Amide compound and synthesis method thereof

Abstract

The method comprises the following steps: by taking a carboxylic acid compound, triethylamine and norbornene as reaction raw materials and 2.5 mol% of tris (dibenzylideneacetone) dipalladium as a catalyst, adding 1 mL of cyclohexane / anisole (1: 1) into 1 equivalent of lithium carbonate, 1 mol% of fluorotriphenylphosphine, 10 mol% of x-phos and 1.5 equivalent of tert-valeric anhydride in a nitrogen atmosphere, heating to 150 DEG C, reacting for 1 hour at the temperature of 150 DEG C, and reacting for 1 hour at the temperature of 150 DEG C; the effective reaction is performed for 10 hours, and the amide compound is obtained at a relatively high yield. The method has the characteristics that the reaction conditions are relatively mild, the substrate applicability is good, and the amide compound is synthesized.

Description

[Technical field]

[0001] The invention belongs to the field of transition metal catalyzed organic synthesis, and specifically relates to an amide compound and a synthesis method thereof. [Background technology]

[0002] The formation of amide bonds is one of the most important reactions in organic chemistry. Because amides are widely present in modern drugs and bioactive substances, existing methods have their inherent limitations, and avoiding waste and reducing costs are increasingly valued. Amide bonds are not only key chemical bonds in proteins, but also the basic units for the synthesis of many polymers. The functionality of amides is ubiquitous, especially in peptides and proteins. The good properties of amides, such as large polarity, stability and structural diversity, make it one of the most common and most reliable functional groups in all branches of organic chemistry.

[0003] Catalytic methods for the synthesis of amides are now having a direct impact on the synthesis of compounds containing amide bonds. These reactions are not only environmentally friendly, but also can be made at minimal cost. These methods were initially applied to the synthesis of small molecules, but the principles and mechanisms can be extended to the synthesis of peptide structures, especially those containing non-natural amino acid residues. The high efficiency and inherent selectivity of catalytic methods will provide new opportunities for enantioselective and chemoselective reactions, including the amidation of some reactive groups. As we develop better methods to synthesize complex, high-performance amides without the need for corrosive reagents and cumbersome protecting groups, the synthesis of amides will provide a new generation of high-performance materials with functional properties such as adhesion, cell growth regulation and biomineralization. Until now, synthetic methods have not been able to keep up with such promising materials.

[0004] Norbornene is an important chemical entity that has been widely used in chemistry as a building block and a medium for modern synthetic chemistry. It contains a cis-olefin part, and these unique structural properties provide norbornene with special reactivity compared to conventional olefins. For example, norbornene can be difunctionalized and participate in CH / X activation reactions as an intermediate. Based on the reading and thinking of all the existing reported difunctionalization research literature on carbonyl migration, it is found that the shortcomings of the existing reported research are that the carbonyl sources used are mostly relatively complex compounds and toxic acyl chlorides, which greatly increase the limitations of the reaction. Therefore, this paper uses green and non-toxic carboxylic acids as carbonyl sources, and reacts with amine compounds with norbornene as a skeleton to achieve acylation and amination. The acylation of norbornene is successfully achieved by using acid anhydrides to activate the carboxylic acid acyl CO bond online, and then the inert CN bond of triethylamine is broken to achieve difunctional amination on norbornene. [Summary of the invention]

[0005] The object of the present invention is to provide a method for preparing amide compounds by using norbornene, triethylamine and carboxylic acid compounds as raw materials under the promotion of alkali, palladium catalyst system and acid anhydride.

[0006] In order to achieve the above-mentioned object of the invention, the present invention proposes the following technical solutions:

[0007] An amide compound and a synthesis method thereof, wherein the amide compound I has the following general structural formula:

[0008]

[0009] Wherein R is one of phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-trimethylphenyl, 4-trifluoromethylphenyl, 4-methylnaphthyl, 4-methoxynaphthyl, and 4-fluoronaphthyl. The synthesis method of compound I is characterized in that the raw materials 1-naphthoic acid, norbornene, triethylamine, and base, ligand, acid anhydride, catalyst, and organic solvent are placed in a reaction container and mixed, and stirred at 150° C. for 10 hours under an inert gas environment; after the reaction is completed, the organic solvent is removed by vacuum distillation and concentration, and the crude product is separated by column chromatography to obtain an amide compound as shown in formula I.

[0010] In the above synthesis method, the structural formulas of the raw materials carboxylic acid ⅠⅠ, triethylamine Ⅲ and norbornene Ⅳ are as follows:

[0011]

[0012] Wherein R is phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-trimethylphenyl, 4-trifluoromethylphenyl, 4-methylnaphthyl, 4-methoxynaphthyl, 4-fluoronaphthyl.

[0013] In the above synthesis method, the base is selected from at least one of lithium carbonate, cesium carbonate, potassium phosphate, sodium hydroxide, potassium hydroxide, sodium methoxide, potassium methoxide, sodium tert-butoxide, and potassium tert-butoxide.

[0014] In the above synthesis method, the catalyst is selected from at least one of Pd2(dba)3, Pd(TFA)2, PdCl2, Pd(OAc)2, Pd(dba)2, Pd(CH3CN)2Cl2, Pd(cod)Cl2, Pd(PhCN)2Cl2, Pd(dppf)2Cl2, and Pd(PPh3)2Cl2.

[0015] In the above synthesis method, the ligand is selected from at least one of x-phos, DPE-phos, Xantphos, Ruphos, t-Bu-phos, S-phos, dppm, dppb, dppp, dpph, and dppf.

[0016] In the above synthesis method, the organic solvent is selected from at least one of cyclohexane, tetrahydrofuran, 1,4-dioxane, acetonitrile and toluene.

[0017] In the synthesis method, the inert gas is selected from at least one of nitrogen, argon and helium.

[0018] The synthesis method of a class of amide compounds provided by the present invention is a class of green and efficient synthesis route, and its advantages are: the reaction uses green and simple carboxylic acid compounds instead of toxic acyl chlorides or complex carbonyl compounds, and obtains CO migration products under the condition of no external CO added inside the system and realizes bifunctionalization to construct amide compounds. A new method for synthesizing amide compounds with relatively mild reaction conditions and good substrate applicability is obtained.

Brief Description of the Drawings

[0019] Attached Figure 1 Shown is a route map for preparing amide compounds provided by the present invention. [Specific implementation method]

[0020] The present invention provides a method for synthesizing an amide compound, as shown in the accompanying drawings: a carboxylic acid compound, triethylamine and norbornene are used as raw materials, cyclohexane / anisole (1:1) is used as a solvent, 2.5 mol% tris(dibenzylideneacetone)dipalladium is used as a catalyst, and the mixture is placed in a reaction container, heated to 150° C. in a nitrogen atmosphere, and reacted for 10 hours. After the reaction is completed, the corresponding target product is separated and purified by column chromatography to obtain the target product.

[0021] The present invention will be further described below in conjunction with specific preparation examples:

[0022] Preparation Example 1

[0023] 0.2 mmol of 1-naphthoic acid, 0.5 mmol of norbornene, 0.6 mmol of triethylamine, 0.005 mmol of tris(dibenzylideneacetone)dipalladium, 0.002 mmol of p-fluorotriphenylphosphine, 0.02 mmol of x-phos, 0.2 mmol of lithium carbonate, 0.3 mmol of tert-valeric anhydride were added to a 10 mL tubular reactor, and 1 mL of cyclohexane / anisole (1:1) was added under nitrogen atmosphere, and the mixture was reacted at 150°C for 10 hours. After the reaction, the product was separated and purified by column chromatography, and the separation yield was 85%. 1H NMR (400MHz, CDCl3) δ8.19-8.16(m,1H),7.80-7.78(m,1H),7.66(d,J=7.6Hz,1H),7.44- 7.37(m,4H),4.11(d,J=5.2Hz,1H),3.49-3.27(m,3H),3.14-3.05(m,1H),2.91-2.89(m,1 H),2.68(d,J=2.8Hz,1H),2.47(s,1H),1.97(d,J=9.6Hz,1H),1.84-1.70(m,3H),1.51(dd ,J=10.0,1.6Hz,1H),1.47-1.39(m,1H),1.16(t,J=7.2Hz,3H),0.84(t,J=7.2Hz,3H); 13C NMR (100MHz, CDCl3) δ172.2,142.84,134.01,132.14,128.37,126.22,125.69,125.36,125.1, 125.0,121.95,52.47,45.50,42.62,41.91,41.13,40.69,39.52,29.31,24.42,14.69,13.15.

[0024] Preparation Example 2

[0025] 4-methyl-1-naphthoic acid 0.2mmol, norbornene 0.5mmol, triethylamine 0.6mmol, tri(dibenzylideneacetone)dipalladium 0.005mmol, p-fluorotriphenylphosphine 0.002mmol, x-phos 0.02mmol, lithium carbonate 0.2mmol, tert-valeric anhydride 0.3mmol were added to a 10mL tubular reactor, and cyclohexane / anisole (1:1) 1mL solvent was added under nitrogen atmosphere, and the reaction was carried out at 150°C for 10 hours. After the reaction was completed, the product was separated and purified by column chromatography, and the separation yield was 81%. 1H NMR (400MHz, CDCl3) δ8.20-8.17(m,1H),7.98-7.95(m,1H),7.49-7.42(m,2H),7.32(d,J=7.6Hz,1H),7.24(d,J=8.0Hz,1H),4.08(d,J=4. 8Hz,1H),3.47-3.27(m,3H),3.15-3.06(m,1H),2.90(t,J=4.0Hz,1H),2.67-2.65(m,4H),2.46(s,1H),1.96(d,J=10.0Hz,1H),1.78-1.69 (m,4H),1.51-1.49(m,1H),1.16(t,J=5.6Hz,3H),0.85(t,J=7.2Hz,3H); 13CNMR(100MHz,CDCl3)δ172.32,141.04,133.11,132.20,132.0 1,125.83,125.58,125.38,125.25,124.42,121.67,52.52,45.40,42 .65,41.93,41.12,40.69,39.51,29.27,24.48,19.36,14.73,13.17.

[0026] Preparation Example 3

[0027] 4-methoxy-1-naphthoic acid 0.2mmol, norbornene 0.5mmol, triethylamine 0.6mmol, tri(dibenzylideneacetone)dipalladium 0.005mmol, p-fluorotriphenylphosphine 0.002mmol, x-phos 0.02mmol, lithium carbonate 0.2mmol, tert-valeric anhydride 0.3mmol were added to a 10mL tubular reactor, and cyclohexane / anisole (1:1) 1mL solvent was added under nitrogen atmosphere, and the reaction was carried out at 150°C for 10 hours. After the reaction was completed, the product was separated and purified by column chromatography, and the separation yield was 79%. 1H NMR (400MHz, CDCl3) δ8.19-8.17(m,1H),8.04-8.01(m,1H),7.39-7.34(m,2H),7.2 4(d,J=8.4Hz,1H),6.66(d,J=8.0Hz,1H),3.90(s,3H),3.36-3.26(m,3H),2.79-2. 77(m,1H),2.58(d,J=2.8Hz,1H),2.39(s,1H),1.88(d,J=9.6Hz,1H),1.70-1.60(m ,5H),1.43(dd,J=9.6,1.6Hz,1H),1.38-1.30(m,1H),1.09(s,3H),0.77(s,3H); 13C NMR (100MHz, CDCl3) δ172.42,153.64,134.86,132.94,126.27,126.01,124. 83,122.06,121.65,102.76,55.37,52.63,45.08,42.54,41.93,41.13,40.70 39.51,29.29,24.45,14.73,13.19.

[0028] Preparation Example 4

[0029] 0.2 mmol of 4-fluoro-1-naphthoic acid, 0.5 mmol of norbornene, 0.6 mmol of triethylamine, 0.005 mmol of tris(dibenzylideneacetone)dipalladium, 0.002 mmol of p-fluorotriphenylphosphine, 0.02 mmol of x-phos, 0.2 mmol of lithium carbonate, 0.3 mmol of tert-valeric anhydride were added to a 10 mL tubular reactor, and 1 mL of solvent cyclohexane / anisole (1:1) was added under nitrogen atmosphere, and the mixture was reacted at 150° C. for 10 hours. After the reaction, the product was separated and purified by column chromatography, and the separation yield was 74%. 1H NMR (400MHz, CDCl3) δ8.12-8.09(m,1H),8.02-7.99(m,1H),7.44-7.39(m,3H),7 .26(dd,J=8.0,5.6Hz,1H),6.98(dd,J=10.4,8.0Hz,1H),3.97(d,J=4.8Hz,1H),2 .78-2.75(m,1H),2.58(s,1H),2.41(s,1H),1.88(d,J=9.6Hz,2H),1.70-1.62(m ,4H),1.45(dd,J=10.0,1.6Hz,1H),1.38-1.33(m,2H),1.18(d,J=5.6Hz,6H).13C NMR(100MHz,CDCl3)δ172.16,157.24(d,J C-F =248.3Hz),138.77(d,J C-F =4.3Hz),133.31(d,J C-F =4.1Hz),126.64,125.71(d,J C-F =1.5Hz),125.12(d,J C-F =2.5Hz),124.06(d,J C-F =15.4Hz),121.51(d,J C-F =8.0Hz),120.71(d,J C-F =5.9Hz),108.23(d,J C-F =19.1Hz),52.83,45.18,42.60,41.16,39.54,29.68,29.35,24.34.

[0030] Preparation Example 5

[0031] 0.2 mmol of 3,4,5,6-tetrahydro-1-naphthoic acid, 0.5 mmol of norbornene, 0.6 mmol of triethylamine, 0.005 mmol of tris(dibenzylideneacetone)dipalladium, 0.002 mmol of p-fluorotriphenylphosphine, 0.02 mmol of x-phos, 0.2 mmol of lithium carbonate, 0.3 mmol of tert-valeric anhydride were added to a 10 mL tubular reactor, and 1 mL of solvent cyclohexane / anisole (1:1) was added under nitrogen atmosphere, and the mixture was reacted at 150° C. for 10 hours. After the reaction, the product was separated and purified by column chromatography, and the separation yield was 60%. 1H NMR (400MHz, CDCl3) δ7.25-7.04(m,2H),6.91(d,J=7.2Hz,1H),3.58(d,J=4 .4Hz,1H),3.52-3.40(m,2H),3.30-3.21(m,2H),3.04-3.01(m,1H),2.78-2 .72(m,3H),2.68-2.60(m,1H),2.47(s,1H),2.29(s,1H),1.74-1.55(m,6H) ,1.39-1.36(m,2H),1.25(s,2H),1.13-1.11(m,3H),1.10-1.08(m,3H); 13C NMR (100MHz, CDCl3) δ171.91,144.57,137.57,135.96,126.90,124.77,122.56,50.88,45.21 ,43.66,41.77,40.93,40.46,38.84,30.47,29.57,26.69,24.21,23.48,22.71,14.89,13.14.

[0032] Preparation Example 6

[0033] 0.2 mmol of 2-naphthoic acid, 0.5 mmol of norbornene, 0.6 mmol of triethylamine, 0.005 mmol of tris(dibenzylideneacetone)dipalladium, 0.002 mmol of p-fluorotriphenylphosphine, 0.02 mmol of x-phos, 0.2 mmol of lithium carbonate, 0.3 mmol of tert-valeric anhydride were added to a 10 mL tubular reactor, and 1 mL of solvent cyclohexane / anisole (1:1) was added under a nitrogen atmosphere, and the mixture was reacted at 150° C. for 10 hours. After the reaction was completed, the product was separated and purified by column chromatography, and the separation yield was 64%. 1H NMR(400MHz,CDCl3)δ7.78-7.73(m,3H),7.63(s,1H),7.45-7.37(m,2H),7.31-7.25(m,1H),3.64(dd,J=13.6,7.2Hz,1H),3.49-3.40(m,1H),3.27-3.17(m,2H),2.97-2.94(m,1H),2.67(d,J=3.2Hz,1H),2.52(s,1H),1.92-1.90(m,1H),1.75-1.64(m,2H),1.63-1.55(m,1H),1.49(dd,J=10.0,1.6Hz,1H),1.26(d,J=4.0Hz,2H),1.14(t,J=7.2Hz,3H),1.07(t,J=7.2Hz,3H); 13 CNMR(100MHz,CDCl3)δ171.81,144.36,133.46,131.75,127.98,127.60,127.4,126.56,125.81,125.04,123.68,54.07,48.94,41.88,41.56,41.32,40.29,39.32,29.80,29.68,23.75,14.87,13.27.

[0034] Preparation Example 7

[0035] To a 10mL tubular reactor, 0.2mmol of benzoic acid, 0.5mmol of norbornene, 0.6mmol of triethylamine, 0.005mmol of tris(dibenzylideneacetone)dipalladium, 0.002mmol of p-fluorotriphenylphosphine, 0.02mmol of x-phos, 0.2mmol of lithium carbonate, and 0.3mmol of tert-valeric anhydride were added, and 1mL of solvent cyclohexane / anisole (1:1) was added under a nitrogen atmosphere, and the reaction was carried out at 150°C for 10 hours. After the reaction was completed, the product was separated and purified by column chromatography, and the separation yield was 55%. 1H NMR (400MHz, CDCl3) δ7.28-7.12(m,5H),3.65-3.56(m,1H),3.48-3.39(m,1H),3.28-3.16(m,2H),2.90-2.87(m,1H),2.54-2.48(m 13C NMR (100MHz, CDCl3) δ171.82,146.92,128.30,126.67,125.42,54.03,48. 80,42.06,41.55,41.19,40.26,39.22,29.77,27.05,23.67,14.86,13.24.

[0036] Preparation Example 8

[0037] To a 10mL tubular reactor, 0.2mmol of p-toluic acid, 0.5mmol of norbornene, 0.6mmol of triethylamine, 0.005mmol of tris(dibenzylideneacetone)dipalladium, 0.002mmol of p-fluorotriphenylphosphine, 0.02mmol of x-phos, 0.2mmol of lithium carbonate, and 0.3mmol of tert-valeric anhydride were added. 1mL of solvent cyclohexane / anisole (1:1) was added under a nitrogen atmosphere, and the mixture was reacted at 150°C for 10 hours. After the reaction, the product was separated and purified by column chromatography, and the separation yield was 51%. 1H NMR (400MHz, CDCl3) δ7.26 (s, 1H), 7.08 (d, J = 1.2Hz, 3H), 3.64-3.55 (m, 1H), 3.49 (d, J = 4.8Hz, 1H), 3.46 -3.40(m,2H),3.26-3.17(m,2H),3.01(s,1H),2.91-2.86(m,1H),2.50-2.47(m,2H),2.30(s,3H),1.61(s ,3H),1.25(s,2H),1.12(t,J=6.8Hz,3H),1.09(t,J=6.8Hz,3H); 13CNMR(100MHz,CDCl3)δ171.89,134.8 5,128.99,126.61,54.04,48.48,42.29,41.54,41.19,40.23,39.19,29.79,23.72,20.88,14.91,13.26.

[0038] Preparation Example 9

[0039] To a 10mL tubular reactor, 0.2mmol of p-tert-butylbenzoic acid, 0.5mmol of norbornene, 0.6mmol of triethylamine, 0.005mmol of tris(dibenzylideneacetone)dipalladium, 0.002mmol of p-fluorotriphenylphosphine, 0.02mmol of x-phos, 0.2mmol of lithium carbonate, and 0.3mmol of tert-valeric anhydride were added. 1mL of solvent cyclohexane / anisole (1:1) was added under a nitrogen atmosphere, and the mixture was reacted at 150°C for 10 hours. After the reaction, the product was separated and purified by column chromatography, and the separation yield was 49%. 1H NMR (400MHz, CDCl3) δ7.30-7.26(m,2H),7.13(d,J=8.0Hz,2H),3.59-3.39(m,3H),3.30-3.16(m,2H),2.93- 2.90(m,1H),2.51-2.48(m,2H),1.82(d,J=9.6Hz,1H),1.70(s,1H),1.62-1.57(m,2H),1.40(dd,J=9.6,1.6H z,2H),1.29(s,6H),1.25(s,3H),1.12(q,J=7.2Hz,6H);13CNMR(100MHz,CDCl3)δ171.87,148.14,143.84,1 26.36,125.15,53.70,48.34,42.24,41.54,41.14,40.21,39.12,34.25,31.36,29.69,23.76,14.91,13.25.

[0040] The above-mentioned embodiments only express several implementation methods of the present invention, and the description thereof is relatively specific and detailed, but it cannot be understood as limiting the scope of the patent of the present invention. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. A method for synthesizing an amide compound, comprising the following steps: The raw material carboxylic acid compound, triethylamine and norbornene, cyclohexane / anisole (1:1) as solvent, and 2.5 mol% tris(dibenzylideneacetone)dipalladium as catalyst are placed in a reaction container, heated to 150°C under a nitrogen atmosphere, and reacted for 10 hours. After the reaction is completed, the crude product is separated by column chromatography to obtain an amide compound as shown in Formula I. In the formula I, R is one of phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-trimethylphenyl, 4-trifluoromethylphenyl, 4-methylnaphthyl, 4-methoxynaphthyl and 4-fluoronaphthyl.

2. The method for synthesizing an amide compound according to claim 1, characterized in that The structural formulas of the raw materials carboxylic acid ⅠⅠ, triethylamine Ⅲ and norbornene Ⅳ are as follows: In the formula Ⅱ, R is phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-trimethylphenyl, 4-trifluoromethylphenyl, 4-methylnaphthyl, 4-methoxynaphthyl, or 4-fluoronaphthyl.

3. The method for synthesizing amide compounds according to claim 1, characterized in that: The base is selected from at least one of lithium carbonate, cesium carbonate, potassium phosphate, sodium hydroxide, potassium hydroxide, sodium methoxide, potassium methoxide, sodium tert-butoxide, and potassium tert-butoxide.

4. The method for synthesizing amide compounds according to claim 1, characterized in that: The catalyst is selected from at least one of Pd2(dba)3, Pd(TFA)2, PdCl2, Pd(OAc)2, Pd(dba)2, Pd(CH3CN)2Cl2, Pd(cod)Cl2, Pd(PhCN)2Cl2, Pd(dppf)2Cl2, and Pd(PPh3)2Cl2.

5. The method for synthesizing amide compounds according to claim 1, characterized in that: The ligand is selected from at least one of x-phos, DPE-phos, Xantphos, Ruphos, t-Bu-phos, S-phos, dppm, dppb, dppp, dpph, and dppf.

6. The method for synthesizing amide compounds according to claim 1, characterized in that: The organic solvent is selected from at least one of cyclohexane, tetrahydrofuran, 1,4-dioxane, acetonitrile and toluene.

7. The method for synthesizing amide compounds according to claim 1, characterized in that: The inert gas is selected from at least one of nitrogen, argon and helium.

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