Acyl transfer reagent and preparation method of amide compound

Abstract

The invention relates to an acyl transfer reagent and a preparation method of an amide compound, and belongs to the field of organic synthesis in organic chemistry. Polyfluoro-substituted aromatic hydrocarbon, acyl chloride and a sulfur transfer reagent are adopted as raw materials, polyfluoro aryl thioester is obtained through two continuous electrophilic substitution reactions, and then further application research proves that the compound is an efficient acyl transfer reagent and can be used for acylation reactions of various amines. The route and reaction conditions adopted in the method are green, environment-friendly, simple and mild, the raw materials are easy to obtain, the product selectivity is high, the variety is rich, and the method is expected to be further applied to industrial production.

Description

Technical Field

[0001] This invention relates to a method for synthesizing novel acyl transfer reagents, belonging to the field of organic synthesis in organic chemistry. Background Technology

[0002] Thioesters are an important class of functional molecules, their importance extending beyond synthetic chemistry to various interdisciplinary fields such as materials science, food, cosmetics, antibiotics, and bioscience. For example, in organic synthesis, they have long been used as acyl reagents for the acylation of amine compounds. However, in practical applications, thioesters exhibit poor reactivity, leading to harsh reaction conditions and poor selectivity. Therefore, developing a highly reactive thioester acyl transfer reagent is of significant research importance. Summary of the Invention

[0003] To overcome the aforementioned shortcomings, and driven by the pursuit of green synthetic methodologies, we have developed a simple, universal, and thiol- and transition metal-free method for synthesizing polyfluoroaryl thioesters. This invention uses polyfluoroaromatic hydrocarbon 1 and sulfur transfer reagent 2 as raw materials. After adding a solvent and reacting to generate a sulfur-negative intermediate, acyl chloride 3 is added to continue the reaction and yield the polyfluoroaryl thioester. Subsequent experiments have confirmed that this type of thioester is a novel acyl transfer reagent with high activity.

[0004]

[0005] Where: R1 = -COPh2, -CONEt2, -CON i Pr2, -COOMe, -COOEt, -COO i Pr, -COOCy, -COOPh, -CF3, -CN, -F, -H, -CH3, -C6F5, and other types of polyfluoroaromatics 1 are still applicable, such as pentafluoropyridine, 3,4,5-trifluorobenzonitrile, methyl 3,4,5-trifluorobenzoate, etc.

[0006] R2 = -Ph, -4- n Aryl groups such as Bu-Ph, -4-F-Ph, -4-Cl-Ph, -4-CN-Ph, -3-Me-Ph, -3-F-Ph, and -2-F-Ph are applicable. In addition, other types of acyl chlorides are also applicable, such as aliphatic acyl chlorides such as acetyl chloride, propionyl chloride, isobutyryl chloride, and hexanoyl chloride, as well as cinnamoyl chloride.

[0007] Furthermore, in the novel acyl transfer reagent synthesized in the above technical solution, the sulfur transfer reagent is selected from thiourea, potassium sulfide, sodium sulfide, potassium ethyl xanthate, potassium thioacetate, potassium thiocyanate, and carbon disulfide.

[0008] Further, in the above technical solution, the molar ratio of the new acyl transfer reagent synthesized to the polyfluoroarene compound is 1-3:1.

[0009] Further, in the above technical solution, the molar ratio of the new acyl transfer reagent synthesized to the polyfluoroarene compound is 1-3:1.

[0010] Further, in the above technical solution, the reaction temperature of the new acyl transfer reagent synthesized is selected from 25-110°C.

[0011] Further, in the above technical solution, the reaction solvent of the new acyl transfer reagent synthesized is water, acetonitrile, DMF or DMSO.

[0012] Inventive beneficial effects: The present application provides a simple, inexpensive and efficient synthesis method for the new acyl transfer reagent, the raw materials used in the reaction are simple and easy to obtain, the product selectivity is high, and the yield of the target product can reach 94% at most, which is expected to be applied to industrial production, and then pushed to the market, helping the development of synthetic chemistry, medicinal chemistry and material chemistry. DETAILED DESCRIPTION

[0013] The technical solutions of the present application will be described below in conjunction with the embodiments of the present application. Obviously, the described embodiments are only a part of the embodiments of the present application, not all embodiments.

[0014] Example 1 The preparation method of the new acyl transfer reagent is as follows:

[0015] In a 10 ml Schlenk tube, potassium sulfide (83.8 mg, 0.3 mmol, 1.5 equiv) and solvent water (2 mL) were added, and after stirring at room temperature for 3 min, polyfluoroarene compound (0.2 mmol) was added. The mixture was stirred at 100°C for 12h, and the reaction progress was monitored by thin layer chromatography (TLC). After the polyfluoroarene was completely consumed, p-tolyl benzoyl chloride (0.4 mmol, 2.0 equiv) was added, and then stirring was continued at room temperature for 4h until TLC showed that the reaction was complete. The reaction mixture was extracted with ethyl acetate (3x5 mL), the organic phases were combined and dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel flash column chromatography to obtain the target product with a yield of 82%, 64.6 mg.

[0016] 1 H NMR:(600 MHz, Chloroform-d): δ 7.90 (d, J= 8.4 Hz, 2H), 7.30 (d, J =8.4 Hz, 2H), 3.61 (q, J = 7.2 Hz, 2H), 3.28 (q, J = 7.2 Hz, 2H), 2.43 (s, 3H),1.27 (t, J = 7.2 Hz, 3H), 1.16 (t, J = 7.2 Hz, 3H). 13 C NMR:(150 MHz, Chloroform-d): δ 184.4, 158.3, 147.0 (dm, J = 247.5 Hz),146.0, 142.5 (dm, J = 243.0 Hz), 132.7, 129.8, 128.2, 119.2 (t, J = 22.5 Hz),108.8 (t, J = 20.3 Hz), 43.4, 39.8, 21.9, 14.1, 12.8. 19 F NMR:(565 MHz, Chloroform-d): δ -129.55 – -129.69 (m, 2F), -140.95– -141.15 (m, 2F). HRMS:(ESI-TOF) (m / z): Calcd for C 19 H 18 F4NO2S ([M+H] + ), 400.0989, found,400.0995. Example 2

[0017] In a 10 ml Schlenk tube, potassium sulfide (83.8 mg, 0.3 mmol, 1.5 equiv) and solvent water (2 mL) were added. After stirring at room temperature for 3 min, the polyfluoroarene compound (0.2 mmol) was added. The mixture was stirred at 100 °C for 12 h, and the reaction progress was monitored by thin layer chromatography (TLC). After the complete consumption of the polyfluoroarene, the acyl chloride (0.4 mmol, 2.0 equiv) was added, followed by continued stirring at room temperature for 4 h until TLC showed the completion of the reaction. The reaction mixture was extracted with ethyl acetate (3 x 5 mL), and the organic phases were combined and dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product obtained was purified by silica gel flash column chromatography to obtain the target product in 88% yield, 64.8 mg.

[0018] 1 H NMR: (600 MHz, Chloroform-d): δ 7.92 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H), 2.46 (s, 3H). 13 C NMR: (150 MHz, Chloroform-d): δ 183.5, 147.4 (dm, J = 252.0 Hz), 146.4, 144.3 (dm, J = 252.0 Hz), 132.5, 130.0, 128.3, 113.5 (t, J = 20.3 Hz), 111.6 (t, J = 34.5 Hz), 22.0. 19 F NMR: (565 MHz, Chloroform-d): δ -56.33 (s, 3F), -128.56 – -128.73 (m, 2F), -139.24 – -139.48 (m, 2F). HRMS: (ESI-TOF) (m / z): Calcd for C 15 H8F7OS ([M+H] + ), 369.0179, found, 369.0177. Example 3

[0019] In a 10 ml Schlenk tube, potassium sulfide (83.8 mg, 0.3 mmol, 1.5 equiv) and solvent water (2 mL) were added. After stirring at room temperature for 3 min, the polyfluoroarene compound (0.2 mmol) was added. The mixture was stirred at 100 °C for 12 h, and the reaction progress was monitored by thin layer chromatography (TLC). After the complete consumption of the polyfluoroarene, the acyl chloride (0.4 mmol, 2.0 equiv) was added, followed by continued stirring at room temperature for 4 h until TLC showed the completion of the reaction. The reaction mixture was extracted with ethyl acetate (3 x 5 mL), and the organic phases were combined and dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by flash column chromatography on silica gel to give the target product in 69% yield, 39.9 mg.

[0020] 1 H NMR: (600 MHz, Chloroform-d): δ 7.91 (s, 2H), 7.33 (d, J = 20.4 Hz, 4H), 2.45 (s, 3H). 13 C NMR: (150 MHz, Chloroform-d): δ 184.4, 163.1 (dd, J = 254.3, 5.1 Hz), 145.9, 132.9, 129.9, 128.3, 116.4, 115.9, 115.7, 112.4 (t, J = 22.5 Hz), 22.0. 19 F NMR: (565 MHz, Chloroform-d): δ -98.87 (s, 2F). HRMS: (ESI-TOF) (m / z): Calcd for C 15 H 10 F2NOS ([M+H] + ), 290.0446, found, 290.0441. Example 4

[0021] In a 10 ml Schlenk tube, potassium sulfide (83.8 mg, 0.3 mmol, 1.5 equiv) and solvent water (2 mL) were added. After stirring at room temperature for 3 min, the polyfluoroarene compound (0.2 mmol) was added. The mixture was stirred at 100 °C for 12 h, and the reaction progress was monitored by thin layer chromatography (TLC). After the complete consumption of the polyfluoroarene, the acyl chloride (0.4 mmol, 2.0 equiv) was added, followed by continued stirring at room temperature for 4 h until TLC showed the completion of the reaction. The reaction mixture was extracted with ethyl acetate (3 x 5 mL), and the organic phases were combined and dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel to give the target product in 93% yield, 76.8 mg.

[0022] 1 H NMR:(600 MHz, Chloroform-d): δ 7.62 (s, 2H), 7.28 (s, 1H), 3.61(q, J = 7.2 Hz, 2H), 3.29 (q, J = 7.2 Hz, 2H), 2.39 (s, 6H), 1.28 (t, J = 7.2 Hz,3H), 1.17 (t, J = 7.2 Hz, 3H). 13 C NMR:(150 MHz, Chloroform-d): δ 185.0, 158.3, 147.0 (dm, J = 256.5Hz), 142.5 (dm, J = 255.0 Hz), 139.1, 136.4, 135.3, 125.8, 119.3 (t, J = 22.5Hz), 108.9 (t, J = 20.3 Hz), 43.4, 39.8, 21.3, 14.1, 12.8. 19 F NMR:(565 MHz, Chloroform-d): δ -129.36 – -129.89 (m, 2F), -140.79– -141.45 (m, 2F). HRMS:(ESI-TOF) (m / z): Calcd for C 20 H 20 F4NO2S ([M+H] +), 414.1146, found,414.1143. Example 5

[0023] In a 10 ml Schlenk tube, potassium sulfide (83.8 mg, 0.3 mmol, 1.5 equiv) and solvent water (2 mL) were added. After stirring at room temperature for 3 min, the polyfluoroarene compound (0.2 mmol) was added. The mixture was stirred at 100 °C for 12 h, and the reaction progress was monitored by thin layer chromatography (TLC). After the complete consumption of the polyfluoroarene, the acyl chloride (0.4 mmol, 2.0 equiv) was added, followed by continued stirring at room temperature for 4 h until TLC showed the completion of the reaction. The reaction mixture was extracted with ethyl acetate (3 x 5 mL), and the organic phases were combined and dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel to obtain the target product in 87% yield, 56.2 mg.

[0024] 1 H NMR:(600 MHz, Chloroform-d): δ 3.58 (q, J = 7.2 Hz, 2H), 3.24 (q, J =7.2 Hz, 2H), 2.50 (s, 3H), 1.25 (t, J = 7.2 Hz, 3H), 1.13 (t, J = 7.2 Hz, 3H). 13 C NMR:(150 MHz, Chloroform-d): δ 188.3, 158.2, 146.4 (dm, J = 253.5Hz), 142.3 (dm, J = 255.0 Hz), 141.5, 119.3 (t, J = 22.5 Hz), 108.7 (t, J = 21.0Hz), 43.3, 39.8, 30.2, 14.1, 12.8. 19 F NMR:(565 MHz, Chloroform-d): δ -129.91 – -130.24 (m, 2F), -140.61– -141.10 (m, 2F). HRMS:(ESI-TOF) (m / z): Calcd for C13 H 14 F4NO2S ([M+H]+), 324.0676, found,324.0673. Example 6

[0025] In a 10 ml Schlenk tube, add the sulfide (79.8 mg, 0.2 mmol) and solvent acetonitrile (2 mL) and stir at room temperature, then add the amine (0.2 mmol, 1.0 equiv). Stir the mixture at 50 °C for 120 min, monitor the reaction progress by thin layer chromatography (TLC). Extract the reaction mixture with ethyl acetate (3 x 2 mL), combine the organic phases and dry over anhydrous sodium sulfate, concentrate under reduced pressure. Purify the resulting crude product by flash column chromatography on silica gel to obtain the target product amide in 89% yield, 34.1 mg.

[0026] 1 H NMR:(600 MHz, Chloroform-d): δ 7.65 (d, J = 8.4 Hz, 2H), 7.19 (d, J =7.8 Hz, 2H), 6.34 (s, 1H), 3.43 – 3.39 (m, 2H), 2.36 (s, 3H), 1.59 – 1.54 (m,2H), 1.40 – 1.35 (m, 2H), 0.93 (t, J = 7.2 Hz, 3H). 13 C NMR:(150 MHz, Chloroform-d): δ 167.6, 141.7, 132.1, 129.2, 126.9,39.8, 31.9, 21.5, 20.2, 13.9. HRMS:(ESI-TOF) (m / z): Calcd for C 12 H 18 NO ([M+H]+), 192.1383, found,192.1388. Application of novel acyl transfer reagents: Example 7

[0027] In a 10 ml Schlenk tube, add the sulfone (79.8 mg, 0.2 mmol) and solvent acetonitrile (2 mL) and stir at room temperature, then add the amine (0.2 mmol, 1.0 equiv). Stir the mixture at 50 °C for 120 min, monitor the reaction progress by thin layer chromatography (TLC). Extract the reaction mixture with ethyl acetate (3 x 2 mL), combine the organic phases and dry over anhydrous sodium sulfate, concentrate under reduced pressure. Purify the resulting crude product by flash column chromatography on silica gel to obtain the target product amide in 87% yield, 44.0 mg.

[0028] 1 H NMR: (600 MHz, Chloroform-d): δ 7.67 (d, J = 8.4 Hz, 2H), 7.36 - 7.32 (m, 4H), 7.28 - 7.24 (m, 1H), 7.20 (d, J = 7.8 Hz, 2H), 6.47 (d, J = 8.4 Hz, 1H), 5.08 (q, J = 7.2 Hz, 1H), 2.38 (s, 3H), 1.98 - 1.88 (m, 2H), 0.95 (t, J = 7.2 Hz, 3H). 13 C NMR: (150 MHz, Chloroform-d): δ 166.9, 142.4, 141.9, 131.9, 129.3, 128.8, 127.4, 127.1, 126.8, 55.4, 29.3, 21.5, 10.9. HRMS: (ESI-TOF) (m / z): Calcd for C 17 H 20 NO ([M+H] + ), 254.1539, found, 254.1533. Example 8

[0029] In a 10 ml Schlenk tube, add the sulfonate (79.8 mg, 0.2 mmol), cesium carbonate Cs2C03(65.0 mg, 0.2 mmol, 1.0 equiv) and solvent acetonitrile (2 mL). Then add ethylenediamine (0.2 mmol, 1.0 equiv). Stir the mixture at 80 °C for 120 min, thin layer chromatography (TLC) monitor the reaction progress. The reaction mixture is extracted with ethyl acetate (3 x 2 mL), combine the organic phase and dry over anhydrous sodium sulfate, concentrate under reduced pressure. The resulting crude product is purified by silica gel flash column chromatography to give the target product amide, yield 87%, 36.7 mg.

[0030] 1 H NMR: (600 MHz, Chloroform-d): δ 7.89 (s, 1H), 7.76 (d, J = 8.4 Hz,2H), 7.64 (d, J = 7.2 Hz, 2H), 7.37 – 7.34 (m, 2H), 7.27 (d, J = 7.8 Hz, 2H),7.14 (t, J = 7.2 Hz, 1H), 2.42 (s, 3H). 13 C NMR: (150 MHz, Chloroform-d): δ 165.9, 142.5, 138.2, 132.2, 129.6, 129.2, 127.2, 124.6, 120.3, 21.6. HRMS: (ESI-TOF) (m / z): Calcd for C 14 H 14 NO ([M+H] + ), 212.1070, found,212.1066. Example 9

[0031] In a 10 ml Schlenk tube, add the sulfonate (79.8 mg, 0.2 mmol), cesium carbonate Cs2C03(65.0 mg, 0.2 mmol, 1.0 equiv) and solvent acetonitrile (2 mL). Subsequently, add ethylenediamine (0.2 mmol, 1.0 equiv). Stir the mixture at 80 °C for 120 min, thin layer chromatography (TLC) monitor the reaction progress. The reaction mixture is extracted with ethyl acetate (3 x 2 mL), combine the organic phase and dry over anhydrous sodium sulfate, concentrate under reduced pressure. The resulting crude product is purified by silica gel flash column chromatography to give the target product amide, yield 94%, 44.2 mg.

[0032] 1 H NMR: (600 MHz, Chloroform-d): δ 8.41 (d, J = 8.4 Hz, 1H), 7.66 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 7.8 Hz, 1H), 7.41 - 7.38 (m, 1H), 7.35 - 7.30 (m, 4H), 6.62 (d, J = 3.6 Hz, 1H), 2.47 (s, 3H). 13 C NMR: (150 MHz, Chloroform-d): δ 168.9, 142.7, 136.2, 131.8, 130.9, 129.5, 129.4, 127.8, 124.9, 123.9, 121.0, 116.4, 108.4, 21.7. HRMS: (ESI-TOF) (m / z): Calcd for C 16 H 14 NO ([M+H] + ), 236.1070, found, 236.1073. Example 10

[0033] In a 10 mL Shrek tube, a thioester (79.8 mg, 0.2 mmol) and acetonitrile (2 mL) were added. Then, an amine (0.2 mmol, 1.0 equiv) was added. The mixture was stirred at room temperature for 2 min, and the reaction was monitored by thin-layer chromatography (TLC). The reaction mixture was extracted with ethyl acetate (3 × 2 mL), and the combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give the target product, amide, in 91% yield (32.6 mg).

[0034] 1 H NMR: (600 MHz, Chloroform-d): δ 7.63 (d, J = 8.4 Hz, 2H), 7.13 (d, J =8.4 Hz, 2H), 7.11 (s, 1H), 3.95 (s, 1H), 3.73 (t, J = 5.4 Hz, 2H), 3.53 (q, J =5.4 Hz, 2H), 2.33 (s, 3H). 13 C NMR: (150 MHz, Chloroform-d): δ 168.9, 142.2, 131.3, 129.3, 127.1, 62.0, 42.9, 21.5. HRMS:(ESI-TOF) (m / z): Calcd for C 10 H 14 NO2([M+H] + ), 180.1019, found, 180.1013. Similarly, the technical solution of the present invention also verified the following application activity test of the novel acyl transfer reagent: Example 11 Comparative studies were conducted with phenyl and butyl-substituted thioesters. Experiments showed that selective arylation of ethylenediamine can be effectively achieved by optimizing the molar ratio of polyfluoroaryl thioesters to ethylenediamine and the reaction temperature. Notably, the reaction exhibited high reactivity, completing within 2 minutes. Further evaluation of the acyl transfer efficiency of phenyl and butyl-substituted thioesters revealed that while phenyl thioesters can also mediate the selective arylation of ethylenediamine, their reactivity and selectivity are slightly lower than those of polyfluoroaryl thioesters. Butyl-substituted thioesters exhibited even lower reactivity. These experiments demonstrate that our synthesized polyfluoroaryl thioesters are novel and highly active acyl transfer reagents.

[0035] In a 10 ml Shrek tube, add amine and solvent acetonitrile (2 mL), then place the mixture in a T ( o C) Stir the reaction mixture for 2 min, then add the thioester. Continue stirring the mixture at the appropriate temperature for t min, monitoring the reaction progress by thin-layer chromatography (TLC) until the thioester is completely consumed. Extract the reaction mixture with ethyl acetate (3 × 2 mL), combine the organic phases, dry them over anhydrous sodium sulfate, and concentrate under reduced pressure. Purify the crude product by silica gel rapid column chromatography to obtain the target products amides 6 and 7.

Claims

1. A method for synthesizing polyfluoroaryl thioesters, characterized in that, Includes the following steps: Polyfluoroaromatic compounds are reacted with a sulfur transfer reagent in a solvent to generate a sulfur-negative intermediate. Subsequently, an acyl chloride compound is added to continue the reaction, yielding a polyfluoroaryl thioester. The reaction formula is as follows: R¹ is selected from: -COPh2, -CONEt2, -CON 1 Pr2, -COOMe, -COOEt, -COO 1 Pr, -COOCy, -COOPh, -CF3, -CN, -F, -H, -CH3, -C6F5.

2. The method according to claim 1, characterized in that, The polyfluoroaromatic compound may also be selected from any one of pentafluoropyridine, 3,4,5-trifluorobenzonitrile, or methyl 3,4,5-trifluorobenzoate.

3. The method according to claim 1, characterized in that, The sulfur transfer reagent is selected from: thiourea, potassium sulfide, sodium sulfide, potassium ethyl xanthate, potassium thioacetate, potassium thiocyanate, and carbon disulfide.

4. The method according to claim 1, characterized in that, The acyl chloride compound is selected from compounds represented by the following general formula: R 2 -COCl, where R 2 Selected from: phenyl, 4-n-butylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-cyanophenyl, 3-methylphenyl, 3-fluorophenyl, 2-fluorophenyl.

5. The method according to claim 1, characterized in that, The acyl chloride compound is selected from acetyl chloride, propionyl chloride, isobutyryl chloride, hexanoyl chloride, and cinnamoyl chloride, and the solvent is selected from water, acetonitrile, N,N-dimethylformamide (DMF), and dimethyl sulfoxide (DMSO).

6. The method according to claim 1, characterized in that, The molar ratio of the sulfur transfer reagent, acyl chloride, and polyfluoroaromatic compound is 1-3:1-5:

1.

7. The method according to claim 1, characterized in that, The reaction temperature is from room temperature to 25-110°C.

8. A polyfluoroaryl thioester, characterized in that, It is synthesized using the method described in any one of claims 1-7.

9. The application of the polyfluoroaryl thioester of claim 8 as an acyl transfer reagent in the acylation reaction of amine compounds.

10. A method for acylation of amine compounds, characterized in that, Includes the following steps: In the reaction system, an amine compound is contacted with a polyfluoroaryl thioester compound synthesized by any one of claims 1-7 to undergo an acyl transfer reaction, generating the corresponding amide compound; Preferably, the amine compound is an aliphatic amine, an aromatic amine, a diamine, or a derivative thereof; Preferably, the reaction is carried out in the presence of a base, wherein the base is cesium carbonate; Preferably, the solvent for the reaction is acetonitrile; Preferably, the reaction temperature is between room temperature and 80°C.

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