A process for the reductive amidation of aryl fluorosulfonate esters with isocyanates

Abstract

The application discloses a method for reductive amidation of aryl fluorosulfonate ester and isocyanate, and belongs to the technical field of organic compound synthesis. Aryl fluorosulfonate ester and isocyanate are reacted in a solvent under the action of a catalyst, a ligand and a metal reducing agent, and various amide compounds can be obtained in a medium to good yield. The preparation method can not only reduce reaction steps, but also avoid the use of an organic metal compound which is prepared in advance and is sensitive to water and air. The preparation method has the characteristics of mild reaction conditions, simple post-treatment, green steps, low pollution and high economic benefits.

Description

Technical Field

[0001] This invention belongs to the field of organic compound synthesis technology, specifically relating to a method for the reductive amidation of aryl fluorosulfonic acid esters and isocyanates. Background Technology

[0002] Amides are a vital class of organic compounds, serving not only as versatile synthetic intermediates in organic chemistry but also widely found in natural products, pharmaceuticals, pesticides, and materials science. Due to their importance, researchers have consistently strived to develop novel and efficient methods for amide synthesis. While numerous methods for obtaining amides have been developed, recent advances have demonstrated that isocyanates can also serve as attractive reagents for the efficient construction of amides. For example, isocyanates can react with a range of organometallic compounds, including organomagnesium, organotin, organoboranes, and organosilanes, thus providing readily available methods for amide synthesis. Nevertheless, the necessity of using these organometallic reagents has more or less hindered their widespread application in organic synthesis, as most of them are relatively unavailable, expensive, and moisture-sensitive, making their use uneconomical and their handling cumbersome. Therefore, the development of convenient methods for amide synthesis without the use of nucleophilic organometallic compounds remains desirable. Summary of the Invention

[0003] The purpose of this section is to outline some aspects of embodiments of the present invention and to briefly describe some preferred embodiments. Simplifications or omissions may be made in this section, as well as in the abstract and title of this application, to avoid obscuring the purpose of these documents; however, such simplifications or omissions should not be construed as limiting the scope of the invention.

[0004] In view of the problems existing in the above and / or prior art, the present invention is proposed.

[0005] One objective of this invention is to provide a reductive amidation method for aryl fluorosulfonates and isocyanates, wherein the aryl fluorosulfonates and isocyanates are subjected to a reductive amidation reaction via CO bond cleavage under transition metal catalysis, thereby synthesizing amide compounds.

[0006] To solve the above-mentioned technical problems, the present invention provides the following technical solution: a method for the reductive amidation of aryl fluorosulfonate and isocyanate, comprising reacting the aryl fluorosulfonate of Formula I and the isocyanate of Formula II in a solvent under the action of a catalyst, a ligand and a metal reducing agent to obtain the compound of Formula III;

[0007] Ar-OSO2F (Formula I);

[0008] R-NCO (Formula II);

[0009]

[0010] Wherein, Ar in Formula I and Formula III is selected from one of phenyl, p-trifluoromethyl substituted phenyl, p-trifluoromethoxy substituted phenyl, p-methoxycarbonyl substituted phenyl, p-fluoro substituted phenyl, p-methyl substituted phenyl, m-methyl substituted phenyl, 3,5-dimethyl substituted phenyl, 2,4,6-trimethyl substituted phenyl, p-methoxy substituted phenyl, m-methoxy substituted phenyl, o-methoxy substituted phenyl, p-benzyloxy substituted phenyl, p-phenoxy substituted phenyl, p-phenyl substituted phenyl, 2-methoxy-3-allyl substituted phenyl, and naphthyl ring substituted phenyl;

[0011] In Formulas II and III, R is selected from one of p-trifluoromethyl-substituted phenyl, p-methyl-substituted phenyl, 1-naphthyl, benzyl, isopropyl, 1-ethylphenyl, cyclopentyl, cyclohexyl, adamantyl, and 3-isopropyl-dimethylbenzyl.

[0012] As a preferred embodiment of the reductive amidation method of aryl fluorosulfonate and isocyanate of the present invention, wherein the molar ratio of aryl fluorosulfonate to isocyanate is 1:2.

[0013] As a preferred embodiment of the reductive amidation method of aryl fluorosulfonate and isocyanate of the present invention, the catalyst is characterized in that: the catalyst is selected from one of nickel bromide, nickel chloride, nickel chloride ethylene glycol dimethyl ether, bis(triphenylphosphine) nickel dichloride, bis(tricyclohexylphosphine) nickel dichloride, bis(diphenylphosphine)ethane nickel chloride, bis(diphenylphosphine)propane nickel chloride, and bis(diphenylphosphine)ferrocene nickel dichloride, and the molar ratio of the catalyst to the aryl fluorosulfonate is 0.1 to 0.2:1.

[0014] In a preferred embodiment of the reductive amidation method of aryl fluorosulfonate and isocyanate of the present invention, the molar ratio of the catalyst to the aryl fluorosulfonate is 0.1:1.

[0015] As a preferred embodiment of the reductive amidation method of the aryl fluorosulfonate and isocyanate of the present invention, wherein: the ligand is selected from one of 2,2'-bipyridine, 6,6'-dimethyl-2,2'-bipyridine, 2,9-dimethyl-4,7-diphenyl-1,10-phenanthroline, and 4,7-diphenyl-1,10-phenanthroline, and the molar ratio of the ligand to the aryl fluorosulfonate is 0.15 to 0.3:1.

[0016] As a preferred embodiment of the reductive amidation method of the aryl fluorosulfonate and isocyanate of the present invention, the molar ratio of the ligand to the aryl fluorosulfonate is 0.15:1.

[0017] As a preferred embodiment of the reduction amidation method of aryl fluorosulfonate and isocyanate of the present invention, wherein: the metal reducing agent is selected from one of zinc, magnesium and manganese, and the molar ratio of the metal reducing agent to the aryl fluorosulfonate is 2 to 3:1.

[0018] In a preferred embodiment of the reductive amidation method of aryl fluorosulfonate and isocyanate of the present invention, the molar ratio of the metal reducing agent to the aryl fluorosulfonate is 2:1.

[0019] As a preferred embodiment of the reductive amidation method of aryl fluorosulfonate and isocyanate of the present invention, wherein the solvent is selected from one of dimethyl sulfoxide, N,N-dimethylformamide, and N,N-dimethylacetamide.

[0020] As a preferred embodiment of the method for the reduction and amidation of aryl fluorosulfonate and isocyanate of the present invention, the reaction is preferably carried out at room temperature.

[0021] As a preferred embodiment of the reductive amidation method of aryl fluorosulfonate and isocyanate of the present invention, the method further includes a step of purifying the reaction product.

[0022] In summary, the chemical equation for the optimal reaction conditions of this invention is as follows:

[0023]

[0024] Compared with the prior art, the present invention has the following beneficial effects:

[0025] This invention utilizes a one-pot method, under transition metal catalysis, to achieve reductive amidation of aryl fluorosulfonates and isocyanates via CO bond cleavage, thereby synthesizing amide compounds. This not only reduces the number of reaction steps but also avoids the use of pre-prepared organometallic compounds that are sensitive to water and air, providing a novel method for amide synthesis. By employing aryl fluorosulfonates as readily available and chemically stable electrophilic reagents for reductive amidation with isocyanates, the use of traditional organometallic reagents as coupling partners is avoided. This approach is simple, practical, and synthetically attractive, potentially becoming an attractive alternative to existing amide synthesis methods. Attached Figure Description

[0026] To more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings used in the description of the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort. Wherein:

[0027] Figure 1 The 1H N-(tert-butyl)benzamide spectrum of the target product N-(tert-butyl)benzamide in Example 1 of this invention;

[0028] Figure 2 The carbon spectrum of N-(tert-butyl)benzamide, the target product of Example 1 of the present invention.

[0029] Figure 3 The 1H N-(tert-butyl)-4-methoxybenzamide, the target product of Example 2 of this invention;

[0030] Figure 4 The carbon spectrum of N-(tert-butyl)-4-methoxybenzamide, the target product of Example 2 of the present invention.

[0031] Figure 5 The proton NMR spectrum of N-(tert-butyl)-4-methylbenzamide, the target product of Example 3 of this invention;

[0032] Figure 6 The carbon spectrum of N-(tert-butyl)-4-methylbenzamide, the target product of Example 3 of the present invention.

[0033] Figure 7 The proton N-ray spectra of N-(tert-butyl)-4-fluorobenzamide, the target product of Example 4 of this invention;

[0034] Figure 8 The carbon spectrum of N-(tert-butyl)-4-fluorobenzamide, the target product of Example 4 of the present invention.

[0035] Figure 9 The 1H NMR spectrum of N-(2-(3-(prop-1-en-2-yl)phenyl)prop-2-yl)benzamide, the target product of Example 5 of the present invention;

[0036] Figure 10 The carbon spectrum of N-(2-(3-(prop-1-en-2-yl)phenyl)prop-2-yl)benzamide, the target product of Example 5 of the present invention.

[0037] Figure 11 The proton N-carbon spectrum of N-cyclohexylbenzamide, the target product of Example 6 of this invention;

[0038] Figure 12 The carbon spectrum of N-cyclohexylbenzamide, the target product of Example 6 of the present invention. Detailed Implementation

[0039] To make the above-mentioned objects, features and advantages of the present invention more apparent and understandable, the specific embodiments of the present invention will be described in detail below with reference to the examples in the specification.

[0040] Many specific details are set forth in the following description in order to provide a full understanding of the invention. However, the invention may also be practiced in other ways different from those described herein, and those skilled in the art can make similar extensions without departing from the spirit of the invention. Therefore, the invention is not limited to the specific embodiments disclosed below.

[0041] Secondly, the term "one embodiment" or "embodiment" as used herein refers to a specific feature, structure, or characteristic that may be included in at least one implementation of the present invention. The phrase "in one embodiment" appearing in different places in this specification does not necessarily refer to the same embodiment, nor is it a single or selective embodiment that is mutually exclusive with other embodiments.

[0042] The aryl fluorosulfonate used in the embodiments of this invention was prepared with reference to the following literature:

[0043] [1] C. Liu, C. Yang, S. Hwang, SM Ferraro, JPFlynn and J. Niu, A General Approach to O-Sulfation by a Sulfur(VI) Fluoride Exchange Reaction, Angew. Chem. Int. Ed., 2020, 59, 18435-18441.

[0044] [2] C.Ma, C.-Q.Zhao, X.-T.Xu, Z.-M.Li,

[0045] [3]T.Guo, G.Meng, + "Donor ofUnprecedented Reactivity,Selectivity,and Scope,Angew.Chem.Int.Ed.,2018,57,2605-2610.

[0046] [4] J.Dong, KBSharpless, L.Kwisnek, JSOakdale and VVFokin, SuFEx-Based Synthesis ofPolysulfates, Angew.Chem.Int.Ed., 2014, 53, 9466-9470.

[0047] Unless otherwise specified, all other raw materials used in the examples are commercially available.

[0048] Example 1

[0049] (1) Place the sealed tube equipped with a magnetic stirrer in an oven to dry for one hour, take it out and while it is still hot, plug it with a rubber stopper and insert a nitrogen balloon;

[0050] (2) After the sealed tube has cooled to room temperature, add phenylfluorosulfonate (88.1 mg, 0.5 mmol, 1 equiv.), nickel dichloride (6.4 mg, 0.05 mmol, 10 mol%), and 2,2'-bipyridine (11.7 mg, 0.075 mmol, 1 equiv.).

[0051] 15 mol%) and manganese powder (55 mg, 1 mmol, 2 equiv.), then the sealing tube was purged with nitrogen three times, and then 1 mL of ultra-dry N,N-dimethylformamide was added; then tert-butyl isocyanate (99.1 mg, 1 mmol, 2 equiv.) was added to the sealing tube; the mixture was stirred at room temperature for 12 hours;

[0052] (3) Subsequently, extraction was performed using ethyl acetate; the extract was washed with saturated brine, dried over anhydrous sodium sulfate, and then the extract was removed by rotary evaporation. The crude product was purified by silica gel column chromatography. The column chromatography separation conditions were: 200-300 mesh silica gel powder as the stationary phase and petroleum ether / ethyl acetate 200:10-15 as the mobile phase. Finally, 69.9 mg of the target product N-(tert-butyl)benzamide was obtained. The structural formula of this compound is:

[0053]

[0054] The above N-(tert-butyl)benzamide was characterized, such as Figure 1 and 2 As shown, the result is: a white solid; 1 H NMR (400MHz, CDCl3): δ7.76-7.68(m,2H),7.52-7.42(m,1H),7.46-7.36(m,2H),5.97(brs,1H),1.47(s,9H)ppm. 13C NMR(100MHz, CDCl3): δ166.9,135.8,131.1,128.4,126.7,51.6,28.8ppm.HRMS(m / z):calcd for C 11 H 16 NO + [M+H] + 178.1226,found:178.1223.IR(KBr,neat):ν=3649,3447,2360,1653,1595,1559,1362,668cm -1 .

[0055] Characterization data showed that the obtained reaction product was N-(tert-butyl)benzamide (purity > 98%); the product yield was calculated to be 79%.

[0056] Example 2

[0057] (1) Place the sealed tube equipped with a magnetic stirrer in an oven to dry for one hour, take it out and while it is still hot, plug it with a rubber stopper and insert a nitrogen balloon;

[0058] (2) After the sealed tube has cooled to room temperature, add 4-methoxyphenyl fluorosulfonate (1.31 mg, 0.5 mmol, 1 equiv.), nickel dichloride (6.4 mg, 0.05 mmol, 10 mol%), 2,2'-bipyridine (11.7 mg, 0.075 mmol, 15 mol%), and manganese powder (55 mg, 1 mmol, 2 equiv.). Then, purge the sealed tube with nitrogen three times. Next, add 1 mL of ultra-dry N,N-dimethylformamide. Then, add tert-butyl isocyanate (99.1 mg, 1 mmol, 2 equiv.) to the sealed tube. Stir the mixture at room temperature for 12 hours.

[0059] (3) Subsequently, extraction was performed using ethyl acetate; the extract was washed with saturated brine, dried over anhydrous sodium sulfate, and then removed by rotary evaporation. The crude product was purified by silica gel column chromatography under the following conditions: stationary phase was 200–300 mesh silica gel powder, and mobile phase was petroleum ether / ethyl acetate 200:15–20. Finally, 93.3 mg of the target product N-(tert-butyl)-4-methoxybenzamide was obtained. The structural formula of this compound is:

[0060]

[0061] The above-mentioned N-(tert-butyl)-4-methoxybenzamide was characterized, such as Figure 3 and 4 As shown, the result is: a white solid; 1H NMR (400MHz, CDCl3): δ7.71-7.65(m,2H),6.92-6.87(m,2H),5.87(brs,1H),3.83(s,3H),1.46(s,9H)ppm. 13 C NMR(100MHz, CDCl3): δ166.4,161.8,128.4,128.1,113.6,55.4,51.4,28.9ppm.HRMS(m / z):calcd for C 12 H 18 NO2 + [M+H] + 208.1332,found:208.1328.IR(KBr,neat):ν=3327,2973,1631,1550,1507,1255,1033,842cm -1 .

[0062] Characterization data showed that the obtained reaction product was N-(tert-butyl)-4-methoxybenzamide (purity > 98%); the product yield was calculated to be 90%.

[0063] Example 3

[0064] (1) Place the sealed tube equipped with a magnetic stirrer in an oven to dry for one hour, take it out and while it is still hot, plug it with a rubber stopper and insert a nitrogen balloon;

[0065] (2) After the sealed tube has cooled to room temperature, add 4-methylphenyl fluorosulfonate (95.1 mg, 0.5 mmol, 1 equiv.), nickel dichloride (6.4 mg, 0.05 mmol, 10 mol%), 2,2'-bipyridine (11.7 mg, 0.075 mmol, 15 mol%), and manganese powder (55 mg, 1 mmol, 2 equiv.). Then, purge the sealed tube with nitrogen three times. Next, add 1 mL of ultra-dry N,N-dimethylformamide. Then, add tert-butyl isocyanate (99.1 mg, 1 mmol, 2 equiv.) to the sealed tube. Stir the mixture at room temperature for 12 hours.

[0066] (3) Subsequently, extraction was performed using ethyl acetate; the extract was washed with saturated brine, dried over anhydrous sodium sulfate, and then the extract was removed by rotary evaporation. The crude product was purified by silica gel column chromatography. The column chromatography separation conditions were: 200-300 mesh silica gel powder as the stationary phase and petroleum ether / ethyl acetate 200:10-15 as the mobile phase. Finally, 64.6 mg of the target product N-(tert-butyl)-4-methylbenzamide was obtained. The structural formula of this compound is:

[0067]

[0068] The above N-(tert-butyl)-4-methylbenzamide was characterized, such as Figure 5 and 6 As shown, the result is: a white solid; 1 H NMR (400MHz, CDCl3): δ7.61 (d, J = 8.2Hz, 2H), 7.19 (d, J = 7.9Hz, 2H), 5.94 (brs, 1H), 2.37 (s, 3H), 1.46 (s, 9H) ppm. 13 C NMR(100MHz, CDCl3): δ166.8,141.3,133.0,129.1,126.6,51.4,28.8,21.3ppm.HRMS(m / z):calcd for C 12 H 18 NO + [M+H] + 192.1383,found:192.1383.IR(KBr,neat):ν=3352,2980,1636,1546,1362,1320,836,752cm -1 .

[0069] Characterization data showed that the obtained reaction product was N-(tert-butyl)-4-methylbenzamide (purity > 98%); the product yield was calculated to be 68%.

[0070] Example 4

[0071] (1) Place the sealed tube equipped with a magnetic stirrer in an oven to dry for one hour, take it out and while it is still hot, plug it with a rubber stopper and insert a nitrogen balloon;

[0072] (2) After the sealed tube cooled to room temperature, add 4-fluorophenyl fluorosulfonate (97.1 mg, 0.5 mmol, 1 equiv.), nickel dichloride (6.4 mg, 0.05 mmol, 10 mol%), 2,2'-bipyridine (11.7 mg, 0.075 mmol, 15 mol%), and manganese powder (55 mg, 1 mmol, 2 equiv.). Then, purge the sealed tube with nitrogen three times. Next, add 1 mL of ultra-dry N,N-dimethylformamide. Then, add tert-butyl isocyanate (99.1 mg, 1 mmol, 2 equiv.) to the sealed tube. Stir the mixture at room temperature for 12 hours.

[0073] (3) Subsequently, extraction was performed using ethyl acetate; the extract was washed with saturated brine, dried over anhydrous sodium sulfate, and then the extract was removed by rotary evaporation. The crude product was purified by silica gel column chromatography. The column chromatography separation conditions were: 200-300 mesh silica gel powder as the stationary phase and petroleum ether / ethyl acetate 200:10-15 as the mobile phase. Finally, 71.6 mg of the target product N-(tert-butyl)-4-fluorobenzamide was obtained. The structural formula of this compound is:

[0074]

[0075] The above N-(tert-butyl)-4-fluorobenzamide was characterized, such as Figure 3 and 4 As shown, the result is: a white solid; 1 HNMR (400MHz, CDCl3): δ7.74-7.67(m,2H),7.08-7.01(m,2H),5.97(brs,1H),1.44(s,9H)ppm. 13 C NMR(100MHz, CDCl3): δ7.74-7.67(m,2H),7.08-7.01(m,2H),5.97(brs,1H),1.44(s,9H)ppm.HRMS(m / z):calcd for C 11 H 15 FNO + [M+H] + 196.1132,found:196.1130.IR(KBr,neat):ν=3314,2968,1634,1237,1157,847,764,605cm -1 .

[0076] Characterization data showed that the obtained reaction product was N-(tert-butyl)-4-fluorobenzamide (purity > 98%); the product yield was calculated to be 73%.

[0077] Example 5

[0078] (1) Place the sealed tube equipped with a magnetic stirrer in an oven to dry for one hour, take it out and while it is still hot, plug it with a rubber stopper and insert a nitrogen balloon;

[0079] (2) After the sealed tube has cooled to room temperature, add phenyl fluorosulfonate (88.1 mg, 0.5 mmol, 1 equiv.), nickel dichloride (6.4 mg, 0.05 mmol, 10 mol%), 2,2'-bipyridine (11.7 mg, 0.075 mmol, 15 mol%), and manganese powder (55 mg, 1 mmol, 2 equiv.). Then, purge the sealed tube with nitrogen three times. Next, add 1 mL of ultra-dry N,N-dimethylformamide. Then, add 3-isopropyl-dimethylbenzyl isocyanate (201.3 mg, 1 mmol, 2 equiv.) to the sealed tube. Stir the mixture at room temperature for 12 hours.

[0080] (3) Subsequently, extraction was performed using ethyl acetate; the extract was washed with saturated brine, dried over anhydrous sodium sulfate, and then the extract was removed by rotary evaporation. The crude product was purified by silica gel column chromatography. The column chromatography separation conditions were: 200-300 mesh silica gel powder as the stationary phase and petroleum ether / ethyl acetate 200:10-15 as the mobile phase. Finally, 92.9 mg of the target product N-(2-(3-(prop-1-en-2-yl)phenyl)prop-2-yl)benzamide was obtained. The structural formula of this compound is:

[0081]

[0082] The above N-(2-(3-(prop-1-en-2-yl)phenyl)prop-2-yl)benzamide was characterized, as follows: Figure 5 and 6 As shown, the result is: a white solid; 1 H NMR (400MHz, CDCl3): δ7.80-7.75(m,2H),7.57(t,J=1.9Hz,1H),7.51-7.46(m,1H),7.44-7.29(m,5H), 6.57(brs,1H),5.37(dd,J=1.6,0.8Hz,1H),5.10(m,1H),2.17(dd,J=1.5,0.8Hz,3H),1.84(s,6H)ppm. 13 C NMR (100MHz, CDCl3): δ166.5,146.7,143.4,141.3,135.4,131.2,128.4,128. 3,126.7,123.9,123.8,121.8,112.5,56.2,29.1,21.8ppm.HRMS(m / z):calcd for C 19 H 22 NO + [M+H] +280.1696,found:280.1693.IR(KBr,neat):ν=3243,3056,1630,1537,1316,886,806,691cm -1 .

[0083] Characterization data showed that the obtained reaction product was N-(2-(3-(prop-1-en-2-yl)phenyl)prop-2-yl)benzamide (purity > 98%); the product yield was calculated to be 67%.

[0084] Example 6

[0085] (1) Place the sealed tube equipped with a magnetic stirrer in an oven to dry for one hour, take it out and while it is still hot, plug it with a rubber stopper and insert a nitrogen balloon;

[0086] (2) After the sealed tube cooled to room temperature, add phenyl fluorosulfonate (88.1 mg, 0.5 mmol, 1 equiv.), nickel dichloride (6.4 mg, 0.05 mmol, 10 mol%), 2,2'-bipyridine (11.7 mg, 0.075 mmol, 15 mol%), and manganese powder (55 mg, 1 mmol, 2 equiv.). Then, purge the sealed tube with nitrogen three times. Next, add 1 mL of ultra-dry N,N-dimethylformamide. Then, add cyclohexyl isocyanate (125.2 mg, 1 mmol, 2 equiv.) to the sealed tube. Stir the mixture at room temperature for 12 hours.

[0087] (3) Subsequently, extraction was performed using ethyl acetate; the extract was washed with saturated brine, dried over anhydrous sodium sulfate, and then the extract was removed by rotary evaporation. The crude product was purified by silica gel column chromatography. The column chromatography separation conditions were: 200-300 mesh silica gel powder as the stationary phase and petroleum ether / ethyl acetate 200:10-15 as the mobile phase. Finally, 68.5 mg of the target product N-cyclohexylbenzamide was obtained. The structural formula of this compound is:

[0088]

[0089] The above-mentioned N-cyclohexylbenzamide was characterized as follows: Figure 7 and 8 As shown, the result is: a white solid; 1H NMR (400MHz, CDCl3): δ7.78-7.71(m,2H),7.49-7.44(m,1H),7.43-7.37(m,2H),6.08(brs,1H),4.01-3.92 (m,1H),2.03-1.99(m,2H),1.77-1.71(m,2H),1.67-1.61(m,1H),1.46-1.35(m,2H),1.29-1.15(m,3H)ppm. 13 C NMR(100MHz, CDCl3): δ166.6,135.0,131.2,128.4,126.8,48.6,33.2,25.5,24.9ppm.HRMS(m / z):calcd for C 13 H 18 NO + [M+H] + 204.1383,found:204.1382.IR(KBr,neat):ν=3315,2932,2851,1627,1535,1330,1082,693cm -1 .

[0090] Characterization data showed that the obtained reaction product was N-cyclohexylbenzamide (purity > 98%); the product yield was calculated to be 67%.

[0091] Example 7

[0092] Example 7 is basically the same as Example 1, except that the catalyst in step (2) is different, as shown in Table 1 below:

[0093] Table 1

[0094] catalyst Yield (%) none 0 Ferric chloride 0 cobalt chloride 0 manganese chloride 0 Chromium dichloride 0 Palladium chloride 0 Nickel chloride 79 Nickel bromide 30 Nickel iodide 14 Nickel chloride ethylene glycol dimethyl ether 68 Nickel dibis(triphenylphosphine) chloride 62 Ditricyclohexylphosphine nickel dichloride 76 bis(diphenylphosphine)ethane nickel chloride 66 bis(diphenylphosphine)propane nickel chloride 78 Bis(diphenylphosphine)ferrocene nickel dichloride 64

[0095] As shown in Table 1, the reaction cannot proceed without a catalyst. Under the same reaction conditions, the reaction is almost impossible with different catalysts, such as ferric chloride, cobalt chloride, manganese chloride, chromium dichloride, palladium chloride, nickel iodide, and nickel acetylacetonate. However, the reaction can be successfully synthesized with nickel bromide, nickel chloride, nickel chloride ethylene glycol dimethyl ether, bis(triphenylphosphine) nickel dichloride, bis(tricyclohexylphosphine) nickel dichloride, bis(diphenylphosphine)ethane nickel chloride, bis(diphenylphosphine)propane nickel chloride, and bis(diphenylphosphine)ferrocene nickel dichloride as catalysts. Among these, bis(diphenylphosphine)ferrocene nickel dichloride has the best effect, with the highest yield of 65%.

[0096] Example 8

[0097] Example 8 is basically the same as Example 1, except that the ligand in step (2) is different, as shown in Table 2 below:

[0098] Table 2

[0099] ligands Yield (%) 1,1'-Bis(diphenylphosphine)ferrocene 0 1,3-Bis(diphenylphosphine)ethane 0 1,3-Bis(diphenylphosphine)propane 0 1,3-Bis(diphenylphosphine)butane 0 bis(2-diphenylphosphine) ether 0 4,5-Bisdiphenylphosphine-9,9-Dimethyloxanthracene 0 1,2-Bis(diphenylphosphine)benzene 0 2,2'-Bipyridine 79 5,5'-Dimethyl-2,2-Bipyridine 39 6,6'-Di-tert-butyl-2,2'-bipyridine 0 6,6'-Dimethyl-2,2'-Bipyridine 39 2,9-Dimethyl-4,7-diphenyl-1,10-phenanthroline 43 4,7-Diphenyl-1,10-phenanthroline 60 Tripyridine 0

[0100] As shown in Table 2, under the same reaction conditions, different para-ligands, such as 1,3-bis(diphenylphosphine)ethane, 1,3-bis(diphenylphosphine)propane, 1,3-bis(diphenylphosphine)butane, 1,2-bis(diphenylphosphino)benzene, 1,1'-bis(diphenylphosphine)ferrocene, bis(2-diphenylphosphine)ether, 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene, and 5,5'-dimethyl-2 The reactions for 2'-bipyridine, 6,6'-di-tert-butyl-2,2'-bipyridine, and terpyridine were almost impossible; however, the reactions for 2,2'-bipyridine, 6,6'-dimethyl-2,2'-bipyridine, 2,9-dimethyl-4,7-diphenyl-1,10-phenanthroline, and 4,7-diphenyl-1,10-phenanthroline were all successfully synthesized, with 2,2'-bipyridine showing the best results and achieving the highest yield of 79%. Further experiments revealed that adjusting the amount of ligand added to above 0.1 mmol or below 0.05 mmol was detrimental to the synthesis of the product.

[0101] Example 9

[0102] Example 9 is basically the same as Example 1, except that the metal reducing agent in step (2) is different, as shown in Table 3 below:

[0103] Table 3

[0104] Metal reducing agent Yield (%) none 0 Zinc <5 magnesium 33 manganese 79 aluminum 0 iron 0 copper 0 gallium 0 indium 0 bismuth 0 lead 0 tin 0

[0105] As can be seen from Table 2, the reaction cannot proceed without the addition of a metal reducing agent. Under the same reaction conditions, the reaction is almost impossible with different metal reducing agents, such as aluminum, iron, copper, gallium, indium, bismuth, platinum, and tin. However, the reaction can be successfully synthesized with zinc, magnesium, and manganese, with manganese showing the best effect and the highest yield of 79%.

[0106] Example 10

[0107] Example 10 is basically the same as Example 1, except that the solvent in step (2) is different, as shown in Table 4 below:

[0108] Table 4

[0109]

[0110]

[0111] As can be seen from Table 4, under the same reaction conditions, the reaction can hardly proceed when using different solvents, such as ethylene glycol dimethyl ether, methanol, 1,2-dichloroethane, dichloromethane, and toluene; while N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide can all be successfully synthesized. The best results are achieved when N,N-dimethylformamide is used as the solvent, with the highest yield of 79%.

[0112] Example 11

[0113] Example 11 is basically the same as Example 1, except that in step (2), the aryl fluorosulfonate and isocyanate are different, as shown in Table 5 below:

[0114] Table 5

[0115]

[0116]

[0117]

[0118] This invention provides a reductive amidation reaction of aryl fluorosulfonic acid esters with isocyanates. Under conditions of nickel as a catalyst, 2,2'-bipyridine as a ligand, and manganese as the reducing metal, the reaction is carried out in N,N-dimethylformamide solvent at room temperature for 12 hours, yielding structurally diverse amide compounds in moderate to good yields. This reaction not only reduces the number of reaction steps but also avoids the use of pre-prepared organometallic compounds that are sensitive to water and air. The preparation method of this invention features mild reaction conditions, simple post-processing, environmentally friendly procedures, low pollution, and high economic efficiency.

[0119] This invention utilizes a one-pot method, under nickel catalysis, to achieve reductive amidation of aryl fluorosulfonates and isocyanates via CO bond cleavage, thereby synthesizing amide compounds. This not only reduces the number of reaction steps but also avoids the use of pre-prepared organometallic compounds that are sensitive to water and air, providing a novel method for amide synthesis. By employing aryl fluorosulfonates as readily available and chemically stable electrophiles for reductive amidation with isocyanates, the use of traditional organometallic reagents as coupling partners is avoided. This approach is simple, practical, and synthetically attractive, potentially becoming an attractive alternative to existing amide synthesis methods.

[0120] It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit it. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, and all such modifications or substitutions should be covered within the scope of the claims of the present invention.

Claims

1. A process for the reductive amidation of aryl fluorosulfonates with isocyanates, characterized in that: The application relates to a preparation method of aryl fluorosulfonate. The aryl fluorosulfonate shown in formula I and the isocyanate shown in formula II are reacted in a solvent under the action of a catalyst, a ligand and a metal reducing agent to obtain a compound shown in formula III. Ar-OSO2F (formula I); R-NCO (formula II); In formula I and formula III, Ar is selected from one of the following: a phenyl group, a p-trifluoromethyl-substituted phenyl group, a p-trifluoromethoxy-substituted phenyl group, a p-methoxycarbonyl-substituted phenyl group, a p-fluoro-substituted phenyl group, a p-methyl-substituted phenyl group, a m-methyl-substituted phenyl group, a 3,5-dimethyl-substituted phenyl group, a 2,4,6-trimethyl-substituted phenyl group, a p-methoxy-substituted phenyl group, a m-methoxy-substituted phenyl group, an o-methoxy-substituted phenyl group, a p-benzyloxy-substituted phenyl group, a p-phenoxy-substituted phenyl group, a p-phenyl-substituted phenyl group, a 2-methoxy-3-allyl-substituted phenyl group and a naphthalene ring-substituted phenyl group; In formula II and formula III, R is selected from one of the following: a p-trifluoromethyl-substituted phenyl group, a p-methyl-substituted phenyl group, a 1-naphthyl group, a benzyl group, an isopropyl group, a 1-ethylphenyl group, a cyclopentyl group, a cyclohexyl group, an adamantyl group and a 3-isopropyl-dimethylbenzyl group; The catalyst is selected from one of the following: nickel chloride, nickel bromide, nickel iodide, nickel chloride ethylene glycol dimethyl ether, double tricyclohexylphosphine dichloride nickel, double triphenylphosphine dichloride nickel, tetrapyridine dichloride nickel, double (diphenyl phosphor) ethane chlorinated nickel, double (diphenyl phosphor) propane chlorinated nickel and double (diphenyl phosphor) ferrocene dichloride nickel; the molar ratio of the catalyst to the aryl fluorosulfonate is 0.1-0.2:1; The ligand is selected from one of the following: 2,2'-dipyridyl, 5,5'-dimethyl-2,2'-dipyridyl, 6,6'-dipyridyl, 4,7-diphenyl-1,10-phenanthroline and 2,9-dimethyl-4,7-diphenyl-1,10-phenanthroline; the molar ratio of the ligand to the aryl fluorosulfonate is 0.15-0.3:1; The metal reducing agent is selected from one of the following: zinc, magnesium and manganese; the molar ratio of the metal reducing agent to the aryl fluorosulfonate is 2-3:1; The solvent is selected from one of the following: dimethyl sulfoxide, N,N-dimethylformamide and N,N-dimethylacetamide.

2. The process for the reductive amidation of aryl fluorosulfonates with isocyanates according to claim 1, characterized in that: The molar ratio of the aryl fluorosulfonate to the isocyanate is 1:

2.

3. The process for the reductive amidation of aryl fluorosulfonates with isocyanates according to claim 1, characterized in that: The molar ratio of the catalyst to the aryl fluorosulfonate is 0.1:

1.

4. The process for the reductive amidation of aryl fluorosulfonates with isocyanates according to claim 1, characterized in that: The molar ratio of the ligand to the aryl fluorosulfonate is 0.15:

1.

5. The process for the reductive amidation of aryl fluorosulfonates with isocyanates according to claim 1, characterized in that: The molar ratio of the metal reducing agent to the isocyanate is 2:

1.

6. The process for the reductive amidation of aryl fluorosulfonates with isocyanates according to any one of claims 1 to 5, characterized in that: The method further comprises a step of purifying the reaction product.

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