.7, 111.1, 81.0,69.1, 66.8, 55.5, 52.2, 48.8, 32.4, 28.6, 26.6. ESI HRMS: calculated forC 25 H 33 N₂O₅S [M+H] + 473.2110, found 473.2151.

[0214] Example 31

[0215] A method for preparing isothiourea, referring to route 31, includes the following steps:

[0216]

[0217] Route 31.

[0218] At room temperature, α-diazo ester 1a (0.2 mmol), 2-fluorophenyl isothiocyanate 2 g (0.2 mmol), morpholine 3a (0.1 mmol), tetrahydrofuran 4a (12 mmol), and toluene (1 ml) were added sequentially to a 20 mL reaction tube. The mixture was stirred for 3 h under a 3W blue LED lamp. The reaction was monitored by TLC until the reaction was complete. The mixture was then concentrated under vacuum (0.08 MPa) until solvent-free to obtain the crude product. The crude product was then washed with a mixture of petroleum ether and ethyl acetate in a volume ratio of 5:1 and subjected to rapid silica gel column chromatography to obtain the product 5ga, which was a yellow oily substance of 42.8 mg, with a yield of 93%.

[0219] The NMR results of the product 5ga in this embodiment are as follows: 1 H NMR (500 MHz, CDCl3) d 7.42 - 7.40(m, 2H), 7.37 - 7.33 (m, 3H), 7.02 - 6.99 (m, 2H), 6.95 - 6.91 (m, 1H), 6.89- 6.86 (m, 1H), 4.81 (s, 1H), 3.73 - 3.71 (m, 4H), 3.70 (s, 3H), 3.67 - 3.65 (m, 4H), 3.48 - 3.44 (m, 1H), 3.37 - 3.33 (m, 1H), 2.56 - 2.51 (m, 2H), 1.59 (s, 4H). 13 C NMR (125 MHz, CDCl3) d 171.3, 157.6, 153.9 (d, J = 241.8 Hz), 138.0(d, J = 12.0 Hz), 136.5, 128.7, 128.6, 127.1, 123.9 (d, J = 3.6 Hz), 123.8 (d, J =2.2 Hz), 123.2 (d, J = 7.3 Hz), 115.6 (d, J= 20.2 Hz), 81.1, 69.0, 66.7, 52.2,48.7, 32.7, 28.5, 26.6. ESI HRMS: calculated for C 24 H 30 FN2O4S [M+H] + 461.1910, found 461.1932.

[0220] Example 32

[0221] A method for preparing isothiourea, referring to route 32, includes the following steps:

[0222]

[0223] Route 32.

[0224] At room temperature, α-diazo ester 1a (0.2 mmol), 3-fluorophenyl isothiocyanate 2h (0.2 mmol), morpholine 3a (0.1 mmol), tetrahydrofuran 4a (12 mmol), and toluene (1 ml) were added sequentially to a 20 mL reaction tube. The mixture was stirred for 3 h under a 3 W blue LED lamp. The reaction was monitored by TLC until the reaction was complete. The mixture was then concentrated under vacuum (0.09 MPa) until solvent-free to obtain the crude product. The crude product was then washed with a mixture of petroleum ether and ethyl acetate in a volume ratio of 5:1 and subjected to rapid silica gel column chromatography to obtain 5 ha of the product of this example, which was 45.1 mg of a yellow oil, with a yield of 98%.

[0225] The NMR results of the 5ha product in this embodiment are as follows: 1 H NMR (500 MHz, CDCl3) d 7.42 - 7.40(m, 2H), 7.38 - 7.33 (m, 3H), 7.19 - 7.14 (m, 1H), 6.69 - 6.63 (m, 2H), 6.61- 6.58 (m, 1H), 4.81 (s, 1H), 3.73 – 3.70 (m, 4H), 3.70 (s, 3H), 3.64 – 3.61(m 4H), 3.48 – 3.44 (m, 1H), 3.37 – 3.33 (m, 1H), 2.47 – 2.42 (m, 2H), 1.59 -1.57 (m, 4H). 13 C NMR (125 MHz, CDCl3) d 171.3, 163.3 (d, J= 243.3 Hz), 155.7, 151.5 (d, J = 9.7 Hz), 136.5, 129.6 (d, J = 9.7 Hz), 128.7, 128.6, 127.1, 117.3(d, J = 2.6 Hz), 108.9 (d, J = 21.3 Hz), 108.5 (d, J = 22.2 Hz), 81.1, 69.0, 66.7,52.2, 48.7, 32.3, 28.4, 26.7. ESI HRMS: calculated for C 24 H 30 FN2O4S [M+H] + 461.1910, found 461.1953.

[0226] Example 33

[0227] A method for preparing isothiourea, referring to route 33, includes the following steps:

[0228]

[0229] Route 33.

[0230] At room temperature, α-diazo ester 1a (0.2 mmol), 4-trifluoromethylphenyl isothiocyanate 2i (0.2 mmol), morpholine 3a (0.1 mmol), tetrahydrofuran 4a (12 mmol), and toluene (1 ml) were added sequentially to a 20 mL reaction tube. The mixture was stirred for 3 h under a 3 W blue LED lamp. The reaction was monitored by TLC until the reaction was complete. The mixture was then concentrated under vacuum (0.09 MPa) until solvent-free to obtain the crude product. The crude product was then washed with a mixture of petroleum ether and ethyl acetate in a volume ratio of 5:1 and subjected to rapid silica gel column chromatography to obtain product 5ia, which was a yellow oily substance of 44.9 mg, with a yield of 88%.

[0231] The NMR results of product 5ia in this embodiment are as follows: 1 H NMR (500 MHz, CDCl3) d 7.47 (d, J = 8.4Hz, 2H), 7.42 - 7.40 (m, 2H), 7.37 - 7.33 (m, 3H), 6.93 (d, J= 8.2 Hz, 2H), 4.80 (s, 1H), 3.74 – 3.71 (m, 4H), 3.69 (s, 3H), 3.67 – 3.63 (m, 4H), 3.47 -3.43 (m, 1H), 3.36 – 3.32 (m, 1H), 2.45 – 2.39 (m, 2H), 1.59 – 1.55 (m, 4H). 13 C NMR (125 MHz, CDCl3) d 171.3, 155.8, 152.9, 136.5, 128.7, 128.6, 127.1,125.9 (q, J = 3.7 Hz), 124.70 (q, J = 271.2 Hz), 123.97 (q, J = 32.5 Hz), 121.5,81.1, 68.9, 66.7, 52.2, 48.6, 32.4, 28.4, 26.7. ESI HRMS: calculated forC 25 H 30 F3N2O4S [M+H] + 511.1878, found 511.1907.

[0232] Example 34

[0233] A method for preparing isothiourea, referring to route 34, includes the following steps:

[0234]

[0235] Route 34.

[0236] At room temperature, α-diazo ester 1a (0.2 mmol), 4-acetylphenyl isothiocyanate 2j (0.2 mmol), morpholine 3a (0.1 mmol), tetrahydrofuran 4a (12 mmol), and toluene (1 ml) were added sequentially to a 20 mL reaction tube. The mixture was stirred for 3 h under a 3 W blue LED lamp. The reaction was monitored by TLC until the reaction was complete. The mixture was then concentrated under vacuum (0.09 MPa) until solvent-free to obtain a crude product. The crude product was then washed with a mixture of petroleum ether and ethyl acetate in a volume ratio of 3:1 and subjected to rapid silica gel column chromatography to obtain product 5ja, which was a yellow oil containing 48.4 mg, with a yield of 100%.

[0237] The NMR results of the product 5ja in this embodiment are as follows: 1H NMR (500 MHz, CDCl3) d 7.87 (d, J = 8.5Hz, 2H), 7.42 - 7.40 (m, 2H), 7.37 - 7.33 (m, 3H), 6.92 (d, J = 8.5 Hz, 2H), 4.80 (s, 1H), 3.74 – 3.71 (m, 4H), 3.69 (s, 3H), 3.68 – 3.65 (m, 4H), 3.47 -3.43 (m, 1H), 3.36 – 3.33 (m, 1H), 2.56 (s, 3H), 2.45 – 2.38 (m, 2H), 1.60 -1.54 (m, 4H). 13 C NMR (125 MHz, CDCl3) d 197.2, 171.3, 155.5, 154.5, 136.5,131.2, 129.6, 128.7, 128.6, 127.1, 121.3, 81.0, 68.9, 66.7, 52.2, 48.6, 32.3,28.4, 26.6, 26.4. ESI HRMS: calculated for C 26 H 33 N₂O₅S [M+H] + 485.2110, found 485.2146.

[0238] Example 35

[0239] A method for preparing isothiourea, referring to route 35, includes the following steps:

[0240]

[0241] Route 35.

[0242] At room temperature, α-diazo ester 1a (0.2 mmol), phenyl isothiocyanate 2a (0.2 mmol), diethylamine 3b (0.1 mmol), tetrahydrofuran 4a (12 mmol), and toluene (1 ml) were added sequentially to a 20 mL reaction tube and mixed thoroughly. The mixture was then stirred for 3 h under a 3 W blue LED lamp. The reaction was monitored by TLC until completion. The mixture was then concentrated under vacuum (0.09 MPa) until solvent-free to obtain a crude product. The crude product was then washed with a mixture of petroleum ether and ethyl acetate in a volume ratio of 10:1 and subjected to rapid silica gel column chromatography to obtain the product of this example, 5 kDa, which was 36.4 mg of a yellow oil, with a yield of 85%.

[0243] The NMR results of the product at 5 ka in this embodiment are as follows: 1 H NMR (500 MHz, CDCl3) d 7.41 (d, J = 6.7Hz, 2H), 7.37 – 7.32 (m, 3H), 7.20 (t, J = 7.7 Hz, 2H), 6.93 – 6.87 (m, 3H), 4.80 (s, 1H), 3.70 (s, 3H), 3.57 – 3.53 (m, 4H), 3.43 – 3.39 (m, 1H), 3.32 -3.28 (m, 1H), 2.31 – 2.25 (m, 2H), 1.54 – 1.48 (m, 4H), 1.18 (t, J = 7.0 Hz, 6H). 13 C NMR (125 MHz, CDCl3) d ESI HRMS:calculated for C 24 H 32 N₂O₃S [M+H] + 429.2212, found 429.2248.

[0244] Example 36

[0245] A method for preparing isothiourea, referring to route 36, includes the following steps:

[0246]

[0247] Route 36.

[0248] At room temperature, α-diazo ester 1a (0.2 mmol), phenyl isothiocyanate 2a (0.2 mmol), piperidine 3c (0.1 mmol), tetrahydrofuran 4a (12 mmol), and toluene (1 ml) were added sequentially to a 20 mL reaction tube and mixed thoroughly. The mixture was then stirred for 3 h under a 3 W blue LED lamp. The reaction was monitored by TLC until completion. The mixture was then concentrated under vacuum (0.09 MPa) until solvent-free to obtain a crude product. The crude product was then washed with a mixture of petroleum ether and ethyl acetate in a volume ratio of 5:1 and subjected to rapid silica gel column chromatography to obtain product 5a, a yellow oily substance of 35.7 mg, with a yield of 81%.

[0249] The NMR results of product 5la in this embodiment are as follows: 1 H NMR (500 MHz, CDCl3) d 7.42 (d, J = 7.6Hz, 2H), 7.37 – 7.32 (m, 3H), 7.21 (t, J = 7.4 Hz, 2H), 6.96 - 6.93 (m 1H), 6.85 - 6.83 (m, 2H), 4.81 (s, 1H), 3.69 (d, J = 0.8 Hz, 3H), 3.58 – 3.56 (m,4H), 3.47 – 3.43 (m, 1H), 3.36 – 3.32 (m, 1H), 2.45 – 2.40 (m, 2H), 1.64 -1.58 (m, 10H). 13 C NMR (125 MHz, CDCl3) d 171.3, 155.6, 150.3, 136.6, 128.7,128.6, 128.6, 127.1, 121.9, 121.6, 81.0, 69.1, 52.2, 49.4, 32.2, 28.5, 26.7,26.0, 25.0. ESI HRMS: calculated for C 25 H 33 N₂O₃S [M+H] + 441.2212, found 441.2231.

[0250] Example 37

[0251] A method for preparing isothiourea, referring to route 37, includes the following steps:

[0252]

[0253] Route 37.

[0254] At room temperature, α-diazo ester 1a (0.2 mmol), phenyl isothiocyanate 2a (0.2 mmol), 4-methylpiperidine 3d (0.1 mmol), tetrahydrofuran 4a (12 mmol), and toluene (1 ml) were added sequentially to a 20 mL reaction tube. The mixture was thoroughly mixed and stirred for 3 h under a 3W blue LED lamp. The reaction was monitored by TLC until complete. The mixture was then concentrated under vacuum (0.09 MPa) until solvent-free to obtain a crude product. The crude product was then washed with a mixture of petroleum ether and ethyl acetate (5:1 v / v) as eluent, followed by rapid silica gel column chromatography. The product of this example, 5 mg, was obtained as a yellow oil, 42.2 mg, with a yield of 93%. The product of this example is shown in the figure.

[0255] The NMR results of the 5 mA product in this embodiment are as follows: 1 H NMR (500 MHz, CDCl3) d 7.42 (d, J = 6.7Hz, 2H), 7.37 – 7.34 (m, 3H), 7.21 (t, J = 7.6 Hz, 2H), 6.95 (t, J = 7.3 Hz, 1H), 6.84 (d, J = 7.8 Hz, 2H), 4.81 (s, 1H), 4.29 (d, J = 13.1 Hz, 2H), 3.70 (s, 3H), 3.47 - 3.42 (m, 1H), 3.36 - 3.32 (m, 1H), 2.86 (t, J = 12.6 Hz, 2H), 2.47 –2.39 (m, 2H), 1.67 (d, J = 13.0 Hz, 2H), 1.59 – 1.57 (m, 4H), 1.25 – 1.15 (m,3H), 0.97 (d, J = 6.5 Hz, 3H). 13 C NMR (125 MHz, CDCl3) d171.3, 155.5, 150.3,136.6, 128.7, 128.6, 128.6, 127.1, 121.9, 121.6, 81.0, 69.1, 52.2, 48.7,34.3, 32.2, 31.5, 28.5, 26.6, 21.8. ESI HRMS: calculated for C 26 H 34 N₂O₃S [M+H] + 455.2368, found 455.2384.

[0256] Example 38

[0257] A method for preparing isothiourea, referring to route 38, includes the following steps:

[0258]

[0259] Route 38.

[0260] At room temperature, α-diazo ester 1a (0.2 mmol), phenyl isothiocyanate 2a (0.2 mmol), 2,6-dimethylmorpholine 3e (0.1 mmol), tetrahydrofuran 4a (12 mmol), and toluene (1 ml) were added sequentially to a 20 mL reaction tube. The mixture was stirred for 3 h under a 3W blue LED lamp. The reaction was monitored by TLC until the reaction was complete. The mixture was then concentrated under vacuum (0.09 MPa) until solvent-free to obtain the crude product. The crude product was then washed with a mixture of petroleum ether and ethyl acetate in a volume ratio of 5:1 and subjected to rapid silica gel column chromatography to obtain the product 5na, which was a yellow oily substance of 35.7 mg, with a yield of 76%.

[0261] The NMR results of the product 5na in this embodiment are as follows: 1 H NMR (500 MHz, CDCl3) d 7.41 (d, J = 6.6Hz, 2H), 7.36 – 7.33 (m, 3H), 7.23 (t, J = 7.8 Hz, 2H), 6.97 (t, J = 7.4 Hz, 1H), 6.85 (d, J = 7.6 Hz, 2H), 4.81 (s, 1H), 4.17 (d, J= 12.9 Hz, 2H), 3.69 (s, 3H), 3.67 – 3.63 (m, 2H), 3.45 – 3.42 (m, 1H), 3.34 – 3.31 (m, 1H), 2.66 – 2.61(m, 2H), 2.42 – 2.36 (m, 2H), 1.56 – 1.54 (m, 4H), 1.21 (d, J = 6.2 Hz, 6H). 13 CNMR (125 MHz, CDCl3) d 171.3, 154.8, 149.8, 136.5, 128.7, 128.7, 128.6, 127.1,122.3, 121.5, 81.0, 71.7, 69.0, 53.8, 52.2, 32.2, 28.5, 26.7, 18.8. ESI HRMS:calculated for C 26 H 34 N₂O₄S [M+H] + 471.2318, found 471.2330.

[0262] Example 39

[0263] A method for preparing isothiourea, referring to route 39, includes the following steps:

[0264]

[0265] Route 39.

[0266] At room temperature, α-diazo ester 1a (0.2 mmol), phenyl isothiocyanate 2a (0.2 mmol), N-isopropylcyclohexylamine 3f (0.1 mmol), tetrahydrofuran 4a (12 mmol), and toluene (1 ml) were added sequentially to a 20 mL reaction tube. The mixture was stirred for 3 h under a 3W blue LED lamp. The reaction was monitored by TLC until the reaction was complete. The mixture was then concentrated under vacuum (0.09 MPa) until solvent-free to obtain the crude product. The crude product was then washed with a mixture of petroleum ether and ethyl acetate in a volume ratio of 15:1 and subjected to rapid silica gel column chromatography to obtain product 5oa of this example, which was 26.8 mg of a yellow oil, with a yield of 54%.

[0267] The NMR results of product 5oa in this embodiment are as follows: 1 H NMR (500 MHz, CDCl3) d 7.41 (d, J= 6.8Hz, 2H), 7.37 – 7.32 (m, 3H), 7.19 (t, J = 7.8 Hz, 2H), 6.89 – 6.86 (m, 3H), 4.80 (s, 1H), 4.15 – 4.09 (m, 1H), 3.84 – 3.80 (m, 1H), 3.70 (s, 3H), 3.42 –3.38 (m, 1H), 3.31 - 3.27 (m, 1H), 2.29 - 2.22 (m, 2H), 1.96 - 1.90 (m, 2H), 1.81 - 1.75 (m, 2H), 1.74 - 1.67 (m, 2H), 1.63 - 1.57 (m, 1H), 1.53 – 1.45(m, 4H), 1.33(d, J = 6.7 Hz, 6H), 1.30 – 1.24 (m, 2H), 1.13 – 1.06 (m, 1H). 13 CNMR (125 MHz, CDCl3) d 171.4, 152.1, 150.0, 136.6, 128.6, 128.6, 128.6, 127.1,121.3, 120.7, 81.0, 69.1, 59.0, 52.2, 50.0, 31.8, 31.75, 28.6, 26.4, 26.2,25.5, 21.5. ESI HRMS: calculated for C 29 H 40 N₂O₃S [M+H] + 497.2838, found 497.2888.

[0268] Example 40

[0269] A method for preparing isothiourea, referring to route 40, includes the following steps:

[0270]

[0271] Route 40.

[0272] At room temperature, α-diazo ester 1a (0.2 mmol), phenyl isothiocyanate 2a (0.2 mmol), N-methyl-1-phenylethylamine 3g (0.1 mmol), tetrahydrofuran 4a (12 mmol), and toluene (1 ml) were added sequentially to a 20 mL reaction tube. The mixture was stirred for 3 h under a 3 W blue LED lamp. The reaction was monitored by TLC until the reaction was complete. The mixture was then concentrated under vacuum (0.09 MPa) until solvent-free to obtain the crude product. The crude product was then washed with a mixture of petroleum ether and ethyl acetate in a volume ratio of 10:1 and subjected to rapid silica gel column chromatography to obtain the product 5 Pa, which was a yellow oily substance of 45.2 mg, with a yield of 95%.

[0273] The NMR results of the product at 5 Pa in this embodiment are as follows: 1 H NMR (500 MHz, CDCl3) d 7.42 - 7.40(m, 2H), 7.36 - 7.32 (m, 5H), 7.29 - 7.26 (m 3H), 7.22 (t, J = 7.8 Hz, 2H),6.96 - 6.92 (m, 3H), 4.80 (s, 2H), 4.79 (s, 1H), 3.69 (s, 3H), 3.42 - 3.38(m, 1H), 3.31 - 3.27 (m, 1H), 3.03 (s, 3H), 2.38 – 2.31 (m, 2H), 1.51 – 1.48(m, 4H). 13 C NMR (125 MHz, CDCl3) d 171.3, 154.7, 150.0, 138.2, 136.6, 128.7,128.7, 128.6, 128.6, 127.4, 127.2, 127.1, 121.8, 121.6, 81.0, 69.1, 55.5,52.2, 37.7, 32.0, 28.4, 26.5. ESI HRMS: calculated for C 28 H 33 N₂O₃S [M+H] + 477.2212, found 477.2246.

[0274] Example 41

[0275] A method for preparing isothiourea, referring to route 41, includes the following steps:

[0276]

[0277] Route 41.

[0278] At room temperature, α-diazo ester 1a (0.2 mmol), phenyl isothiocyanate 2a (0.2 mmol), morpholine 3a (0.1 mmol), tetrahydropyran 4b (12 mmol), and toluene (1 ml) were added sequentially to a 20 mL reaction tube. The mixture was thoroughly mixed and stirred for 3 h under a 3W blue LED lamp. The reaction was monitored by TLC until complete. The mixture was then concentrated under vacuum (0.09 MPa) until solvent-free to obtain a crude product. The crude product was then washed with a mixture of petroleum ether and ethyl acetate (5:1 v / v) as eluent and subjected to rapid silica gel column chromatography to obtain product 5qa, a yellow oily substance, in a yield of 21.4 mg (47%). The product of this example is shown in the figure.

[0279] The NMR results of product 5qa in this embodiment are as follows: 1 H NMR (500 MHz, CDCl3) d 7.44 - 7.42(m, 2H), 7.38-7.33 (m, 3H), 7.23 (t, J = 7.8 Hz, 2H), 6.98 (t, J = 7.4 Hz, 1H), 6.86 (d, J = 7.5 Hz, 2H), 4.83 (s, 1H), 3.74 – 3.71 (m, 4H), 3.70 (s, 3H), 3.63– 3.60 (m, 4H), 3.49 – 3.45 (m, 1H), 3.39 – 3.34 (m, 1H), 2.40 – 2.36 (m,2H), 1.57 – 1.54 (m, 2H), 1.46 – 1.43 (m, 2H), 1.31 – 1.28 (m, 2H). 13 C NMR (125 MHz, CDCl3) d 171.4, 155.4, 149.7, 136.6, 128.7 (2C), 128.6, 127.1, 122.4,121.4, 81.1, 69.6, 66.8, 52.2, 48.8, 32.3, 29.8, 29.0, 25.1. ESI HRMS:calculated for C 25 H 33 N₂O₄S [M+H] + 457.2161, found 457.2186.

[0280] Example 42

[0281] A method for preparing isothiourea, referring to route 42, includes the following steps:

[0282]

[0283] Route 42.

[0284] At room temperature, α-diazo ester 1a (0.2 mmol), phenyl isothiocyanate 2a (0.2 mmol), morpholine 3a (0.1 mmol), 2,5-dihydrofuran 4c (12 mmol), and toluene (1 ml) were added sequentially to a 20 mL reaction tube. The mixture was stirred for 3 h under a 3W blue LED lamp. The reaction was monitored by TLC until completion. The mixture was then concentrated under vacuum (0.09 MPa) until solvent-free to obtain a crude product. The crude product was then washed with a mixture of petroleum ether and ethyl acetate in a volume ratio of 5:1 and subjected to rapid silica gel column chromatography to obtain the product 5ra, which was a yellow oil containing 15.4 mg, with a yield of 35%.

[0285] The NMR results of the product 5ra in this embodiment are as follows: 1 H NMR (500 MHz, CDCl3) d 7.42 - 7.40(m, 2H), 7.38 - 7.35 (m, 3H), 7.22 (t, J = 7.8 Hz, 2H), 6.98 (t, J = 7.4 Hz, 1H), 6.84 (d, J = 7.5 Hz, 2H), 5.67 - 5.63 (m, 1H), 5.54 - 5.49 (m, 1H), 4.83 (s,1H), 3.98 - 3.93 (m, 2H), 3.70 - 3.69 (m, 7H), 3.59 (t, J = 4.7 Hz, 4H), 3.06(d, J = 7.9 Hz, 2H). 13 C NMR (125 MHz, CDCl3) d171.0, 152.0, 147.6, 136.1, 128.9,128.8, 128.7, 128.7, 128.5, 127.3, 122.5, 121.5, 80.1, 66.7, 64.5, 52.3,48.7, 29.3. ESI HRMS: calculated for C 24 H 29 N₂O₄S [M+H] + 441.1848, found 441.1840.

[0286] Example 43

[0287] The antiproliferative activity of the novel S-alkyl isothiourea compound prepared in this invention against tumor cells was detected using a CCK-8 assay kit.

[0288] Experimental methods (1) Cell lines: Lung cancer cell line: NCI-H460; Colorectal cancer cell line: Colo-205.

[0289] (2) Experimental reagents: 1640 cell culture medium (gibco), PBS buffer, EDTA-0.25% trypsin, fetal bovine serum, penicillin-streptomycin mixture, CCK8 kit, DMSO solvent, etc.

[0290] (3) Experimental steps: The effect of the novel S-alkyl isothiourea compound prepared in this invention on tumor cell proliferation was detected using the CCK-8 kit: Logarithmic growth phase cells were digested with trypsin containing 0.25% and prepared into a single-cell suspension with complete culture medium (gibco) containing 10% FBS. 5000 cells per well were seeded in 96-well plates and incubated overnight in a constant temperature incubator at 37°C and 5% CO2. Different concentrations (50, 25, 12.5, 6.25, 3.13, 1.56, 0.78, 0.39 M) of the compound (compound 5aa prepared in Example 1 of this invention, compounds 5ab-5la prepared in Examples 11-42) were added to the cells for culture. Sorafenib was used as a positive control, and a DMSO group (containing 0.1% DMSO) was set up as a negative control. A cell-free group was used as a blank control. Each group had three replicates. After 48 h of incubation, 20 μL of CCK8 reagent was added. After 3 h, the absorbance of each well at 450 nm and 650 nm was measured using a microplate reader, and the IC50 was calculated. 50 .

[0291] Experimental results

[0292] The results are shown in the table below: The values ​​in the table represent the half-maximal inhibitory concentrations (IC50) of compound 5aa prepared in Example 1 and compounds (5ab-5la) prepared in Examples 11-42 after 48 h of action on tumor cells. 50 The half-maximal inhibitory concentration (IC50) of the compounds on cells was compared with that of the positive control sorafenib (Sora). The results showed that the S-alkyl isothiourea compounds synthesized in this invention have a certain inhibitory effect on both lung cancer cells and colorectal cancer cells. Among them, the inhibitory effects of compounds 5ag, 5ar, 5ia and 5na on tumor cells were comparable to those of the positive control sorafenib (Sora).

[0293] The compound's IC50 on tumor cells 50

[0294]

[0295] The above description merely illustrates several embodiments of the present invention and should not be construed as limiting the scope of the present invention. It should be noted that those skilled in the art can make modifications, substitutions, and improvements without departing from the concept and scope of the present invention, and these all fall within the protection scope of the present invention. Therefore, the patent protection scope of the present invention should be determined by the described claims.

Claims

1. The application of an S-alkylisothiourea in the preparation of an antitumor drug, characterized in that, The tumors are lung cancer and colorectal cancer; The structural formula of the S-alkylisothiourea is: , , or .

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