Reductive amidation method of aryl fluorosulfonate and isocyanate

Abstract

The invention discloses a reduction amidation method of aryl fluorosulfonate and isocyanate, and belongs to the technical field of organic compound synthesis. Aryl fluorosulfonate and isocyanate react in a solvent under the action of a catalyst, a ligand and a metal reducing agent, and amide compounds with various structures can be obtained at medium to good yield. According to the preparation method disclosed by the invention, reaction steps can be reduced, and an organic metal compound which is prepared in advance and is relatively sensitive to water and air can also be prevented from being used; the preparation method disclosed by the invention has the characteristics of mild reaction conditions, simple post-treatment, green steps, low pollution, high economic benefits and the like.

Description

Technical Field

[0001] The invention belongs to the technical field of organic compound synthesis, and specifically relates to a method for reducing amidation of aromatic fluorosulfonic acid esters and isocyanate. Background Art

[0002] Amides are very important organic compounds, not only as versatile synthetic intermediates in organic chemistry, but also widely present in natural products, pharmaceuticals, pesticides and materials science. Due to their importance, people have been committed to developing new and effective methods for synthesizing amides. Although many methods for obtaining amides have been developed, recent progress has shown that isocyanates can also serve as attractive reagents for effectively building amides. For example, isocyanates can react with a series of organometallic compounds, including organomagnesium, organotin, organoborane and organosilane, thereby providing a method for easily synthesizing amides. Nevertheless, the necessity of using these organometallic reagents has more or less hindered their widespread use in organic synthesis, because most of them are relatively difficult to obtain, expensive and sensitive to moisture, making their use less economical and cumbersome to handle. Therefore, it is still desirable to develop a method for conveniently synthesizing amides without using nucleophilic organometallic compounds. Summary of the invention

[0003] The purpose of this section is to summarize some aspects of embodiments of the present invention and briefly introduce some preferred embodiments. Some simplifications or omissions may be made in this section and the specification abstract and the invention title of this application to avoid blurring the purpose of this section, the specification abstract and the invention title, and such simplifications or omissions cannot be used to limit the scope of the present invention.

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

[0005] One of the objects of the present invention is to provide a method for the reductive amidation of aromatic fluorosulfonates and isocyanates, wherein aromatic fluorosulfonates and isocyanates are subjected to a reductive amidation reaction by breaking the CO bond under transition metal catalysis, thereby synthesizing amide compounds.

[0006] In order to solve the above technical problems, the present invention provides the following technical solutions: a method for reducing amidation of an aromatic fluorosulfonate with an isocyanate, comprising reacting an aromatic fluorosulfonate of formula I and an isocyanate of formula II in a solvent under the action of a catalyst, a ligand and a metal reducing agent to obtain a 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 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] R in formula II and formula III 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 method for reductive amidation of aryl fluorosulfonate with isocyanate of the present invention, the molar ratio of the aryl fluorosulfonate to the isocyanate is 1:2.

[0013] As a preferred embodiment of the method for reducing amidation of aromatic fluorosulfonate with isocyanate of the present invention, it is characterized in that: the catalyst is selected from one of nickel bromide, nickel chloride, nickel chloride ethylene glycol dimethyl ether, bistriphenylphosphine nickel dichloride, bistricyclohexylphosphine 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 aromatic fluorosulfonate is 0.1 to 0.2:1.

[0014] As a preferred embodiment of the method for reductive amidation of aryl fluorosulfonate with 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 method for reductive amidation of aromatic fluorosulfonate with isocyanate of the present invention, 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 aromatic fluorosulfonate is 0.15 to 0.3:1.

[0016] As a preferred embodiment of the method for reductive amidation of aryl fluorosulfonate with 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 method for reductive amidation of aryl fluorosulfonate with isocyanate of the present invention, the metal reducing agent is selected from zinc, magnesium and manganese, and the molar ratio of the metal reducing agent to the aryl fluorosulfonate is 2 to 3:1.

[0018] As a preferred embodiment of the method for reductive amidation of aryl fluorosulfonate with 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 method for reductive amidation of aryl fluorosulfonate with isocyanate of the present invention, 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 reducing amidation of aryl fluorosulfonate with isocyanate of the present invention, the reaction is preferably carried out at room temperature.

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

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

[0023]

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

[0025] The present invention uses a "one-pot method" to synthesize amide compounds by cleaving the CO bond of aromatic fluorosulfonic acid esters and isocyanates under transition metal catalysis. This not only reduces the reaction steps, but also avoids the use of pre-prepared organic metal compounds that are sensitive to water and air, providing a new method for the synthesis of amides. The aromatic fluorosulfonic acid ester is used as an easily available, chemically stable electrophilic reagent to perform reductive amidation with isocyanate, avoiding the use of traditional organic metal reagents as coupling partners. The scheme is simple, practical and synthetically attractive, and may become an attractive alternative to existing amide synthesis methods. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the following briefly introduces the drawings required for describing the embodiments. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without creative labor. Among them:

[0027] Figure 1 This is the hydrogen spectrum of the target product N-(tert-butyl)benzamide in Example 1 of the present invention;

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

[0029] Figure 3 This is the hydrogen spectrum of the target product N-(tert-butyl)-4-methoxybenzamide of Example 2 of the present invention;

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

[0031] Figure 5 This is the hydrogen spectrum of the target product N-(tert-butyl)-4-methylbenzamide of Example 3 of the present invention;

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

[0033] Figure 7 This is the hydrogen spectrum of the target product N-(tert-butyl)-4-fluorobenzamide of Example 4 of the present invention;

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

[0035] Fig. 9 This is the hydrogen spectrum of the target product N-(2-(3-(prop-1-en-2-yl)phenyl)prop-2-yl)benzamide of Example 5 of the present invention;

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

[0037] Fig.11 This is the hydrogen spectrum of the target product N-cyclohexylbenzamide of Example 6 of the present invention;

[0038] Fig.12 This is the carbon spectrum of the target product N-cyclohexylbenzamide of Example 6 of the present invention. DETAILED DESCRIPTION

[0039] In order to make the above-mentioned objects, features and advantages of the present invention more obvious and easy to understand, the specific implementation methods of the present invention are described in detail below in conjunction with the embodiments of the specification.

[0040] In the following description, many specific details are set forth to facilitate a full understanding of the present invention, but the present invention may also be implemented in other ways different from those described herein, and those skilled in the art may make similar generalizations without violating the connotation of the present invention. Therefore, the present 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 term "in one embodiment" that appears in different places in this specification does not necessarily refer to the same embodiment, nor does it refer to a separate or selective embodiment that is mutually exclusive with other embodiments.

[0042] The raw material aryl fluorosulfonate used in the examples of the present 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, other raw materials used in the examples were purchased commercially.

[0048] Example 1

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

[0050] (2) When the sealed tube cools 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,

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

[0052] (3) Then, ethyl acetate was used for extraction; the extract was washed with saturated brine and 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: the stationary phase was 200-300 mesh silica gel powder, and the mobile phase was petroleum ether / ethyl acetate 200:10-15. Finally, 69.9 mg of the target product N-(tert-butyl)benzamide was obtained. The structural formula of the compound is:

[0053]

[0054] The above N-(tert-butyl)benzamide was characterized, as Figure 1 and 2 As shown, the result is: 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] According to the characterization data, the obtained reaction product is N-(tert-butyl)benzamide (purity>98%); the product yield is calculated and the result is 79%.

[0056] Example 2

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

[0058] (2) After the sealed tube cools to room temperature, 4-methoxyphenyl fluorosulfonate (1.3.1 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.) are added thereto, and then the sealed tube is evacuated with nitrogen three times, and then 1 mL of ultra-dry N,N-dimethylformamide is added thereto; then tert-butyl isocyanate (99.1 mg, 1 mmol, 2 equiv.) is added to the sealed tube; the mixture is stirred at room temperature for 12 hours;

[0059] (3) Then, ethyl acetate was used for extraction; the extract was washed with saturated brine and 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: the stationary phase was 200-300 mesh silica gel powder, and the 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 the compound is:

[0060]

[0061] The above N-(tert-butyl)-4-methoxybenzamide was characterized, as Figure 3 and 4 As shown, the result is: 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] According to the characterization data, the obtained reaction product is N-(tert-butyl)-4-methoxybenzamide (purity>98%); the product yield is calculated and the result is 90%.

[0063] Example 3

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

[0065] (2) After the sealed tube cools to room temperature, 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.) are added thereto, and then the sealed tube is evacuated with nitrogen three times, and then 1 mL of ultra-dry N,N-dimethylformamide is added thereto; then tert-butyl isocyanate (99.1 mg, 1 mmol, 2 equiv.) is added to the sealed tube; the mixture is stirred at room temperature for 12 hours;

[0066] (3) Then, ethyl acetate was used for extraction; the extract was washed with saturated brine and 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: the stationary phase was 200-300 mesh silica gel powder, and the mobile phase was petroleum ether / ethyl acetate 200:10-15. Finally, 64.6 mg of the target product N-(tert-butyl)-4-methylbenzamide was obtained. The structural formula of the compound is:

[0067]

[0068] The above N-(tert-butyl)-4-methylbenzamide was characterized, as Figure 5 and 6 As shown, the result is: 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] According to the characterization data, the obtained reaction product is N-(tert-butyl)-4-methylbenzamide (purity>98%); the product yield is calculated and the result is 68%.

[0070] Example 4

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

[0072] (2) After the sealed tube cools to room temperature, 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.) are added thereto, and then the sealed tube is evacuated with nitrogen three times, and then 1 mL of ultra-dry N,N-dimethylformamide is added thereto; then tert-butyl isocyanate (99.1 mg, 1 mmol, 2 equiv.) is added to the sealed tube; the mixture is stirred at room temperature for 12 hours;

[0073] (3) Then, ethyl acetate was used for extraction; the extract was washed with saturated brine and 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: the stationary phase was 200-300 mesh silica gel powder, and the mobile phase was petroleum ether / ethyl acetate 200:10-15. Finally, 71.6 mg of the target product N-(tert-butyl)-4-fluorobenzamide was obtained. The structural formula of the compound is:

[0074]

[0075] The above N-(tert-butyl)-4-fluorobenzamide was characterized, as Figure 3 and 4 As shown, the result is: 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] According to the characterization data, the obtained reaction product is N-(tert-butyl)-4-fluorobenzamide (purity>98%); the product yield is calculated to be 73%.

[0077] Example 5

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

[0079] (2) After the sealed tube cools to room temperature, 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.) are added thereto, and then the sealed tube is evacuated with nitrogen three times, and then 1 mL of ultra-dry N,N-dimethylformamide is added thereto; then 3-isopropyl-dimethylbenzyl isocyanate (201.3 mg, 1 mmol, 2 equiv.) is added to the sealed tube; the mixture is stirred at room temperature for 12 hours;

[0080] (3) Then, ethyl acetate was used for extraction; the extract was washed with saturated brine and 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: the stationary phase was 200-300 mesh silica gel powder, and the mobile phase was petroleum ether / ethyl acetate 200:10-15. 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 the compound is:

[0081]

[0082] The above N-(2-(3-(prop-1-en-2-yl)phenyl)prop-2-yl)benzamide was characterized as Figure 5 and 6 As shown, the result is: 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] According to the characterization data, the obtained reaction product is N-(2-(3-(prop-1-en-2-yl)phenyl)prop-2-yl)benzamide (purity>98%); the product yield is calculated to be 67%.

[0084] Example 6

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

[0086] (2) After the sealed tube cools to room temperature, 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.) are added thereto, and then the sealed tube is evacuated with nitrogen three times, and then 1 mL of ultra-dry N,N-dimethylformamide is added thereto; then cyclohexyl isocyanate (125.2 mg, 1 mmol, 2 equiv.) is added to the sealed tube; the mixture is stirred at room temperature for 12 hours;

[0087] (3) Then, ethyl acetate was used for extraction; the extract was washed with saturated brine and 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: the stationary phase was 200-300 mesh silica gel powder, and the mobile phase was petroleum ether / ethyl acetate 200:10-15. Finally, 68.5 mg of the target product N-cyclohexylbenzamide was obtained. The structural formula of the compound is:

[0088]

[0089] The above N-cyclohexylbenzamide is characterized, as Figure 7 and 8 As shown, the result is: 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] According to the characterization data, the obtained reaction product is N-cyclohexylbenzamide (purity>98%); the product yield is calculated and the result is 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 Ferrous 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 dimethyl ether 68 Bistriphenylphosphine nickel dichloride 62 Bis(tricyclohexylphosphine)nickel dichloride 76 Bis(diphenylphosphine)ethanenickel chloride 66 Bis(diphenylphosphino)propanenickel chloride 78 Bis(diphenylphosphino)ferrocenenickel dichloride 64

[0095] As can be seen from Table 1, the reaction cannot proceed without adding a catalyst; under the same reaction conditions, for different catalysts, such as ferric chloride, cobalt chloride, manganese chloride, chromium dichloride, palladium chloride, nickel iodide, and nickel acetylacetonate, the reaction can hardly proceed; while for nickel bromide, nickel chloride, nickel chloride glycol dimethyl ether, bistriphenylphosphine nickel dichloride, bistricyclohexylphosphine nickel dichloride, bis(diphenylphosphine)ethane nickel chloride, bis(diphenylphosphine)propane nickel chloride, and bis(diphenylphosphine)ferrocene nickel dichloride as catalysts, they can be successfully synthesized, and bis(diphenylphosphine)ferrocene nickel dichloride has the best effect, with a maximum yield of 65%.

[0096] Example 8

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

[0098] Table 2

[0099] Ligand Yield (%) 1,1'-Bis(diphenylphosphino)ferrocene 0 1,3-Bis(diphenylphosphino)ethane 0 1,3-Bis(diphenylphosphino)propane 0 1,3-Bis(diphenylphosphino)butane 0 Bis(2-diphenylphosphinophenyl)ether 0 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene 0 1,2-Bis(diphenylphosphino)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 Terpyridine 0

[0100] It can be seen from Table 2 that under the same reaction conditions, different ligands, such as 1,3-bis(diphenylphosphino)ethane, 1,3-bis(diphenylphosphino)propane, 1,3-bis(diphenylphosphino)butane, 1,2-bis(diphenylphosphino)benzene, 1,1'-bis(diphenylphosphino)ferrocene, bis(2-diphenylphosphinophenyl)ether, 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene, 5,5'-dimethyl-2 ,2'-bipyridine, 6,6'-di-tert-butyl-2,2'-bipyridine, and terpyridine, the reaction was almost impossible to proceed; while 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, they were all successfully synthesized, with 2,2'-bipyridine having the best effect, with the highest yield of 79%. Further experiments found that adjusting the amount of ligand added to more than 0.1mmol or less than 0.05mmol was not conducive to product synthesis.

[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] It can be seen from Table 2 that the reaction cannot proceed without adding a metal reducing agent; under the same reaction conditions, the reaction can hardly proceed for different metal reducing agents, such as aluminum, iron, copper, gallium, indium, bismuth, platinum, and tin; while zinc, magnesium, and manganese can all be successfully synthesized, with manganese having the best effect, with 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] It can be seen from Table 4 that under the same reaction conditions, the reaction can hardly proceed when different solvents are used, such as ethylene glycol dimethyl ether, methanol, 1,2-dichloroethane, dichloromethane, and toluene. However, N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide can all be successfully synthesized, and the best effect is achieved when N,N-dimethylformamide is used as the solvent, with the highest yield of 79%.

[0112] Embodiment 11

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

[0114] Table 5

[0115]

[0116]

[0117]

[0118] The present invention provides a reductive amidation reaction of an aromatic fluorosulfonic acid ester and an isocyanate, wherein nickel is used as a catalyst, 2,2'-bipyridine is used as a ligand, and manganese is used as a reducing metal, and the reaction is carried out in an N,N-dimethylformamide solvent at room temperature for 12 hours, and amide compounds with various structures can be obtained with a moderate to good yield. The reaction can not only reduce the reaction steps, but also avoid the use of pre-prepared organic metal compounds that are sensitive to water and air. The preparation method of the present invention has mild reaction conditions, simple post-treatment, green steps, low pollution, high economic benefits, and the like.

[0119] The present invention uses a "one-pot method" to synthesize amide compounds by cleaving the CO bond of aromatic fluorosulfonic acid esters and isocyanates under the condition of transition metal nickel catalysis. This not only reduces the reaction steps, but also avoids the use of pre-prepared organic metal compounds that are sensitive to water and air, providing a new method for the synthesis of amides. The aromatic fluorosulfonic acid ester is used as an easily available, chemically stable electrophilic reagent to perform reductive amidation with isocyanate, avoiding the use of traditional organic metal reagents as coupling partners. The scheme is simple, practical and synthetically attractive, and may become 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 rather than to limit it. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the present invention may be modified or replaced by equivalents without departing from the spirit and scope of the technical solutions of the present invention, which should all be included in the scope of the claims of the present invention.

Claims

1. A method for the reductive amidation of an aromatic fluorosulfonic acid ester and an isocyanate, characterized in that: include, The aromatic fluorosulfonic acid ester represented by formula I and the isocyanate represented by formula II are reacted in a solvent under the action of a catalyst, a ligand and a metal reducing agent to obtain a compound represented by formula III; Ar-OSO2F (Formula I); R-NCO (Formula II); Wherein, Ar in Formula I and Formula III is selected from 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; R in formula II and formula III 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.

2. The method for reductive amidation of aromatic fluorosulfonic acid esters and isocyanates according to claim 1, characterized in that: The molar ratio of the aryl fluorosulfonate to the isocyanate is 1:

2.

3. The method for reductive amidation of aromatic fluorosulfonic acid esters with isocyanates according to claim 1 or 2, characterized in that: The catalyst is selected from one of nickel chloride, nickel bromide, nickel iodide, nickel chloride ethylene glycol dimethyl ether, bistricyclohexylphosphine nickel dichloride, bistriphenylphosphine nickel dichloride, tetrapyridine 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 aromatic fluorosulfonate is 0.1 to 0.2:

1.

4. The method for reductive amidation of aryl fluorosulfonic acid ester and isocyanate according to claim 3, characterized in that: The molar ratio of the catalyst to the aryl fluorosulfonate is 0.1:

1.

5. The method for reductive amidation of an aromatic fluorosulfonic acid ester with an isocyanate according to any one of claims 1, 2 and 4, characterized in that: The ligand is selected from one of 2,2'-bipyridine, 5,5'-dimethyl-2,2'-bipyridine, 6,6'-bipyridine, 4,7-diphenyl-1,10-phenanthroline, and 2,9-dimethyl-4,7-diphenyl-1,10-phenanthroline, and the molar ratio of the ligand to the aryl fluorosulfonate is 0.15 to 0.3:

1.

6. The method for reductive amidation of aryl fluorosulfonic acid ester and isocyanate according to claim 5, characterized in that: The molar ratio of the ligand to the aryl fluorosulfonate is 0.15:

1.

7. The method for reductive amidation of an aromatic fluorosulfonic acid ester with an isocyanate according to any one of claims 1, 2, 4 and 6, characterized in that: 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.

8. The method for reductive amidation of aryl fluorosulfonate and isocyanate according to claim 7, characterized in that: The molar ratio of the metal reducing agent to the isocyanate is 2:

1.

9. The method for reductive amidation of an aromatic fluorosulfonic acid ester with an isocyanate according to any one of claims 1, 2, 4, 6, and 8, characterized in that: The solvent is selected from one of dimethyl sulfoxide, N,N-dimethylformamide and N,N-dimethylacetamide.

10. The method for reductive amidation of an aromatic fluorosulfonic acid ester with an isocyanate according to any one of claims 1, 2, 4, 6, and 8, characterized in that: The method also includes a step of purifying the reaction product.

Images