A method for preparing cyanamide and thiols

Abstract

This invention belongs to the technical field of organic synthesis and discloses a method for preparing cyanamide and thiols. The method involves reacting arylthiourea with a haloalkane in the presence of a base or a base and a copper salt using an aprotic organic solvent as the reaction medium to obtain cyanamide and thiols; the structure of the arylthiourea is Formula IV, and the structure of the cyanamide is Formula I. The method of this invention is simple to operate, operates under mild conditions, and can rapidly and efficiently obtain structurally diverse cyanamide and thiols, exhibiting high functional group compatibility.

Description

Technical Field

[0001] This invention belongs to the field of organic chemical synthesis, specifically relating to a one-pot synthesis method for preparing cyanamide and thiols. Background Technology

[0002] Cyanamide is a compound containing N-CN functional groups. Cyanamide compounds contain a nucleophilic nitrogen atom and an electrophilic cyano functional group attached to that nitrogen atom, exhibiting unique chemical properties. Therefore, these compounds can be further transformed into structurally diverse nitrogen-containing compounds in organic synthesis. Cyanamide has important applications in both medicinal chemistry and coordination chemistry.

[0003] For the preparation of substituted cyanamides, N-electropeptidating reagents such as cyanogen bromide (BrCN) are widely used to cyano-modify amines. However, cyanogen bromide is a highly toxic chemical; its vapor can enter the human body through the respiratory tract or be absorbed through the skin, causing convulsions or death. Therefore, preparing cyanogen bromide in situ and directly cyano-modifying it can reduce the toxicity of this hazardous chemical to humans. Safe electrophilic cyano-modifying reagents can also be developed to effectively obtain substituted cyanamides. Nucleophilic substitution of cyanamides using nucleophilic reagents is also an effective method for preparing substituted cyanamides. All of the above methods require a cyano source (an electrophilic cyano reagent or a substrate containing a cyanamine group), thus limiting the diversity of substrates for this type.

[0004] Patel et al. (A one-pot preparation of cyanamide from dithiocarbamate using molecular iodine, Green Chem., 2009, 11, 1503-1506) disclosed a method for preparing cyanamide derivatives by desulfurizing dithiocarbamates with iodine, achieving moderate to excellent yields, and producing only N-arylcyanamides. However, this reaction is relatively cumbersome, requiring the removal of excess NH3 under reduced pressure in the first step before proceeding to the second step. This one-pot, two-step process makes the method inconvenient and unsuitable for large-scale production. Doris et al. (Triphenylbismuth Dichloride-Mediated Conversion of Thioamides to Nitriles, Eur. J. Org. Chem. 2019, 4043-4045) studied a method using triphenylbismuth dichloride-assisted desulfurization, which can convert thioamides to cyanides and thioureas to cyanamides. However, the amount of triphenylbismuth dichloride used is 1.2 equivalents of the substrate, which greatly increases the cost and is not conducive to subsequent processing and purification.

[0005] Sulfur-containing compounds also have important applications in organic chemistry and medicinal chemistry. Currently, there are not many reported methods for preparing thiols.

[0006] Overall, while there are some existing methods for preparing cyanamide, many safety and environmental issues remain. Furthermore, the use of reagents such as precious metals leads to high costs, and the increase in waste materials causes serious environmental problems.

[0007] Therefore, developing simple and mild synthetic methods to construct structurally diverse substituted cyanamides using readily available compounds as substrates remains a highly challenging research topic. Summary of the Invention

[0008] To overcome the shortcomings and deficiencies of existing technologies, the present invention aims to provide a method for the simultaneous preparation of cyanamides and thiols. This invention employs a one-pot method, using arylthiourea as the cyano and mercapto source substrates, and reacts with haloalkanes to obtain structurally diverse substituted cyanamides and thiols. This method is simple to operate, operates under mild conditions, and has high functional group compatibility, providing important technical support for the efficient synthesis of cyanamides and thiols with potential biological and pharmacological activities.

[0009] This invention is achieved through the following technical solution:

[0010] A method for preparing cyanamide and thiols includes the following steps:

[0011] Using an aprotic organic solvent as the reaction medium, arylthiourea reacts with haloalkanes under the action of a base or a base and a copper salt to obtain cyanamide and thiol.

[0012] The structure of arylthiourea is Formula IV:

[0013] The structure of haloalkanes is shown in formula V:

[0014] The structure of the cyanamide is as shown in Formula I:

[0015]

[0016] The structure of the thiol is Formula II:

[0017] In each formula, R 1 It is at least one of hydrogen, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, tert-butyl, phenyl, benzyl, methoxy, methylthio, benzyloxy, fluorine, chlorine, bromine, iodine, trifluoromethyl, trifluoromethoxy, acetyl, cyano, nitro, and ester; the dashed line in Formula IV indicates that the cyclic structure is phenyl or naphthyl;

[0018] In the haloalkanes, X is Cl, Br, or I, where R 2 R' represents hydrogen, methyl, ethyl, 2-propyl, cyclopentyl, cyclohexyl, benzyl, substituted benzyl, phenyl, substituted phenyl, phenethyl, phenylpropyl, styryl, 1-naphthyl, 2-naphthyl, haloalkyl, lactenyl, terminal lactenyl, terminal alkynyl, etc. R' represents at least one of vinyl, methyl, ethyl, 1-propyl, 1-butyl, and benzyl. Lactenyl refers to an alkyl group in which the carbon atom is replaced by a C=C substitution.

[0019] When the structure of the halohydrocarbon is When the cyanamide has a structure where R is H; when the haloalkane has a structure of... In this case, R in the structure of the cyanamide is R'.

[0020] The substituted phenyl group includes one or more substituted phenyl groups containing halogen, alkyl, alkoxy, trifluoromethyl, or acetyl groups; the substituted benzyl group refers to a benzene ring in which one or more hydrogen atoms are substituted by halogen or alkyl groups.

[0021] The molar ratio of the arylthiourea to the haloalkanes is 1:2 to 3, preferably 1:2.1 to 2.5, and even more preferably 1:2.4 to 2.5.

[0022] The alkali is an inorganic alkali. In this invention, the alkali includes one or more of the following: lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, lithium methoxide, sodium methoxide, potassium methoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, and cesium bicarbonate; preferably one or more of sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, and cesium carbonate; more preferably one or more of sodium carbonate and potassium carbonate.

[0023] The molar ratio of the arylthiourea to the base is 1:2 to 4, preferably 1:2.4 to 3, and even more preferably 1:2.5.

[0024] The copper salt includes one or more of CuCl, CuI, CuBr, CuCl2, Cu(OAc)2, Cu(OH)2, Cu(OTf)2, CuTc, and Cu(NO3)2; preferably one or more of cuprous chloride, copper chloride, copper hydroxide, and basic copper bromide; more preferably copper hydroxide.

[0025] The molar ratio of the copper salt to the arylthiourea is 1:1 to 100, more preferably 1:10 to 100, and even more preferably 1:10 to 20.

[0026] The aprotic organic solvent includes one or more of acetonitrile (MeCN), toluene, dimethyl sulfoxide (DMSO), hexamethylphosphoric triamine (HMPA), dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), tetrahydrofuran (THF), 1,4-dioxane, and acetone, more preferably one or more of dimethyl sulfoxide, dimethylformamide, dimethylacetamide, and 1,4-dioxane, and even more preferably one or more of dimethyl sulfoxide and dimethylformamide.

[0027] The reaction can be carried out in an air atmosphere. The reaction temperature is 80–150°C, more preferably 90–130°C, and even more preferably 110–125°C. After the reaction is complete, dilute hydrochloric acid is added, and the mixture is extracted with ethyl acetate. The organic phases are combined, dried, filtered, concentrated under reduced pressure, and then purified by column chromatography.

[0028] Preparation of arylthiourea IV: Aromatic amine III is mixed evenly with ammonium thiocyanate, dilute hydrochloric acid is added, the mixture is heated to reflux, cooled, and water is added to precipitate the solid. After filtration, the solid is dried to obtain arylthiourea IV. This compound does not require further purification and can be used directly in subsequent reactions.

[0029] The structure of aromatic amine III is The structure of ammonium thiocyanate is HSCN·NH3.

[0030] The molar ratio of aromatic amine III to ammonium thiocyanate is 1:(1.5-2.5); the molar ratio of aromatic amine III to hydrochloric acid is 1:2-4; the reaction temperature is 95-105℃; the reaction time is 1-15 hours; and the concentration of the dilute hydrochloric acid is 1.5-2.5M. The reaction equation for the method of this invention is as follows:

[0031]

[0032] Compared with the prior art, the present invention has the following beneficial effects and advantages:

[0033] (1) The present invention provides a method for synthesizing substituted cyanamide compounds using arylthiourea and haloalkanes. The required raw materials are readily available, the reaction has high atom economy, good adaptability to functional groups, and a wide range of applicable substrates.

[0034] (2) The method of the present invention is simple to operate, safe and low in cost, and has extremely high conversion rate and selectivity, and has high industrialization value. Attached Figure Description

[0035] Figure 1 and Figure 2 The images are the hydrogen NMR spectrum and carbon NMR spectrum of the product obtained in Example 1, respectively.

[0036] Figure 3 and Figure 4 The images are the 1H NMR spectrum and 1C NMR spectrum of the product 3aa obtained in Examples 5-10, respectively.

[0037] Figure 5 and Figure 6 The images are the 1H NMR spectrum and 1C NMR spectrum of product 4a obtained in Examples 5-10, respectively.

[0038] Figure 7 and Figure 8 The images are the hydrogen NMR spectrum and carbon NMR spectrum of product 3ab obtained in Example 11, respectively.

[0039] Figure 9 and Figure 10 These are the 1H NMR spectrum and 1C NMR spectrum of product 4b obtained in Example 11, respectively.

[0040] Figure 11 and Figure 12 These are the hydrogen NMR spectrum and carbon NMR spectrum of product 3af obtained in Example 15, respectively.

[0041] Figure 13 and Figure 14 These are the hydrogen NMR spectrum and carbon NMR spectrum of product 4f obtained in Example 15, respectively.

[0042] Figure 15 and Figure 16 The images are the hydrogen NMR spectrum and carbon NMR spectrum of the product 3ha obtained in Example 27, respectively.

[0043] Figure 17 , Figure 18 and Figure 19 These are the 1H NMR spectrum, 1C NMR spectrum, and fluorine NMR spectrum of product 3ja obtained in Example 29. Detailed Implementation

[0044] The present invention will be further described in detail below with reference to the embodiments, but the implementation and protection of the present invention are not limited thereto. Examples 1-4 are examples of methods for synthesizing arylthiourea; Examples 5-36 are examples of one-pot simultaneous preparation of cyanamide and thiol.

[0045] Example 1: Preparation of phenylthiourea

[0046]

[0047] In a 50 mL round-bottom flask containing a PTFE-coated magnetic stirrer, 1.0 g (10.74 mmol) of aniline, 1.63 g (21.48 mmol) of ammonium thiocyanate and 11 mL of dilute hydrochloric acid (2.0 M) were added sequentially. The mixture was heated under reflux for 12 hours, cooled to room temperature, diluted with water, filtered, and the resulting white solid was collected. After drying, 1.50 g (92%) of the desired phenylthiourea was obtained. 1 H NMR (400MHz, CDCl3) δ8.51 (s, 1H), 7.45 (t, J = 8.0Hz, 2H), 7.34 (tt, J = 7.6, 1.2Hz, 1H), 7.30-7.23 (m, 1H); 13 C NMR (101 MHz, CDCl3) δ 181.4, 136.4, 130.2, 127.7, 125.1. Proton and carbon spectra are shown below. Figure 1 and 2 As shown.

[0048] Example 2: Preparation of 3,5-dimethylphenylthiourea

[0049]

[0050] In a 50 mL round-bottom flask containing a PTFE-coated magnetic stirrer, 1.0 g (8.25 mmol) of 3,5-dimethylaniline, 1.26 g (16.50 mmol) of ammonium thiocyanate, and 10 mL of dilute hydrochloric acid (2.0 M) were added sequentially. The mixture was heated under reflux for 12 hours, cooled to room temperature, diluted with water, filtered, and the resulting white solid was collected. After drying, 1.350 g (87%) of the desired 3,5-dimethylphenylthiourea was obtained.

[0051] 1 H NMR (400MHz, DMSO-d6) δ9.55(s,1H),6.96(s,2H),6.77(s,1H),2.24(s,6H); 13 CNMR(101MHz,DMSO-d6)δ181.2,139.1,138.3,126.6,121.3,21.4.

[0052] Example 3: Preparation of 2,4-dichlorophenylthiourea

[0053]

[0054] In a 50 mL round-bottom flask containing a PTFE-coated magnetic stirrer, 1.0 g (6.17 mmol) of 2,4-dichloroaniline, 0.940 g (12.34 mmol) of ammonium thiocyanate, and 7 mL of dilute hydrochloric acid (2.0 M) were added sequentially. The mixture was heated under reflux for 12 hours, cooled to room temperature, diluted with water, filtered, and the resulting white solid was collected. After drying, 1.20 g (88%) of the desired 2,4-dichlorophenylthiourea was obtained.

[0055] 1 H NMR (400MHz, DMSO-d6) δ9.34(s,1H),7.68(d,J=8.8Hz,1H),7.65(d,J=2.4Hz,1H),7.40(dd,J=8.8,2.4Hz,1H); 13 C NMR (101MHz, DMSO-d6) δ182.6,135.8,131.0,130.9,130.7,129.3,127.8.

[0056] Example 4: Preparation of 2,5-dimethoxyphenylthiourea

[0057]

[0058] In a 50 mL reaction vessel containing a PTFE-coated magnetic stir bar, 1.0 g (6.53 mmol) of 2,5-dimethoxyaniline, 0.993 g (13.06 mmol) of ammonium thiocyanate, and 7 mL of dilute hydrochloric acid (2.0 M) were added sequentially. The mixture was heated under reflux for 12 hours, cooled to room temperature, diluted with water, filtered to collect the resulting white solid, and dried to obtain 1.12 g (81%) of the desired 2,5-dimethoxyphenylthiourea.

[0059] 1 H NMR (400MHz, CDCl3) δ7.81 (s, 1H), 6.95 (d, J = 2.8Hz, 1H), 6.92 (d, J = Hz, 1H), 6.78 (dd, J = 8.8, 2.8Hz, 1H); 13 C NMR (101MHz, CDCl3) δ182.6,135.8,131.0,130.9,130.7,129.3,127.8.

[0060] Example 5

[0061]

[0062] Phenylacetylthiourea 1a (30.4 mg, 0.2 mmol), 2-chloroethylbenzene 2a (67.5 mg, 0.48 mmol), sodium carbonate (69.1 mg, 0.5 mmol), Cu(OH)₂ (1 mg), and DMSO (0.5 mL) were added to a reaction tube. A PTFE-coated magnetic stir bar was used, and the reaction was carried out at 120 °C for 1 hour with a rotation speed of 500 rpm. After stirring was stopped, dilute hydrochloric acid solution (2 M, 10 mL) was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried over anhydrous magnesium sulfate. The mixture was filtered, concentrated under reduced pressure, and then purified by column chromatography to obtain the target product. The yield of 3aa was 95%, and the yield of 4a was 79%.

[0063] 3aa: 1 H NMR (400MHz, CDCl3) δ7.42-7.30(m,4H),7.29-7.20(m,3H),7.15-7.04(m,3H),3.84-3.76(m,2H),3.15-3.06(m,2H); 13 C NMR(101MHz, CDCl3)δ139.8,136.9,129.7,128.9,128.8,127.1,123.7,116.0,113.4,50.9,33.8; HRMS(ESI)[M+H] + Calcd.forC 15 H 15 N2,223.1230; found,223.1226.

[0064] 4a: 1 H NMR (400MHz, CDCl3) δ7.37-7.26(m,2H),7.25-7.15(m,3H),3.04-2.96(m,2H),2.96-2.88(m,2H); 13 C NMR(101MHz, CDCl3)δ140.1,128.6,128.6,126.4,40.2,35.8; HRMS(ESI)[M+H] + Calcd.for C8H 11 S, 139.0576; found, 139.0572.

[0065] Example 6

[0066]

[0067] Phenylacetylthiourea 1a (30.4 mg, 0.2 mmol), 2-chloroethylbenzene 2a (67.5 mg, 0.48 mmol), potassium carbonate (0.5 mmol), Cu(OH)₂ (1 mg), and DMSO (0.5 mL) were added to a reaction tube. A magnetic stir bar wrapped with polytetrafluoroethylene was used, and the reaction was carried out at 120 °C for 1 hour with a rotation speed of 500 rpm. After stirring was stopped, dilute hydrochloric acid solution (2 M, 10 mL) was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried over anhydrous magnesium sulfate. The mixture was filtered, concentrated under reduced pressure, and then purified by column chromatography to obtain the target product. The yield of 3aa was 97%, and the yield of 4a was 70%.

[0068] 3aa: 1 H NMR (400MHz, CDCl3) δ7.42-7.30(m,4H),7.29-7.20(m,3H),7.15-7.04(m,3H),3.84-3.76(m,2H),3.15-3.06(m,2H); 13 C NMR(101MHz, CDCl3)δ139.8,136.9,129.7,128.9,128.8,127.1,123.7,116.0,113.4,50.9,33.8; HRMS(ESI)[M+H] + Calcd.forC 15 H 15 N2,223.1230; found,223.1226.

[0069] 4a: 1 H NMR (400MHz, CDCl3) δ7.37-7.26(m,2H),7.25-7.15(m,3H),3.04-2.96(m,2H),2.96-2.88(m,2H); 13 C NMR(101MHz, CDCl3)δ140.1,128.6,128.6,126.4,40.2,35.8; HRMS(ESI)[M+H] + Calcd.for C8H 11 S, 139.0576; found, 139.0572.

[0070] Example 7

[0071]

[0072] Phenylacetyl thiourea 1a (30.4 mg, 0.2 mmol), 2-chloroethylbenzene 2a (67.5 mg, 0.48 mmol), cesium carbonate (0.5 mmol), Cu(OH)₂ (1 mg), and DMSO (0.5 mL) were added to a reaction tube. A PTFE-coated magnetic stir bar was used, and the reaction was carried out at 120 °C for 1 hour with a rotation speed of 500 rpm. After stirring was stopped, dilute hydrochloric acid solution (2 M, 10 mL) was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried over anhydrous magnesium sulfate. The mixture was filtered, concentrated under reduced pressure, and then purified by column chromatography to obtain the target product. The yield of 3aa was 72%, and the yield of 4a was 50%.

[0073] 3aa: 1 H NMR (400MHz, CDCl3) δ7.42-7.30(m,4H),7.29-7.20(m,3H),7.15-7.04(m,3H),3.84-3.76(m,2H),3.15-3.06(m,2H); 13 C NMR(101MHz, CDCl3)δ139.8,136.9,129.7,128.9,128.8,127.1,123.7,116.0,113.4,50.9,33.8; HRMS(ESI)[M+H] + Calcd.forC 15 H 15 N2,223.1230; found,223.1226.

[0074] 4a: 1 H NMR (400MHz, CDCl3) δ7.37-7.26(m,2H),7.25-7.15(m,3H),3.04-2.96(m,2H),2.96-2.88(m,2H); 13 C NMR(101MHz, CDCl3)δ140.1,128.6,128.6,126.4,40.2,35.8; HRMS(ESI)[M+H] + Calcd.for C8H 11 S, 139.0576; found, 139.0572.

[0075] Example 8

[0076]

[0077] Phenylacetylthiourea 1a (30.4 mg, 0.2 mmol), 2-chloroethylbenzene 2a (67.5 mg, 0.48 mmol), potassium bicarbonate (0.5 mmol), Cu(OH)₂ (1 mg), and DMSO (0.5 mL) were added to a reaction tube. A magnetic stir bar wrapped with polytetrafluoroethylene was used, and the reaction was carried out at 120 °C for 1 hour with a rotation speed of 500 rpm. After stirring was stopped, dilute hydrochloric acid solution (2 M, 10 mL) was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried over anhydrous magnesium sulfate. The mixture was filtered, concentrated under reduced pressure, and then purified by column chromatography to obtain the target product. The yield of 3aa was 92%, and the yield of 4a was 79%.

[0078] 3aa: 1 H NMR (400MHz, CDCl3) δ7.42-7.30(m,4H),7.29-7.20(m,3H),7.15-7.04(m,3H),3.84-3.76(m,2H),3.15-3.06(m,2H); 13 C NMR(101MHz, CDCl3)δ139.8,136.9,129.7,128.9,128.8,127.1,123.7,116.0,113.4,50.9,33.8; HRMS(ESI)[M+H] + Calcd.forC 15 H 15 N2,223.1230; found,223.1226.

[0079] 4a: 1 H NMR (400MHz, CDCl3) δ7.37-7.26(m,2H),7.25-7.15(m,3H),3.04-2.96(m,2H),2.96-2.88(m,2H); 13 C NMR(101MHz, CDCl3)δ140.1,128.6,128.6,126.4,40.2,35.8; HRMS(ESI)[M+H] + Calcd.for C8H 11 S, 139.0576; found, 139.0572.

[0080] Example 9

[0081]

[0082] Phenylacetylthiourea 1a (30.4 mg, 0.2 mmol), 2-chloroethylbenzene 2a (67.5 mg, 0.48 mmol), sodium bicarbonate (0.5 mmol), Cu(OH)₂ (1 mg), and DMSO (0.5 mL) were added to a reaction tube. A magnetic stir bar wrapped with polytetrafluoroethylene was used, and the reaction was carried out at 120 °C for 1 hour with a rotation speed of 500 rpm. After stirring was stopped, dilute hydrochloric acid solution (2 M, 10 mL) was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried over anhydrous magnesium sulfate. The mixture was filtered, concentrated under reduced pressure, and then purified by column chromatography to obtain the target product. The yield of 3aa was 90%, and the yield of 4a was 75%.

[0083] 3aa: 1 H NMR (400MHz, CDCl3) δ7.42-7.30(m,4H),7.29-7.20(m,3H),7.15-7.04(m,3H),3.84-3.76(m,2H),3.15-3.06(m,2H); 13 C NMR(101MHz, CDCl3)δ139.8,136.9,129.7,128.9,128.8,127.1,123.7,116.0,113.4,50.9,33.8; HRMS(ESI)[M+H] + Calcd.forC 15 H 15 N2,223.1230; found,223.1226.

[0084] 4a: 1 H NMR (400MHz, CDCl3) δ7.37-7.26(m,2H),7.25-7.15(m,3H),3.04-2.96(m,2H),2.96-2.88(m,2H); 13 C NMR(101MHz, CDCl3)δ140.1,128.6,128.6,126.4,40.2,35.8; HRMS(ESI)[M+H] + Calcd.for C8H 11 S, 139.0576; found, 139.0572.

[0085] Example 10

[0086]

[0087] Phenylacetylthiourea 1a (30.4 mg, 0.2 mmol), 2-chloroethylbenzene 2a (67.5 mg, 0.48 mmol), lithium hydroxide (0.5 mmol), Cu(OH)₂ (1 mg), and DMSO (0.5 mL) were added to a reaction tube. A magnetic stir bar wrapped with polytetrafluoroethylene was used, and the reaction was carried out at 120 °C for 1 hour with a rotation speed of 500 rpm. After stirring was stopped, dilute hydrochloric acid solution (2 M, 10 mL) was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried over anhydrous magnesium sulfate. The mixture was filtered, concentrated under reduced pressure, and then purified by column chromatography to obtain the target product. The yield of 3aa was 58%, and the yield of 4a was 44%.

[0088] 3aa: 1 H NMR (400MHz, CDCl3) δ7.42-7.30(m,4H),7.29-7.20(m,3H),7.15-7.04(m,3H),3.84-3.76(m,2H),3.15-3.06(m,2H); 13 C NMR(101MHz, CDCl3)δ139.8,136.9,129.7,128.9,128.8,127.1,123.7,116.0,113.4,50.9,33.8; HRMS(ESI)[M+H] + Calcd.forC 15 H 15 N2,223.1230; found,223.1226.

[0089] 4a: 1 H NMR (400MHz, CDCl3) δ7.37-7.26(m,2H),7.25-7.15(m,3H),3.04-2.96(m,2H),2.96-2.88(m,2H); 13 C NMR(101MHz, CDCl3)δ140.1,128.6,128.6,126.4,40.2,35.8; HRMS(ESI)[M+H] + Calcd.for C8H 11 S, 139.0576; found, 139.0572.

[0090] Figure 3 and Figure 4 The images are the 1H NMR spectrum and 1C NMR spectrum of the product 3aa obtained in Examples 5-10, respectively. Figure 5 and Figure 6 These are the hydrogen NMR spectrum and carbon NMR spectrum of product 4a obtained in Examples 5-10, respectively.

[0091] Example 11

[0092]

[0093] Phenylacetide 1a (30.4 mg, 0.2 mmol), 1-chloro-4-(2-chloroethyl)benzene 2b (0.48 mmol), sodium carbonate (0.5 mmol), Cu(OH)₂ (1 mg), and DMSO (0.5 mL) were added to a reaction tube. A PTFE-coated magnetic stir bar was used, and the reaction was carried out at 120 °C for 1 hour with a rotation speed of 500 rpm. After stirring was stopped, dilute hydrochloric acid solution (2 M, 10 mL) was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried over anhydrous magnesium sulfate. The mixture was filtered, concentrated under reduced pressure, and then purified by column chromatography to obtain the target product. The yield of 3ab was 91%, and the yield of 4b was 76%.

[0094] 3ab: 1 H NMR (400MHz, CDCl3) δ7.38(d,J=7.6Hz,1H),7.36(d,J=7.6Hz,1H),7.29(d,J=8.4Hz,2H) ,7.17(d,J=8.4Hz,2H),7.14-7.06(m,3H),3.79(t,J=7.2Hz,2H),3.08(t,J=7.2Hz,2H); 13 C NMR(101MHz, CDCl3)δ139.7,135.4,133.0,130.2,129.8,129.0,123.9,116.1,113.3,50.7,33.1; HRMS(ESI)[M+H] + Calcd.for C 15 H 14 ClN2,257.0840; found,257.0836.

[0095] 4b: 1 H NMR (400MHz, CDCl3) δ7.26 (d, J = 8.4Hz, 2H), 7.11 (d, J = 8.4Hz, 2H), 2.98-2.92 (m, 2H), 2.91-2.84 (m, 2H); 13 C NMR(100MHz, CDCl3)δ138.3,132.3,130.0,128.7,39.9,34.9; HRMS(ESI)[M+H] + Calcd.for C8H 10 ClS,173.0186; found,173.0184.

[0096] Figure 7 and Figure 8The images are the hydrogen NMR spectrum and carbon NMR spectrum of product 3ab obtained in Example 11, respectively. Figure 9 and Figure 10 These are the hydrogen NMR spectrum and carbon NMR spectrum of product 4b obtained in Example 11, respectively.

[0097] Example 12

[0098]

[0099] Phenylacetide 1a (30.4 mg, 0.2 mmol), 1-fluoro-4-(2-chloroethyl)benzene 2c (0.48 mmol), sodium carbonate (0.5 mmol), Cu(OH)₂ (1 mg), and DMSO (0.5 mL) were added to a reaction tube. A magnetic stir bar wrapped with polytetrafluoroethylene was used, and the reaction was carried out at 120 °C for 1 hour with a rotation speed of 500 rpm. After stirring was stopped, dilute hydrochloric acid solution (2 M, 10 mL) was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried over anhydrous magnesium sulfate. The mixture was filtered, concentrated under reduced pressure, and then purified by column chromatography to obtain the target product. The yield of 3ac was 68%, and the yield of 4c was 59%.

[0100] 3ac: 1 H NMR (400MHz, CDCl3) δ7.42-7.33(m,2H),7.23-7.16(m,2H),7.14-7.06(m,3H),7.04-6.98(m,2H),3.79(t,J=7.6Hz,2H),3.08(t,J=7.6Hz,2H); 13 C NMR(101MHz,CDCl3)δ162.0(d,J C-F =245.5Hz), 139.7, 132.6 (d, J) C-F =3.3Hz), 130.4(d,J C-F =8.0Hz),129.78,123.83,116.05,115.8(d,J C-F =21.4Hz),113.38,50.90,50.89,32.96; 19 F NMR (376MHz, CDCl3) δ-115.5 (tt, J = 8.8, 5.3Hz); HRMS (ESI) [M+H] + Calcd.for C 15 H 14 FN2,241.1136; found,241.1132.

[0101] 4c: 1H NMR (400MHz, CDCl3) δ7.15(d,J=5.2Hz,1H),7.12(d,J=5.2Hz,1H),6.98(d,J=8.8Hz,2H),6.96(d,J=8.8Hz,2H),2.99-2.92(m,2H),2.92-2.85(m,2H); 13 C NMR(101MHz,CDCl3)δ161.6(d,J C-F =244.3Hz), 135.6(d,J) C-F =3.3Hz), 130.0(d,J C-F =7.9Hz), 115.3(d,J C-F =21.3Hz), 40.2, 34.80; 19 F NMR (376MHz, CDCl3) δ-116.6 (ddd, J=14.1, 8.7, 5.1Hz); HRMS (ESI) [M+H] - Calcd.for C8H8FS,155.0335; found,155.0326.

[0102] Example 13

[0103]

[0104] Phenylacetyl thiourea 1a (30.4 mg, 0.2 mmol), 4-fluorobutylbenzene 2d (0.48 mmol), sodium carbonate (0.5 mmol), Cu(OH)₂ (1 mg), and DMSO (0.5 mL) were added to a reaction tube. A magnetic stir bar wrapped with polytetrafluoroethylene was used, and the reaction was carried out at 120 °C for 1 hour with a stirring speed of 500 rpm. After stirring was stopped, dilute hydrochloric acid solution (2 M, 10 mL) was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried over anhydrous magnesium sulfate. The mixture was filtered, concentrated under reduced pressure, and then purified by column chromatography to obtain the target product. The yield of 3ad was 95%, and the yield of 4d was 95%.

[0105] 3ad: 1 H NMR (400MHz, CDCl3) δ7.42-7.33(m,2H),7.33-7.27(m,2H),7.24-7.16(m,2H),7.14-7.06( m,3H),3.56(t,J=7.2Hz,2H),2.69(t,J=7.2Hz,2H),1.94-1.84(m,2H),1.84-1.74(m,2H); 13C NMR(101MHz, CDCl3)δ141.5,140.0,129.7,128.5,128.4,126.1,123.6,115.9,113.7,77.4,77.1,76.8,49.3,35.3,28.2,27; HRMS(ESI)[M+H] + Calcd.forC 17 H 19 N2,251.1543; found,251.1537.

[0106] 4d: 1 H NMR (400MHz, CDCl3) δ7.33-7.27(m,2H),7.23-7.14(m,3H),2.73-2.67(m,2H),2.67-2.60(m,2H),1.80-1.65(m,4H); 13 C NMR(101MHz, CDCl3)δ142.1,128.4,128.4,128.4,125.8,39.0,35.5,30.2,28.8; HRMS(ESI)[MH] - Calcd.for C 10 H 13 S, 165.0743; found, 165.0734.

[0107] Example 14

[0108]

[0109] Phenylacetyl thiourea 1a (30.4 mg, 0.2 mmol), benzyl chloride 2e (0.48 mmol), sodium carbonate (0.5 mmol), Cu(OH)₂ (1 mg), and DMSO (0.5 mL) were added to a reaction tube. A PTFE-coated magnetic stir bar was used, and the reaction was carried out at 120 °C for 1 hour with a rotation speed of 500 rpm. After stirring was stopped, dilute hydrochloric acid solution (2 M, 10 mL) was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried over anhydrous magnesium sulfate. The mixture was filtered, concentrated under reduced pressure, and then purified by column chromatography to obtain the target product. The yield of 3ae was 81%, and the yield of 4e was 99%.

[0110] 3ae: 1 H NMR (400MHz, CDCl3) δ7.45-7.37(m,4H),7.37-7.30(m,3H),7.18-7.12(m,2H),7.12-7.06(m,1),4.80(s,1H); 13C NMR(101MHz, CDCl3)δ139.8,134.3,129.7,129.1,128.6,127.4,123.7,116.1,114.0,53.7; HRMS(ESI)[M+H] + Calcd.for C 14 H 13 N2,209.1073; found,209.1069.

[0111] 4e: 1 H NMR (400MHz, CDCl3) δ7.40-7.10(m,5H),3.77(d,J=7.6Hz,2H),1.78(t,J=7.6Hz,1H); 13 C NMR(101MHz, CDCl3)δ141.2,128.7,128.0,127.1,29.0; HRMS(ESI)[MH] - Calcd.for C7H7S,123.0274; found,123.0262.

[0112] Example 15

[0113]

[0114] Phenylacetide 1a (30.4 mg, 0.2 mmol), 1,3-dichloro-2-chloromethylbenzene 2f (0.48 mmol), sodium carbonate (0.5 mmol), Cu(OH)₂ (1 mg), and DMSO (0.5 mL) were added to a reaction tube. A magnetic stir bar wrapped with polytetrafluoroethylene was used, and the reaction was carried out at 120 °C for 1 hour with a rotation speed of 500 rpm. After stirring was stopped, dilute hydrochloric acid solution (2 M, 10 mL) was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried over anhydrous magnesium sulfate. The mixture was filtered, concentrated under reduced pressure, and then purified by column chromatography to obtain the target product. The yield of 3af was 99%, and the yield of 4f was 97%.

[0115] 3af: 1 H NMR (400MHz, CDCl3) δ7.44-7.34(m,4H),7.27(dd,J=8.8,7.2Hz,1H),7.25-7.20(m,2H),7.23(tt,J=7.2,1.2Hz,1H),4.93(s,2H); 13 C NMR(101MHz, CDCl3)δ140.3,137.3,131.3,129.7,129.0,128.8,124.2,116.6,112.1,48.1; HRMS(ESI)[M+H]+ Calcd.for C 14 H 11 C l2 N2,277.0294; found,277.0290.

[0116] 4f: 1 H NMR (400MHz, CDCl3) δ7.28 (d, J = 8.0Hz, 2H), 7.11 (t, J = 8.0Hz, 1H), 4.18 (s, 2H); 13 C NMR(101MHz, CDCl3)δ135.7,134.4,128.7,128.4,32.4; HRMS(ESI)[M+H] + Calcd.for C7H5C l2 S, 190.9494; found, 190.9487.

[0117] Figure 11 and Figure 12 These are the hydrogen NMR spectrum and carbon NMR spectrum of product 3af obtained in Example 15, respectively. Figure 13 and Figure 14 The images are the hydrogen NMR spectrum and carbon NMR spectrum of product 4f obtained in Example 15, respectively.

[0118] Example 16

[0119]

[0120] Phenylacetyl thiourea 1a (30.4 mg, 0.2 mmol), cinnamyl chloride 2 g (0.48 mmol), sodium carbonate (0.5 mmol), Cu(OH)₂ (1 mg), and DMSO (0.5 mL) were added to a reaction tube. A PTFE-coated magnetic stir bar was used, and the reaction was carried out at 120 °C for 1 hour with a stirring speed of 500 rpm. After stirring was stopped, dilute hydrochloric acid solution (2 M, 10 mL) was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried over anhydrous magnesium sulfate. The mixture was filtered, concentrated under reduced pressure, and then purified by column chromatography to obtain the target product. The yield was 40% for 3 g and 40% for 4 g.

[0121] 3ag: 1 H NMR (400MHz, CDCl3) δ7.45-7.27(m,7H),7.23-7.17(m,2H),7.17-7.10(m,1H),6.75 (dt,J=16.0,1.6Hz,1H),6.33(dt,J=16.0,6.4Hz,1H),4.41(dd,J=6.4,1.6Hz,2H); 13C NMR(101MHz, CDCl3)δ139.8,135.7,135.2,129.7,128.7,128.4,126.8,123.7,121.1,116.0,113.6,52.0; HRMS(ESI)[M+H] + Calcd.for C 16 H 15 N2,235.1230; found,235.1225.

[0122] 4g: 1 H NMR (400MHz, CDCl3) δ7.44-7.32(m,4H),7.31-7.25(m,1H),6.47(d,J=15.6Hz,1H),6.22(dt,J=15.6,7.2Hz,1H),3.34(dd,J=7.6,1.2Hz,2H); 13 C NMR(101MHz, CDCl3)δ136.8,132.5,128.6,127.6,126.3,126.0,33.2; HRMS(ESI)[MH] - Calcd.forC9H9S,149.0430; found,149.0420.

[0123] Example 17

[0124]

[0125] Phenylacetide 1a (30.4 mg, 0.2 mmol), compound 2h (0.48 mmol), sodium carbonate (0.5 mmol), Cu(OH)₂ (1 mg), and DMSO (0.5 mL) were added to a reaction tube. A PTFE-coated magnetic stir bar was used, and the reaction was carried out at 120 °C for 1 hour with a stirring speed of 500 rpm. After stirring was stopped, dilute hydrochloric acid solution (2 M, 10 mL) was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried over anhydrous magnesium sulfate. The mixture was filtered, concentrated under reduced pressure, and then purified by column chromatography to obtain the target product. The yield was 78% at 3 h and 74% at 4 h.

[0126] 3ah: 11H NMR (400 MHz, CDCl3) δ 7.43 - 7.35 (m, 2H), 7.35 - 7.22 (m, 4H), 7.16 - 7.05 (m, 3H), 6.69 (ddd, J = 17.6, 6.8, 1.6 Hz, 1H), 5.75 (dt, J = 17.6, 1.2 Hz, 1H), 5.27 (ddd, J = 10.8, 4.4, 0.8 Hz, 1H), 4.78 (d, J = 4.8 Hz, 2H); 13 13C NMR (101 MHz, CDCl3) δ 139.8, 139.8, 138.5, 137.9, 136.2, 136.1, 134.7, 133.7, 129.7, 129.7, 129.3, 127.6, 126.9, 126.6, 126.3, 125.2, 123.8, 116.1, 116.0, 114.9, 114.7, 113.9, 77.4, 77.1, 76.8, 53.7, 53.5; HRMS (ESI) [M + H] + Calcd. for C 16 H 15 N2, 235.1230; found, 235.1225.

[0127] 4h: 1 1H NMR (400 MHz, CDCl3) δ 7.39 - 7.33 (m, 1H), 7.32 - 7.14 (m, 3H), 6.70 (ddd, J = 17.6, 10.8, 3.2 Hz, 1H), 5.74 (dd, J = 17.6, 2.8 Hz, 1H), 5.24 (ddd, J = 10.8, 6.8, 0.8 Hz, 1H), 3.61 - 3.55 (m, 2H); 13 13C NMR (101 MHz, CDCl3) δ 138.3, 137.8, 137.7, 136.7, 136.7, 136.5, 136.4, 129.2, 128.7, 128.5, 128.5, 126.9, 126.3, 125.0, 124.9, 114.1, 114.1, 113.7, 77.4, 77.0, 76.7, 35.5, 35.5, 35.4, 35.3; HRMS (ESI) [M - H] - Calcd. for C9H9S, 149.0430; found, 149.0420.

[0128] Example 18

[0129]

[0130] Phenylacetide 1a (30.4 mg, 0.2 mmol), benzyl bromide 2i (0.48 mmol), sodium carbonate (0.5 mmol), Cu(OH)₂ (1 mg), and DMSO (0.5 mL) were added to a reaction tube. A PTFE-coated magnetic stir bar was used, and the reaction was carried out at 120 °C for 1 hour with a stirring speed of 500 rpm. After stirring was stopped, dilute hydrochloric acid solution (2 M, 10 mL) was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried over anhydrous magnesium sulfate. The mixture was filtered, concentrated under reduced pressure, and then purified by column chromatography to obtain the target product. The yield of 3ai was 56%, and the yield of 4i was 58%.

[0131] 3ai: 1 H NMR (400MHz, CDCl3) δ7.45-7.37(m,4H),7.37-7.30(m,3H),7.18-7.12(m,2H),7.12-7.06(m,1),4.80(s,1H); 13 C NMR(101MHz, CDCl3)δ139.8,134.3,129.7,129.1,128.6,127.4,123.7,116.1,114.0,53.7; HRMS(ESI)[M+H] + Calcd.for C 14 H 13 N2,209.1073; found,209.1069.

[0132] 4i: 1 H NMR (400MHz, CDCl3) δ7.40-7.10(m,5H),3.77(d,J=7.6Hz,2H),1.78(t,J=7.6Hz,1H); 13 C NMR(101MHz, CDCl3)δ141.2,128.7,128.0,127.1,29.0; HRMS(ESI)[MH] - Calcd.for C7H7S,123.0274; found,123.0262.

[0133] Example 19

[0134]

[0135] Phenylacetyl thiourea 1a (30.4 mg, 0.2 mmol), iodomethane 2j (0.48 mmol), sodium carbonate (0.5 mmol), Cu(OH)2 (1 mg), and DMSO (0.5 mL) were added to a reaction tube. A PTFE-coated magnetic stir bar was used, and the reaction was carried out at 120 °C for 1 hour with a rotation speed of 500 rpm. After stirring was stopped, dilute hydrochloric acid solution (2 M, 10 mL) was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried over anhydrous magnesium sulfate. The mixture was filtered, concentrated under reduced pressure, and then purified by column chromatography to obtain the target product, 3aj, with a yield of 70%.

[0136] 3aj: 1 H NMR (400MHz, CDCl3) δ7.42-7.34(m,2H),7.16-7.05(m,3H),3.34(s,3H); 13 C NMR(101MHz, CDCl3)δ140.4,129.6,123.4,114.9,114.1,36.8; HRMS(ESI)[M+H] + Calcd.for C8H9N2,133.0760; found,133.0759.

[0137] Example 20

[0138]

[0139] Phenylacetyl thiourea 1a (30.4 mg, 0.2 mmol), 1-iodopropane 2k (0.48 mmol), sodium carbonate (0.5 mmol), Cu(OH)2 (1 mg), and DMSO (0.5 mL) were added to a reaction tube. A PTFE-coated magnetic stir bar was used, and the reaction was carried out at 120 °C for 1 hour with a stirring speed of 500 rpm. After stirring was stopped, dilute hydrochloric acid solution (2 M, 10 mL) was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried over anhydrous magnesium sulfate. The mixture was filtered, concentrated under reduced pressure, and then purified by column chromatography to obtain the target product with a yield of 70% for 3ak.

[0140] 3ak: 1 H NMR (400MHz, CDCl3) δ7.42-7.32(m,2H),7.14-7.05(m,3H),3.55(t,J=7.2Hz,2H),1.86(tq,J=7.6,7.2Hz,2H),1.06(t,J=7.6Hz,3H); 13 C NMR(101MHz, CDCl3)δ140.1,129.7,123.5,115.9,51.1,20.9,11.1; HRMS(ESI)[M+H]+ Calcd.for C 10 H 13 N2,161.1073; found,161.1070.

[0141] Example 21

[0142]

[0143] 1-(2'-methylphenyl)thiourea 1b (0.2 mmol), 2-chloroethylbenzene 2a (0.48 mmol), sodium carbonate (0.5 mmol), Cu(OH)₂ (1 mg), and DMSO (0.5 mL) were added to a reaction tube. A PTFE-coated magnetic stir bar was used, and the reaction was carried out at 120 °C for 1 hour with a rotation speed of 500 rpm. After stirring was stopped, dilute hydrochloric acid solution (2 M, 10 mL) was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried over anhydrous magnesium sulfate. The mixture was filtered, concentrated under reduced pressure, and then purified by column chromatography to obtain the target products. The yield of 3ba was 54%, and the yield of 4a was 70%.

[0144] 3ba: 1 H NMR (400MHz, CDCl3) δ7.36-7.27(m,2H),7.26-7.16(m,6H),7.13-7.06(m,1H),3.70-3.60(m,2H),3.10-3.00(m,2H),2.26(s,3H); 13 C NMR(101MHz, CDCl3)δ139.2,137.2,134.0,131.8,128.9,128.8,127.7,127.3,127.0,124.6,115.4,55.1,34.2,17.7; HRMS(ESI)[M+H] + Calcd.for C 16 H 17 N2,237.1386; found,237.1381.

[0145] Example 22

[0146]

[0147] 1-(2'-chlorophenyl)thiourea 1c (0.2 mmol), 2-chloroethylbenzene 2a (0.48 mmol), sodium carbonate (0.5 mmol), Cu(OH)₂ (1 mg), and DMSO (0.5 mL) were added to a reaction tube. A PTFE-coated magnetic stir bar was used, and the reaction was carried out at 120 °C for 1 hour with a rotation speed of 500 rpm. After stirring was stopped, dilute hydrochloric acid solution (2 M, 10 mL) was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried over anhydrous magnesium sulfate. The mixture was filtered, concentrated under reduced pressure, and then purified by column chromatography to obtain the target product. The yield of 3ca was 80%, and the yield of 4a was 81%.

[0148] 3ca: 1 H NMR (400MHz, CDCl3) δ7.47-7.40(m,1H),7.34-7.28(m,2H),7.27-7.16(m,6H),3.76-3.67(m,2H),3.12-3.05(m,2H); 13 C NMR(101MHz, CDCl3)δ137.8,137.0,131.1,130.5,128.9,128.9,128.8,128.1,127.0,126.9,114.7,55.3,34.2; HRMS(ESI)[M+H] + Calcd.for C 15 H 14 ClN2,257.0840; found,257.0833.

[0149] Example 23

[0150]

[0151] 1-(3'-methylphenyl)thiourea 1d (0.2 mmol), 2-chloroethylbenzene 2a (0.48 mmol), sodium carbonate (0.5 mmol), Cu(OH)2 (1 mg), and DMSO (0.5 mL) were added to a reaction tube. A PTFE-coated magnetic stir bar was used, and the reaction was carried out at 120 °C for 1 hour with a rotation speed of 500 rpm. After stirring was stopped, dilute hydrochloric acid solution (2 M, 10 mL) was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried over anhydrous magnesium sulfate. The mixture was filtered, concentrated under reduced pressure, and then purified by column chromatography to obtain the target product. The yield of 3da was 92%, and the yield of 4a was 70%.

[0152] 3da: 1H NMR (400MHz, CDCl3) δ7.39-7.30(m,2H),7.30-7.16(m,3H),6.95-6.84(m,2H),3.84-3.72(m,2H),3.17-3.03(m,2H),2.34(s,3H); 13 C NMR(101MHz, CDCl3)δ139.9,139.8,137.0,129.5,128.9,128.8,127.1,124.6,116.9,113.6,113.0,50.9,33.8,21.6; HRMS(ESI)[M+H] + Calcd.for C 16 H 17 N2,237.1386; found,237.1381.

[0153] Example 24

[0154]

[0155] 1-(4'-methylphenyl)thiourea 1e (0.2 mmol), 2-chloroethylbenzene 2a (0.48 mmol), sodium carbonate (0.5 mmol), Cu(OH)₂ (1 mg), and DMSO (0.5 mL) were added to a reaction tube. A PTFE-coated magnetic stir bar was used, and the reaction was carried out at 120 °C for 1 hour with a rotation speed of 500 rpm. After stirring was stopped, dilute hydrochloric acid solution (2 M, 10 mL) was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried over anhydrous magnesium sulfate. The mixture was filtered, concentrated under reduced pressure, and then purified by column chromatography to obtain the target product. The yield of 3ea was 63%, and the yield of 4a was 77%.

[0156] 3ea: 1 H NMR (400MHz, CDCl3) δ7.40-7.32(m,2H),7.32-7.24(m,3H),7.22-7.16(m, 2H),7.06-6.98(m,2H),3.85-3.76(m,2H),3.17-3.07(m,2H),2.35(s,3H); 13 C NMR(101MHz, CDCl3)δ137.4,137.0,133.5,130.2,128.9,128.8,127.1,116.3,113.8,51.2,33.8,20.6; HRMS(ESI)[M+H] + Calcd.for C 16 H 17 N2,237.1386; found,237.1382.

[0157] Example 25

[0158]

[0159] 1-(4'-phenylphenyl)thiourea 1f (0.2 mmol), 2-chloroethylbenzene 2a (0.48 mmol), sodium carbonate (0.5 mmol), Cu(OH)₂ (1 mg), and DMSO (0.5 mL) were added to a reaction tube. A PTFE-coated magnetic stir bar was used, and the reaction was carried out at 120 °C for 1 hour with a rotation speed of 500 rpm. After stirring was stopped, dilute hydrochloric acid solution (2 M, 10 mL) was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried over anhydrous magnesium sulfate. The mixture was filtered, concentrated under reduced pressure, and then purified by column chromatography to obtain the target product. The yield of 3fa was 68%, and the yield of 4a was 73%.

[0160] 3fa: 1 H NMR (400MHz, CDCl3) δ7.63-7.53(m,4H),7.46-7.40(m,2H),7.38-7.30(m,2H) ,7.30-7.22(m,2H),7.19-7.12(m,2H),3.90-3.78(m,2H),3.20-3.08(m,2H); 13 C NMR(101MHz, CDCl3)δ139.9,139.0,136.9,136.8,128.9,128.9,128.8,128.3,127.4,127.2,126.8,116.4,113.4,51.0,33.8; HRMS(ESI)[M+H] + Calcd.for C 21 H 19 N2,299.1543; found,299.1537.

[0161] Example 26

[0162]

[0163] 1 g (0.2 mmol) of 1-(4'-methoxyphenyl)thiourea, 0.48 mmol of 2-chloroethylbenzene 2a, 0.5 mmol of sodium carbonate, 1 mg of Cu(OH)2, and 0.5 mL of DMSO were added to a reaction tube. A magnetic stir bar wrapped with polytetrafluoroethylene was used, and the reaction was carried out at 120 °C for 1 hour with a stirring speed of 500 rpm. After stirring was stopped, dilute hydrochloric acid solution (2 M, 10 mL) was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried over anhydrous magnesium sulfate. The mixture was filtered, concentrated under reduced pressure, and then purified by column chromatography to obtain the target product. The yield of 3ga was 98%, and the yield of 4a was 79%.

[0164] 3ga: 1 H NMR (400MHz, CDCl3) δ7.39-7.22(m,5H),7.08-7.02(m,2H),6.95-6.88(m,2H),3.81(s,3H),3.80-3.74(m,2H),3.14-3.06(m,2H); 13 C NMR(101MHz, CDCl3)δ156.4,137.1,133.2,128.9,128.8,127.1,118.5,115.0,114.4,55.6,52.0,33.9; HRMS(ESI)[M+H] + Calcd.for C 16 H 17 N2O,253.1335; found,253.1330.

[0165] Example 27

[0166]

[0167] 1-(4'-bromophenyl)thiourea 1h (0.2 mmol), 2-chloroethylbenzene 2a (0.48 mmol), sodium carbonate (0.5 mmol), Cu(OH)2 (1 mg), and DMSO (0.5 mL) were added to a reaction tube. A PTFE-coated magnetic stir bar was used, and the reaction was carried out at 120 °C for 1 hour with a rotation speed of 500 rpm. After stirring was stopped, dilute hydrochloric acid solution (2 M, 10 mL) was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried over anhydrous magnesium sulfate. The mixture was filtered, concentrated under reduced pressure, and then purified by column chromatography to obtain the target product. The yield of 3ha was 61%, and the yield of 4a was 82%.

[0168] 3ha: 1H NMR (400MHz, CDCl3) δ7.44(d,J=8.8Hz,2H),7.36-7.18(m,5H),6.94(d,J=8.8Hz,2H),3.81-3.72(m,2H),3.14-3.04(m,2H); 13 C NMR(101MHz, CDCl3)δ139.1,136.6,132.7,129.0,128.8,127.3,117.7,116.5,112.9,51.1,33.7; HRMS(ESI)[M+H] + Calcd.forC 15 H 14 BrN2,301.0335; found,301.0327.

[0169] Figure 15 and Figure 16 The images are the hydrogen NMR spectrum and carbon NMR spectrum of the product 3ha obtained in Example 27, respectively.

[0170] Example 28

[0171]

[0172] 1-(4'-acetylphenyl)thiourea 1i (0.2 mmol), 2-chloroethylbenzene 2a (0.48 mmol), sodium carbonate (0.5 mmol), Cu(OH)2 (1 mg), and DMSO (0.5 mL) were added to a reaction tube. A magnetic stir bar wrapped with polytetrafluoroethylene was used, and the reaction was carried out at 120 °C for 1 hour with a stirring speed of 500 rpm. After stirring was stopped, dilute hydrochloric acid solution (2 M, 10 mL) was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried over anhydrous magnesium sulfate. The mixture was filtered, concentrated under reduced pressure, and then purified by column chromatography to obtain the target product. The yield of 3ia was 54%, and the yield of 4a was 75%.

[0173] 3ia: 1 H NMR (400MHz, CDCl3) δ8.00(d,J=8.8Hz,2H),7.40-7.22(m,5H),7.16(d,J=8.8Hz,2H),3.95-3.86(m,2H),3.21-3.11(m,2H),2.60(s,3H); 13 C NMR(101MHz, CDCl3)δ196.4,143.8,136.4,132.5,130.4,129.0,128.8,127.3,115.2,112.2,50.8,33.7,26.4; HRMS(ESI)[M+H] + Calcd.for C17 H 17 N2O,265.1335; found,265.1329.

[0174] Example 29

[0175]

[0176] 1-(4'-trifluoromethylphenyl)thiourea 1j (0.2 mmol), 2-chloroethylbenzene 2a (0.48 mmol), sodium carbonate (0.5 mmol), Cu(OH)2 (1 mg), and DMSO (0.5 mL) were added to a reaction tube. A magnetic stir bar wrapped with polytetrafluoroethylene was used, and the reaction was carried out at 120 °C for 1 hour with a stirring speed of 500 rpm. After stirring was stopped, dilute hydrochloric acid solution (2 M, 10 mL) was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried over anhydrous magnesium sulfate. The mixture was filtered, concentrated under reduced pressure, and then purified by column chromatography to obtain the target product. The yield of 3ja was 43%, and the yield of 4a was 65%.

[0177] 3ja: 1 H NMR (400MHz, CDCl3) δ7.61 (dd, J=6.4, 2.4Hz, 2H), 7.36-7.30 (m, 2H), 7.30-7.26 (m, 1H) ,7.26-7.21(m,2H),7.16(dd,J=6.4,2.4Hz,2H),3.90-3.82(m,2H),3.17-3.09(m,2H); 13 C NMR (101MHz, CDCl3) δ142.8,136.4,129.0,128.8,127.4,127.0(q,J C-H =3.7Hz),125.9,125.6,125.2,122.5,115.6,112.2,50.9,33.7; 19 F NMR(376MHz, CDCl3)δ-62.1; HRMS(ESI)[M+H] + Calcd.for C 16 H 14 F3N2,291.1104; found,291.1097.

[0178] Figure 17 , Figure 18 and Figure 19 These are the 1H NMR spectrum, 1C NMR spectrum, and fluorine NMR spectrum of product 3ja obtained in Example 29.

[0179] Example 30

[0180]

[0181] 1-(2'-methyl-4'-methoxyphenyl)thiourea 1k (0.2 mmol), 2-chloroethylbenzene 2a (0.48 mmol), sodium carbonate (0.5 mmol), Cu(OH)2 (1 mg), and DMSO (0.5 mL) were added to a reaction tube. A PTFE-coated magnetic stir bar was used, and the reaction was carried out at 120 °C for 1 hour with a stirring speed of 500 rpm. After stirring was stopped, dilute hydrochloric acid solution (2 M, 10 mL) was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried over anhydrous magnesium sulfate. The mixture was filtered, concentrated under reduced pressure, and then purified by column chromatography to obtain the target product. The yield of 3k was 60%, and the yield of 4a was 75%.

[0182] 3ka: 1 H NMR (400MHz, CDCl3) δ7.36-7.28(m,2H),7.27-7.19(m,3H),7.00(d,J=8.4Hz,1H), 6.76-6.64(m,2H),3.77(s,3H),3.62-3.54(m,2H),3.07-3.00(m,2H),3,23(s,3H); 13 C NMR(101MHz, CDCl3)δ158.9,137.3,136.0,132.1,128.9,128.7,126.9,126.6,116.5,116.0,112.4,55.5,55.5,34.2,17.8; HRMS(ESI)[M+H] + Calcd.for C 17 H 19 N2O,267.1492; found,267.1487.

[0183] Example 31

[0184]

[0185] 1-(2',4'-dichlorophenyl)thiourea 1l (0.2 mmol), 2-chloroethylbenzene 2a (0.48 mmol), sodium carbonate (0.5 mmol), Cu(OH)2 (1 mg), and DMSO (0.5 mL) were added to a reaction tube. A magnetic stir bar wrapped with polytetrafluoroethylene was used, and the reaction was carried out at 120 °C for 1 hour with a rotation speed of 500 rpm. After stirring was stopped, dilute hydrochloric acid solution (2 M, 10 mL) was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried over anhydrous magnesium sulfate. The mixture was filtered, concentrated under reduced pressure, and then purified by column chromatography to obtain the target product. The yield of 3a was 48%, and the yield of 4a was 71%.

[0186] 3la: 1H NMR (400MHz, CDCl3) δ7.44 (d, J = 2.4Hz, 1H), 7.35-7.28 (m, 2H), 7.28-7.24 (m, 1H) ,7.24-7.17(m,3H),7.05(d,J=8.4Hz,1H),3.75-3.64(m,2H),3.14-2.99(m,2H); 13 CNMR(101MHz, CDCl3)δ136.8,136.6,134.1,131.4,130.8,128.9,128.8,128.3,127.6,127.1,114.2,55.4,34.2; HRMS(ESI)[M+H] + Calcd.for C 15 H 13 Cl2N2,291.0450; found,291.0445.

[0187] Example 32

[0188]

[0189] 1-(2',6'-dimethylphenyl)thiourea 1m (0.2 mmol), 2-chloroethylbenzene 2a (0.48 mmol), sodium carbonate (0.5 mmol), Cu(OH)2 (1 mg), and DMSO (0.5 mL) were added to a reaction tube. A magnetic stir bar wrapped with polytetrafluoroethylene was used, and the reaction was carried out at 120 °C for 1 hour with a rotation speed of 500 rpm. After stirring was stopped, dilute hydrochloric acid solution (2 M, 10 mL) was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried over anhydrous magnesium sulfate. The mixture was filtered, concentrated under reduced pressure, and then purified by column chromatography to obtain the target product. The yield of 3m was 60%, and the yield of 4a was 63%.

[0190] 3ma: 1 H NMR (400MHz, CDCl3) δ7.35-7.20(m,5H),7.17-7.10(m,1H),7.09-7.04(m,2H),3.53-3.44(m,2H),3.17-3.07(m,2H),2.30(s,6H); 13 C NMR (101MHz, CDCl3) δ137.5,137.2,136.2,129.2,128.9,128.8,128.6,127.0,115.3,54.6,34.5,18.0.

[0191] Example 33

[0192]

[0193] 1-(2',6'-difluorophenyl)thiourea 1n (0.2 mmol), 2-chloroethylbenzene 2a (0.48 mmol), sodium carbonate (0.5 mmol), Cu(OH)2 (1 mg), and DMSO (0.5 mL) were added to a reaction tube. A magnetic stir bar wrapped with polytetrafluoroethylene was used, and the reaction was carried out at 120 °C for 1 hour with a stirring speed of 500 rpm. After stirring was stopped, dilute hydrochloric acid solution (2 M, 10 mL) was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried over anhydrous magnesium sulfate. The mixture was filtered, concentrated under reduced pressure, and then purified by column chromatography to obtain the target product. The yield of 3a was 62%, and the yield of 4a was 86%.

[0194] 3na: 1 H NMR (400MHz, CDCl3) δ7.37-7.20(m,6H),7.05-6.94(m,2H),3.78-3.67(m,2H),3.15-3.05(m,2H); 13 C NMR(101MHz,CDCl3)δ159.3(d,J C-F =3.9Hz), 156.8(d,J) C-F =3.8Hz), 136.6, 129.2(t,J) C-F =9.8Hz),128.8,128.7,127.0,112.6(d,J C-F =5.0Hz), 112.4(d,J C-F =5.0Hz),55.7(d,J=5.0Hz),34.4; 19 F NMR(376MHz, CDCl3)δ-118.03(d,J=6.3Hz),-118.05(d,J=6.3Hz); HRMS(ESI)[M+H] + Calcd.for C 15 H 13 F2N2,259.1041; found,259.1036.

[0195] Example 34

[0196]

[0197] 1-(3',4'-dimethylphenyl)thiourea 1o (0.2 mmol), 2-chloroethylbenzene 2a (0.48 mmol), sodium carbonate (0.5 mmol), Cu(OH)2 (1 mg), and DMSO (0.5 mL) were added to a reaction tube. A magnetic stir bar wrapped with polytetrafluoroethylene was used, and the reaction was carried out at 120 °C for 1 hour with a rotation speed of 500 rpm. After stirring was stopped, dilute hydrochloric acid solution (2 M, 10 mL) was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried over anhydrous magnesium sulfate. The mixture was filtered, concentrated under reduced pressure, and then purified by column chromatography to obtain the target product. The yield of 3oa was 68%, and the yield of 4a was 63%.

[0198] 3oa: 1 H NMR (400MHz, CDCl3) δ7.36-7.18(m,5H),7.09(d,J=8.0Hz,1H),6.88(d,J=2.4Hz,1H),6.8 0(dd,J=8.0,2.4Hz,1H),3.80-3.70(m,2H),3.13-3.03(m,2H),2.24(s,3H),2.21(s,3H); 13 C NMR(101MHz, CDCl3)δ138.3,137.6,137.1,132.2,130.6,128.9,128.8,127.1,117.8,114.0,113.5,51.1,33.9,20.0,19.0; HRMS(ESI)[M+H] + Calcd.forC 17 H 19 N2,251.1543; found,251.1538.

[0199] Example 35

[0200]

[0201] 1-(3',5'-dimethylphenyl)thiourea 1p (0.2 mmol), 2-chloroethylbenzene 2a (0.48 mmol), sodium carbonate (0.5 mmol), Cu(OH)₂ (1 mg), and DMSO (0.5 mL) were added to a reaction tube. A PTFE-coated magnetic stir bar was used, and the reaction was carried out at 120 °C for 1 hour with a stirring speed of 500 rpm. After stirring was stopped, dilute hydrochloric acid solution (2 M, 10 mL) was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried over anhydrous magnesium sulfate. The mixture was filtered, concentrated under reduced pressure, and then purified by column chromatography to obtain the target product. The yield of 3pa was 60%, and the yield of 4a was 63%.

[0202] 3pa: 1H NMR (400MHz, CDCl3) δ7.42-7.24(m,5H),6.82-6.70(m,3H),3.87-3.75(m,2H),3.21-3.08(m,2H),2.34(s,6H); 13 C NMR(101MHz, CDCl3)δ139.8,139.6,137.1,128.9,128.9,127.1,125.5,113.9,113.8,50.9,33.9,21.5; HRMS(ESI)[M+H] + Calcd.for C 17 H 19 N2,251.1543; found,251.1536.

[0203] Example 36

[0204]

[0205] 1-(3',5'-dichlorophenyl)thiourea 1q (0.2 mmol), 2-chloroethylbenzene 2a (0.48 mmol), sodium carbonate (0.5 mmol), Cu(OH)₂ (1 mg), and DMSO (0.5 mL) were added to a reaction tube. A PTFE-coated magnetic stir bar was used, and the reaction was carried out at 120 °C for 1 hour with a stirring speed of 500 rpm. After stirring was stopped, dilute hydrochloric acid solution (2 M, 10 mL) was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried over anhydrous magnesium sulfate. The mixture was filtered, concentrated under reduced pressure, and then purified by column chromatography to obtain the target product. The yield of 3qa was 62%, and the yield of 4a was 86%.

[0206] 3qa: 1 H NMR (400MHz, CDCl3) δ7.38-7.20(m,5H),7.07(t,J=1.6Hz,1H),6.95(d,J=1.6Hz,2H),3.83-3.72(m,2H),3.16-3.05(m,2H); 13 C NMR(101MHz, CDCl3)δ142.0,136.3,136.3,129.0,128.8,127.4,123.8,114.5,111.8,51.0,33.7,29.7; HRMS(ESI)[M+H] + Calcd.for C 15 H 13 Cl2N2,291.0450; found,291.0442.

[0207] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. A process for the preparation of cyanamide, characterized in that: The method comprises the following steps: The arylthiourea and the halogenated hydrocarbon are reacted in the presence of a base and a copper salt in a non-protic organic solvent to obtain cyanamide; The structure of the arylthiourea is Formula IV: The structure of the halogenated hydrocarbon is Formula V: The cyanamide has the structure of Formula I: In each formula, R 1 It is at least one of hydrogen, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, tert-butyl, phenyl, benzyl, methoxy, methylthio, benzyloxy, fluorine, chlorine, bromine, iodine, trifluoromethyl, trifluoromethoxy, acetyl, cyano, nitro, and ester; the dashed line in Formula IV indicates that the cyclic structure is phenyl or naphthyl; X is Cl, Br, I; R 2 is hydrogen, methyl, ethyl, 2-propyl, cyclopentyl, cyclohexyl, benzyl, substituted benzyl, phenyl, substituted phenyl, phenethyl, phenpropyl, phenstyryl, 1-naphthyl, 2-naphthyl, halogen-containing alkyl, endo-alkenyl alkyl, terminal-alkenyl alkyl, terminal-alkynyl alkyl; R' is at least one of vinyl, methyl, ethyl, 1-propyl, 1-butyl, benzyl; when the structure of the halogenated hydrocarbon is R is H in the structure of the cyanamide; When the structure of the halogenated hydrocarbon is R is R'; when the structure of the halogenated hydrocarbon is The substituted benzyl group refers to the hydrogen on the benzene ring being substituted by one or more halogens or alkyl groups; The substituted benzyl group refers to the hydrogen on the benzene ring being substituted by one or more halogens or alkyl groups; The base is one or more of sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate and cesium carbonate; The copper salt is copper hydroxide; The non-protic organic solvent is one or more of dimethyl sulfoxide, dimethyl formamide, dimethyl acetamide and 1,4-dioxane.

2. The process for the production of cyanamide according to claim 1, characterized in that: The base is one or more of sodium carbonate and potassium carbonate.

3. The method for preparing cyanamide according to claim 1, characterized in that: The molar ratio of the arylthiourea to the halogenated hydrocarbon is 1:2-3, the molar ratio of the arylthiourea to the base is 1:2-4, the molar ratio of the copper salt to the arylthiourea is 1:1-100, and the reaction temperature is 80-150°C.

4. The process for the production of cyanamide according to claim 3, characterized in that: The molar ratio of the arylthiourea to the halogenated hydrocarbon is 1:2.1-2.5, the molar ratio of the arylthiourea to the base is 1:2.4-3, the molar ratio of the copper salt to the arylthiourea is 1:10-100, and the reaction temperature is 90-130°C.

5. The process for the production of cyanamide according to claim 4, characterized in that: The molar ratio of the arylthiourea to the halogenated hydrocarbon is 1:2.4-2.5, the molar ratio of the arylthiourea to the base is 1:2.5, the molar ratio of the copper salt to the arylthiourea is 1:10-20, and the reaction temperature is 110-125°C.

6. The method for preparing cyanamide according to claim 1, characterized in that: The reaction is carried out in the presence of air.

7. The process for the preparation of cyanamide according to claim 1, characterized in that: The arylthiourea is prepared by uniformly mixing arylamine III with ammonium thiocyanate, adding dilute hydrochloric acid, heating to reflux, adding water after cooling to precipitate a solid, filtering the solid and drying the solid to obtain arylthiourea IV; Arylamine III has the structure of Ammonium thiocyanate has the structure of HSCN·NH3.

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