阅读说明：本技术 一种2,5-取代基1h-咪唑-4-羧酸酯类化合物及其合成纯化方法 (2, 5-substituent 1H-imidazole-4-carboxylic ester compound and synthesis and purification method thereof ) 是由 高鹏 白梓静 陈怀娟 于 2021-01-06 设计创作，主要内容包括：本发明提供了一种2,5-取代基-1H-咪唑-4-羧酸酯类化合物及其合成纯化方法,该方法以碘为氧化剂促进了烯胺化合物氧化环化反应,使得制备2,5-取代基-1H-咪唑-4-羧酸酯类化合物的操作更为简单,制备成本大幅度低,相对收率和纯度更高,环境污染少。另外,本发明提供的2,5-取代基-1H-咪唑-4-羧酸酯类化合物因其特殊的杂环骨架,已在医药、配体化学和材料科学领域中得到广泛应用,是一种有价值的合成中间体和功能有机分子。(The invention provides a 2, 5-substituent-1H-imidazole-4-carboxylic ester compound and a synthesis and purification method thereof, and the method takes iodine as an oxidant to promote the oxidative cyclization reaction of enamine compounds, so that the operation for preparing the 2, 5-substituent-1H-imidazole-4-carboxylic ester compound is simpler, the preparation cost is greatly low, the relative yield and purity are higher, and the environmental pollution is less. In addition, the 2, 5-substituent-1H-imidazole-4-carboxylic ester compound provided by the invention has been widely applied in the fields of medicine, ligand chemistry and material science due to the special heterocyclic skeleton, and is a valuable synthetic intermediate and functional organic molecule.)

1. a2, 5-substituent group 1H-imidazole-4-carboxylic ester compound has the following structural general formula:

wherein R is¹Aryl or trifluoromethyl, R²＝C₁-C₇Alkyl, phenyl, C₁-C₆Alkoxy, phenoxy, benzyl or benzyloxy, R³An ester group or a benzoyl group.

2. The 2, 5-substituent-1H-imidazole-4-carboxylic acid ester compound of claim 1, wherein R is¹Is aryl, and the aryl is phenyl, biphenyl or heterocyclic aryl containing substituent groups.

3. The 2, 5-substituent-1H-imidazole-4-carboxylic acid ester compound according to claim 2, wherein the phenyl group containing a substituent is a phenyl group containing one or more substituents, the biphenyl group is a 4-biphenyl group, and the heterocyclic aryl group is a 2-thienyl group or a 3-thienyl group.

4. The 2, 5-substituent-1H-imidazole-4-carboxylic acid ester compound of claim 3, wherein the substituent is alkyl, alkoxy, haloalkyl, nitro, or halo.

5. The 2, 5-substituent-1H-imidazole-4-carboxylic acid ester compound of claim 1, wherein R is²Selected from one of the following: methyl, ethyl, propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, phenyl, benzyl, methoxy, phenoxy, benzyloxy.

6. The 2, 5-substituent-1H-imidazole-4-carboxylic acid ester compound of claim 1, wherein R is³Is an ester group, the ester group is-CO₂R, R ═ methyl or ethyl.

7. A method for synthesizing 2, 5-substituent-1H-imidazole-4-carboxylic ester compounds according to any one of claims 1 to 6, which comprises the following steps of taking enamine esters or enaminones and azidotrimethylsilane as raw materials, adding mixed alkali into the raw materials, and carrying out reflux reaction in a solvent to obtain a crude product, wherein the reaction formula is as follows:

the mixed alkali consists of potassium carbonate and sodium acetate, and the molar usage ratio of the enamine ester or enaminone to the azidotrimethylsilane, iodine, the potassium carbonate and the sodium acetate is 1 (2.5-3.5) to (0.8-1.2).

8. The method for synthesizing the 2, 5-substituent-1H-imidazole-4-carboxylic ester compounds according to claim 7, wherein the solvent is N, N-dimethylformamide, and the reflux reaction time is 6-12H.

9. A method for purifying a crude product of a 2, 5-substituent-1H-imidazole-4-carboxylic ester compound is characterized by comprising the following steps: taking the crude product of the 2, 5-substituent-1H-imidazole-4-carboxylic ester compound obtained by the synthesis method of claim 7, and carrying out the following steps (4.5-5.5): (9-11): adding water, petroleum ether and ethyl acetate into the mixture according to the volume ratio of 1 for extraction, extracting for 2-4 times, combining organic phases to obtain an extract, and purifying the extract by silica gel column chromatography, wherein the volume ratio of eluent is (2.8-3.2): 1 petroleum ether-ethyl acetate.

10. The method for purifying the crude 2, 5-substituent-1H-imidazole-4-carboxylic acid ester compound of claim 9, comprising the following steps of 5: 10:1, adding water, petroleum ether and ethyl acetate for extraction, extracting for 2-4 times, combining organic phases to obtain an extract, purifying the extract by silica gel column chromatography, wherein the volume ratio of the eluent is 3:1 petroleum ether-ethyl acetate.

Technical Field

The invention belongs to the technical field of chemical synthesis, and particularly relates to a 2, 5-substituent-1H-imidazole-4-carboxylic ester compound and a synthesis and purification method thereof.

Background

Imidazole compounds are special five-membered nitrogen heterocyclic compounds, and have been widely used in the fields of medicine, ligand chemistry and material science due to their special heterocyclic skeletons (org. Lett.2020,22, 1980-. Imidazoles are valuable synthetic intermediates and are therefore commonly used in organic synthesis. The imidazole structure contains two nitrogen donor coordination sites, which makes it completely emergent in coordination chemistry and widely used for constructing target Metal Organic Frameworks (MOFs) (org. lett.2019,21, 9874-. Prior to this, transition metal catalyzed and transition metal-free catalyzed processes have been greatly developed, with the transition metal-free reactions being environmentally friendly (org. lett.2019,21, 9874-. However, the imidazole synthesis method at present has disadvantages, because most reactions still need the participation of transition metal and the substrate needs complex composite substrate, and the synthesis cost is high, so that the search for a high-efficiency, simple and low-cost synthesis method is urgent.

Disclosure of Invention

In view of the defects in the prior art, the inventor establishes a simple and practical preparation method of 2, 5-substituent-1H-imidazole-4-carboxylic ester through a large number of experiments, and synthesizes a series of compounds 2, 5-substituent-1H-imidazole-4-carboxylic ester with novel structures.

Based on the experimental results of the inventor, the first object of the invention is to provide a series of 2, 5-substituent-1H-imidazole-4-carboxylic ester compounds, which have the following structural general formula:

wherein R is¹Aryl or trifluoromethyl, R²＝C₁-C₇Alkyl, phenyl, C₁-C₆Alkoxy, phenoxy, benzyl or benzyloxy, R³An ester group or a benzoyl group.

Further preferred are the 2, 5-substituent-1H-imidazole-4-carboxylic acid ester compounds as described above, wherein R is¹Is aryl, and the aryl is phenyl, biphenyl or heterocyclic aryl containing substituent groups. The phenyl containing the substituent group is phenyl containing one or more substituent groups, the biphenyl is 4-biphenyl, and the heterocyclic aryl is 2-thienyl or 3-thienyl. The substituent is alkyl, alkoxy, halogenated alkyl, nitro or halogen substituent.

It is further preferred that the first and second liquid crystal compositions,the 2, 5-substituent-1H-imidazole-4-carboxylic ester compound as described above, wherein R is²Selected from one of the following: methyl, ethyl, propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, phenyl, benzyl, methoxy, phenoxy, benzyloxy.

Further preferred are the 2, 5-substituent-1H-imidazole-4-carboxylic acid ester compounds as described above, wherein R is³Is an ester group, the ester group is-CO₂R, R ═ methyl or ethyl.

In addition, the second objective of the present invention is to provide a method for synthesizing the above 2, 5-substituent-1H-imidazole-4-carboxylic acid ester compound, the method comprises using enamine ester or enaminoketone compound and azidotrimethylsilane as raw materials, using iodine as oxidant, adding mixed base, and refluxing in a solvent to obtain a crude product, wherein the reaction formula is as follows:

the mixed alkali consists of potassium carbonate and sodium acetate, wherein: the molar ratio of enamine ester or enaminone, azidotrimethylsilane, iodine, potassium carbonate and sodium acetate is 1 (2.5-3.5): (2.5-3.5): (2.5-3.5): 0.8-1.2), preferably 1:3:3:3: 1.

Further preferably, the method for synthesizing the 2, 5-substituent-1H-imidazole-4-carboxylic ester compound is as described above, wherein the solvent is N, N-dimethylformamide, and the reflux reaction time is 6-12H.

Furthermore, the invention also provides a purification method of a crude product of the 2, 5-substituent-1H-imidazole-4-carboxylic ester compound, which comprises the following steps: taking the crude product of the 2, 5-diphenyl 1H-imidazole-4-carboxylic ester obtained by the synthesis method according to the ratio of (4.5-5.5): (9-11): adding water, petroleum ether and ethyl acetate into the mixture according to the volume ratio of 1 for extraction, extracting for 2-4 times, combining organic phases to obtain an extract, and purifying the extract by silica gel column chromatography, wherein the volume ratio of eluent is (2.8-3.2): 1 petroleum ether-ethyl acetate.

Further preferably, the purification method is performed according to the following ratio of 5: 10:1, adding water, petroleum ether and ethyl acetate for extraction, extracting for 2-4 times, combining organic phases to obtain an extract, purifying the extract by silica gel column chromatography, wherein the volume ratio of the eluent is 3:1 petroleum ether-ethyl acetate.

Compared with the prior art, the method creatively takes iodine as an oxidant to promote the oxidative cyclization reaction of the enamine compound, so that the preparation method of the 2, 5-substituent-1H-imidazole-4-carboxylic ester has the advantages of simple operation, greatly reduced preparation cost, higher relative yield and purity, less environmental pollution and more ideal effect, and is one of the most direct and efficient methods for synthesizing the 2, 5-substituent-1H-imidazole-4-carboxylic ester reported at present. In addition, the 2, 5-substituent-1H-imidazole-4-carboxylic ester provided by the invention is a series of compounds with novel structures and potential application values, and can be widely applied to the field of medicines, ligand chemistry and material science.

Detailed Description

The following are specific examples of the present invention and further describe the technical solutions of the present invention, but the scope of the present invention is not limited to these examples. All changes, modifications and equivalents that do not depart from the spirit of the invention are intended to be included within the scope thereof.

Example 1: the synthesis of 2, 5-diphenyl-1H-imidazole-4-carboxylic acid methyl ester (2a) has the following structural formula:

adding 0.3mmol of enamine ester (1a), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mol of potassium carbonate and 0.3mmol of sodium acetate into 6mL of N, N-dimethylformamide, refluxing for 12h, after the reaction is finished, adding 110mL of organic phase (PE: EA is 10:1, PE is petroleum ether, EA is ethyl acetate) in three times (5:3:3), extracting for three times, combining the organic phases to obtain an extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing rapid silica gel column chromatography (V) on the crude product_{Ethyl acetate}∶V_{Petroleum ether}3: 1) to obtain 71mg of product by calculationThe yield thereof was found to be 85%.

The main physicochemical properties are as follows:

yellow solid.¹H NMR(400MHz,CDCl₃):δ7.92-7.95(m,2H),7.84-7.86(m,2H),7.36-7.45(m,6H),3.84(s,3H).¹³C{¹H}NMR(100MHz,CDCl₃):δ161.5,147.5,129.9,129.2,128.9,128.8,128.7,128.0,126.0,51.8.HRMS(ESI-TOF):m/z calcd for C₁₇H₁₅N₂O₂[M+H]⁺279.1128,found:279.1131。

Example 2: synthesis of methyl 2-phenyl-5- (p-tolyl) -1H-imidazole-4-carboxylate (2b), the structural formula of which is specifically as follows:

adding 0.3mmol of enamine ester (1b), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mol of potassium carbonate and 0.3mmol of sodium acetate into 6mL of N, N-dimethylformamide, refluxing for 12h, adding organic phase 110mL (PE: EA ═ 10:1) into three times (5:3:3) after reaction, extracting for three times, combining the organic phases to obtain extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V) on the crude product_{Ethyl acetate}∶V_{Petroleum ether}3: 1) to yield 61mg of product, calculated in 70% yield.

The main physicochemical properties are as follows:

yellow solid.¹H NMR(400MHz,CDCl₃):δ7.92-7.95(m,2H),7.74-7.76(m,2H),7.40-7.45(m,3H),7.20-7.22(m,2H),3.84(s,3H),2.37(s,3H).¹³C{¹H}NMR(100MHz,CDCl₃):δ161.5,147.2,138.8,130.2,129.9,129.2,129.1,128.9,128.7,128.6,126.0,51.8,21.4.HRMS(ESI-TOF):m/z calcd for C₁₈H₁₇N₂O₂[M+H]⁺293.1285,found:293.1291。

Example 3 Synthesis of methyl 2-phenyl-5- (m-tolyl) -1H-imidazole-4-carboxylate (2c), the structural formula is specifically as follows:

adding 0.3mmol of enamine ester (1c), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate into 6mL of N, N-dimethylformamide, refluxing for 12h, adding organic phase 110mL (PE: EA ═ 10:1) into three times (5:3:3) after reaction, extracting for three times, combining the organic phases to obtain extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V) on the crude product_{Ethyl acetate}∶V_{Petroleum ether}3: 1) to yield 60mg of product, calculated yield 68%.

The main physicochemical properties are as follows:

yellow solid.¹H NMR(400MHz,CDCl₃):δ7.89-7.92(m,2H),7.50-7.53(m,2H),7.35-7.37(m,3H),7.19-7.23(m,1H),7.10-7.13(m,1H),3.76(s,3.H),2.3(m,3H).¹³C{¹H}NMR(100MHz,CDCl₃):δ162.1,147.5,137.5,131.4,129.8,129.7,129.5,128.8,128.7,127.7,126.5,126.1,51.7,21.4.HRMS(ESI-TOF):m/z calcd for C₁₈H₁₇N₂O₂[M+H]⁺293.1285,found:293.1281。

Example 4: synthesis of methyl 2-phenyl-5- (o-tolyl) -1H-imidazole-4-carboxylate (2d), the structural formula is specifically as follows:

adding 0.3mmol of enamine ester (1d), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mol of potassium carbonate and 0.3mmol of sodium acetate into 6mL of N, N-dimethylformamide, refluxing for 12h, adding organic phase 110mL (PE: EA ═ 10:1) into three times (5:3:3) after reaction, extracting for three times, combining the organic phases to obtain extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V) on the crude product_{Ethyl acetate}∶V_{Petroleum ether}Purifying at ratio of 3:1 to obtainTo 33mg of product, the calculated yield is 38%.

The main physicochemical properties are as follows:

yellow solid.¹H NMR(400MHz,CDCl₃):δ7.87-7.89(m,2H),7.35-7.37(m,3H),7.14-7.2(m,3H),7.06-7.10(m,1H),3.65(m,3H),2.13(m,3H).¹³C{¹H}NMR(100MHz,CDCl₃):δ162.3,147.2,137.4,130.1,129.9,129.6,128.9,128.8,126.0,125.1,51.6,19.8.HRMS(ESI-TOF):m/z calcd for C₁₈H₁₇N₂O₂[M+H]⁺293.1285,found:293.1297。

Example 5: the synthesis of 2-phenyl-5- (3, 4-dimethylphenyl) -1H-imidazole-4-carboxylic acid methyl ester (2e) has the following specific structural formula:

adding 0.3mmol of enamine ester (1e), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mol of potassium carbonate and 0.3mmol of sodium acetate into 6mL of N, N-dimethylformamide, refluxing for 12h, adding organic phase 110mL (PE: EA ═ 10:1) into three times (5:3:3) after reaction, extracting for three times, combining the organic phases to obtain extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V) on the crude product_{Ethyl acetate}∶V_{Petroleum ether}3: 1) to yield 73mg of product, calculated yield 80%.

The main physicochemical properties are as follows:

yellow solid.¹H NMR(400MHz,CDCl₃):δ7.90-7.93(m,2H),7.50-7.55(m,2H),7.38-7.41(m,3H),7.11-7.13(m,1H),3.81(s,3H),2.25(s,6H).¹³C{¹H}NMR(100MHz,CDCl₃):δ161.7,147.2,137.4,136.2,130.2,129.7,129.2,128.8,126.7,126.0,51.7,19.7,19.6.HRMS(ESI-TOF):m/z calcd for C₁₉H₁₉N₂O₂[M+H]⁺307.1441,found:307.1452。

Example 6: the synthesis of 2-phenyl-5- (p-methoxyphenyl) -1H-imidazole-4-carboxylic acid methyl ester (2f) has the following structural formula:

adding 0.3mmol of enamine ester (1f), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mol of potassium carbonate and 0.3mmol of sodium acetate into 6mL of N, N-dimethylformamide, refluxing for 12h, adding organic phase 110mL (PE: EA ═ 10:1) into three times (5:3:3) after reaction, extracting for three times, combining the organic phases to obtain extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V) on the crude product_{Ethyl acetate}∶V_{Petroleum ether}3: 1) to give 62mg of product, calculated yield 67%.

The main physicochemical properties are as follows:

yellow solid.¹H NMR(400MHz,CDCl₃):δ7.94-7.97(m,2H),7.84-7.87(m,2H),7.41-7.44(m,3H),6.93-6.95(m,2H),3.86(s,3H),3.83(s,3H).¹³C{¹H}NMR(100MHz,CDCl₃):δ.HRMS(ESI-TOF):m/z calcd for C₁₈H₁₇N₂O₃[M+H]⁺309.1233,found:309.1240。

Example 7: synthesis of methyl 2-phenyl-5- (m-methoxyphenyl) -1H-imidazole-4-carboxylate (2g), the structural formula is specifically as follows:

adding 0.3mmol of enamine ester (1g), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mol of potassium carbonate and 0.3mmol of sodium acetate into 6mL of N, N-dimethylformamide, refluxing for 12h, adding organic phase 110mL (PE: EA ═ 10:1) into three times (5:3:3) after reaction, extracting for three times, combining the organic phases to obtain extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V) on the crude product_{Ethyl acetate}∶V_{Petroleum ether}3: 1) to obtain 53mg of product,the calculated yield was 57%.

The main physicochemical properties are as follows:

yellow solid.¹H NMR(400MHz,CDCl₃):δ7.93-7.96(m,2H),7.41-7.47(m,5H),7.28-7.32(m,1H),6.90-6.93(m,1H),3.84(s,3H),3.83(s,3H).¹³C{¹H}NMR(100MHz,CDCl₃):δ161.3,159.2,147.4,133.3,130.0,129.0,128.9,128.5,126.0,121.7,114.9,114.5,55.3,51.9.HRMS(ESI-TOF):m/z calcd for C₁₈H₁₇N₂O₃[M+H]⁺309.1233,found:309.1241。

Example 8: synthesis of methyl 2-phenyl-5- (3, 4-dimethoxyphenyl) -1H-imidazole-4-carboxylate (2H), the structural formula is specifically as follows:

adding 0.3mmol of enamine ester (1h), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mol of potassium carbonate and 0.3mmol of sodium acetate into 6mL of N, N-dimethylformamide, refluxing for 12h, adding organic phase 110mL (PE: EA ═ 10:1) into three times (5:3:3) after reaction, extracting for three times, combining the organic phases to obtain extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing rapid silica gel column chromatography (V) on the crude product_{Ethyl acetate}∶V_{Petroleum ether}3: 1) to yield 82mg of product, calculated in 81% yield.

The main physicochemical properties are as follows:

yellow solid.¹H NMR(400MHz,CDCl₃):δ7.94-7.97(m,2H),7.51-7.57(m,2H),7.40-7.45(m,3H),6.88-6.90(m,1H),3.91(s,3H),3.89(s,3H),3.85(s,3H).¹³C{¹H}NMR(100MHz,CDCl₃):δ161.3,149.5,148.3,147.2,130.0,128.9,128.6,126.0,122.1,112.6,110.6,55.9,55.8,51.8.HRMS(ESI-TOF):m/z calcd for C₁₉H₁₉N₂O₄[M+H]⁺339.1339,found:339.1356。

Example 9: the synthesis of 2-phenyl-5- (p-fluorophenyl) -1H-imidazole-4-carboxylic acid methyl ester (2i) has the following specific structural formula:

adding 0.3mmol of enamine ester (1i), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mol of potassium carbonate and 0.3mmol of sodium acetate into 6mL of N, N-dimethylformamide, refluxing for 12h, adding organic phase 110mL (PE: EA ═ 10:1) into three times (5:3:3) after reaction, extracting for three times, combining the organic phases to obtain extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V) on the crude product_{Ethyl acetate}∶V_{Petroleum ether}3: 1) to yield 54mg of product, calculated yield 61%.

The main physicochemical properties are as follows:

yellow solid.¹H NMR(400MHz,CDCl₃):δ7.92-7.96(m,4H),7.43-7.49(m,3H),7.08-7.13(m,2H),7.87(s,3H).¹³C{¹H}NMR(100MHz,CDCl₃):δ164.3,161.8,147.5,131.3,131.2,130.1,129.0,128.4,126.0,115.1,114.8,51.9.HRMS(ESI-TOF):m/z calcd for C₁₇H₁₄FN₂O₂[M+H]⁺297.1033,found:297.1052。

Example 10: the synthesis of 2-phenyl-5- (p-chlorophenyl) -1H-imidazole-4-carboxylic acid methyl ester (2j) has the following structural formula:

adding 0.3mmol of enamine ester (1j), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mol of potassium carbonate and 0.3mmol of sodium acetate into 6mL of N, N-dimethylformamide, refluxing for 12h, adding organic phase 110mL (PE: EA ═ 10:1) into three times (5:3:3) after reaction, extracting for three times, combining the organic phases to obtain extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V) on the crude product_{Ethyl acetate}∶V_{Petroleum ether}3: 1) to yield 70mg of product, calculated in 75% yield.

The main physicochemical properties are as follows:

yellow solid.¹H NMR(400MHz,CDCl₃):δ7.93-7.95(m,4H),7.43-7.47(m,3H),7.37-7.40(m,2H),3.87(s,3H).¹³C{¹H}NMR(100MHz,CDCl₃):δ134.6,130.6,130.1,129.0,128.6,128.2,125.9,52.HRMS(ESI-TOF):m/z calcd for C₁₇H₁₄ClN₂O₂[M+H]⁺313.0738,found:313.0747。

Example 11: the synthesis of 2-phenyl-5- (m-chlorophenyl) -1H-imidazole-4-carboxylic acid methyl ester (2k) has the following structural formula:

adding 0.3mmol of enamine ester (1k), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mol of potassium carbonate and 0.3mmol of sodium acetate into 6mL of N, N-dimethylformamide, refluxing for 12h, adding organic phase 110mL (PE: EA ═ 10:1) into three times (5:3:3) after reaction, extracting for three times, combining the organic phases to obtain extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V) on the crude product_{Ethyl acetate}∶V_{Petroleum ether}3: 1) to yield 64mg of product, calculated in 68% yield.

The main physicochemical properties are as follows:

yellow solid.¹H NMR(400MHz,CDCl₃):δ10.20(b,1H),7.94-8.00(m,3H),7.86-7.90(m,1H),7.44-7.48(m,3H),7.33-7.35(m,2H),3.88(s,3H).¹³C{¹H}NMR(100MHz,CDCl₃):δ160.5,148.0,146.9,134.9,133.8,130.2,129.3,129.2,129.1,128.5,127.4,126.0,118.5,52.1.HRMS(ESI-TOF):m/z calcd for C₁₇H₁₄ClN₂O₂[M+H]⁺313.0738,found:313.0742。

Example 12: synthesis of methyl 2-phenyl-5- (p-bromophenyl) -1H-imidazole-4-carboxylate (2l) having the following specific structural formula:

adding 0.3mmol of enamine ester (1l), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mol of potassium carbonate and 0.3mmol of sodium acetate into 6mL of N, N-dimethylformamide, refluxing for 12h, adding organic phase 110mL (PE: EA ═ 10:1) into three times (5:3:3) after reaction, extracting for three times, combining the organic phases to obtain extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V) on the crude product_{Ethyl acetate}∶V_{Petroleum ether}3: 1) to yield 74mg of product, calculated yield 69%.

The main physicochemical properties are as follows:

yellow solid.¹H NMR(400MHz,CDCl₃):δ7.94-7.97(m,2H),7.84-7.86(m,2H),7.54-7.56(m,2H),7.45-7.49(m,3H),3.88(s,3H).¹³C{¹H}NMR(100MHz,CDCl₃):δ160.6,147.6,131.2,130.9,130.4,129.1,127.9,126.1,123.2,52.1.HRMS(ESI-TOF):m/z calcd for C₁₇H₁₃NaBrN₂O₂[M+Na]⁺379.0052,found:379.0059。

Example 13: the synthesis of 2-phenyl-5- (p-trifluoromethylphenyl) -1H-imidazole-4-carboxylic acid methyl ester (2m) has the following structural formula:

adding 0.3mmol of enamine ester (1m), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mol of potassium carbonate and 0.3mmol of sodium acetate into 6mL of N, N-dimethylformamide, refluxing for 12h, adding organic phase 110mL (PE: EA ═ 10:1) into three times (5:3:3) after reaction, extracting for three times, combining the organic phases to obtain extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V) on the crude product_{Ethyl acetate}∶V_{Petroleum ether}3: 1) to yield 77mg of product, calculated yield 74%.

The main physicochemical properties are as follows:

a white solid.¹H NMR(400MHz,CDCl₃):δ8.08-8.10(m,2H),7.95-7.97(m,2H),7.66-7.69(m,2H),7.45-7.49(m,3H),3.88(s,3H).¹³C{¹H}NMR(100MHz,CDCl₃):δ160.6,147.9,130.5,130.3,130.2,129.6,129.1,128.4,126.2,126.0,125.5,124.9(J_C-F＝3.81Hz),122.8,52.1.HRMS(ESI-TOF):m/z calcd for C₁₈H₁₄F₃N₂O₂[M+H]⁺347.1001,found:347.1004。

Example 14: the synthesis of 2-phenyl-5- (thiophene-2-yl) -1H-imidazole-4-carboxylic acid methyl ester (2n) has the following structural formula:

adding 0.3mmol of enamine ester (1N), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate into 6mL of N, N-dimethylformamide, refluxing for 12h, adding organic phase 110mL (PE: EA ═ 10:1) into three times (5:3:3) after reaction, extracting for three times, combining the organic phases to obtain extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V) on the crude product_{Ethyl acetate}∶V_{Petroleum ether}3: 1) to yield 57mg of product, calculated in 67% yield.

The main physicochemical properties are as follows:

yellow solid.¹H NMR(400MHz,CDCl₃):δ10.47(b.1H),7.95-8.05(m,3H),7.36-7.40(m,4H),7.06-7.09(m,1H),3.90(m,3H).¹³C{¹H}NMR(100MHz,CDCl₃):δ160.6,148.1,142.5,136.3,130.1,128.9,128.5,128.3,127.5,127.1,126.2,116.8,52.0.HRMS(ESI-TOF):m/z calcd for C₁₅H₁₃N₂O₂S[M+H]⁺285.0692,found:285.0712。

Example 15: the synthesis of 2-phenyl-5- (thiophene-3-yl) -1H-imidazole-4-carboxylic acid methyl ester (2o) has the following structural formula:

adding 0.3mmol of enamine ester (1o), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate into 6mL of N, N-dimethylformamide, refluxing for 12h, adding organic phase 110mL (PE: EA ═ 10:1) into three times (5:3:3) after reaction, extracting for three times, combining the organic phases to obtain extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V) on the crude product_{Ethyl acetate}∶V_{Petroleum ether}3: 1) to yield 63mg of product, calculated yield 74%.

The main physicochemical properties are as follows:

yellow solid.¹H NMR(400MHz,CDCl₃):δ8.17-8.18(m,1H),7.92-7.94(m,2H),7.18-7.80(m,1H),7.41-7.45(m,3H),7.32-7.34(m,1H),3.90(s,3H).¹³C{¹H}NMR(100MHz,CDCl₃):δ161.0,147.3,130.0,128.9,128.8,128.6,128.4,127.9,126.0,125.9,124.8,51.9.HRMS(ESI-TOF):m/z calcd for C₁₅H₁₃N₂O₂S[M+H]⁺285.0692,found:285.0707。

Example 16: the synthesis of 5- ([1, 1' -biphenyl ] -4-yl) -2-phenyl-1H-imidazole-4-carboxylic acid methyl ester (2p) has the following specific structural formula:

adding 0.3mmol of enamine ester (1p), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate into 6mL of N, N-dimethylformamide, refluxing for 12h, adding organic phase 110mL (PE: EA ═ 10:1) into three times (5:3:3) after reaction, extracting for three times, combining the organic phases to obtain extract, drying with anhydrous sodium sulfate, filtering, and reducing the volumeConcentrating under pressure, and performing rapid silica gel column chromatography (V) on the crude product_{Ethyl acetate}∶V_{Petroleum ether}3: 1) to yield 72mg of product, calculated in 68% yield.

The main physicochemical properties are as follows:

yellow solid.¹H NMR(400MHz,CDCl₃):δ7.97-8.01(m,4H),7.61-7.67(m,4H),7.42-7.47(m,5H),7.33-7.37(m,1H),3.89(s,3H).¹³C{¹H}NMR(100MHz,CDCl₃):δ161.2,147.4,141.5,140.7,130.7,130.2,129.7,129.0,128.9,128.8,128.3,127.5,127.3,127.1,126.7,126.1,52.0.HRMS(ESI-TOF):m/z calcd for C₂₃H₁₉N₂O₂[M+H]⁺355.1441,found:355.1454。

Example 17: synthesis of methyl 5- (naphthalen-4-yl) -2-phenyl-1H-imidazole-4-carboxylate (2q), the structural formula of which is specifically as follows:

adding 0.3mmol of enamine ester (1q), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate into 6mL of N, N-dimethylformamide, refluxing for 12h, adding organic phase 110mL (PE: EA ═ 10:1) into three times (5:3:3) after reaction, extracting for three times, combining the organic phases to obtain extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V) on the crude product_{Ethyl acetate}∶V_{Petroleum ether}3: 1) to yield 47mg of product, calculated yield 48%.

The main physicochemical properties are as follows:

yellow solid.¹H NMR(400MHz,CDCl₃):δ7.91-7.93(m,2H),7.85-7.89(m,2H),7.77(m,1H),7.52-7.53(m,1H),7.44-7.49(m,2H),7.38-7.43(m,4H),3.61(s,3H).¹³C{¹H}NMR(100MHz,CDCl₃):δ133.5,132.0,129.8,129.3,129.0,128.8,128.5,128.3,126.3,125.9,125.6,124.9,51.7.HRMS(ESI-TOF):m/z calcd for C₂₁H₁₇N₂O₂[M+H]⁺329.1284,found:329.1293。

Example 18: the synthesis of 2, 5-diphenyl-1H-imidazole-4-carboxylic acid ethyl ester (2r) has the following specific structural formula:

adding 0.3mmol of enamine ester (1r), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate into 6mL of N, N-dimethylformamide, refluxing for 12h, adding organic phase 110mL (PE: EA ═ 10:1) into three times (5:3:3) after reaction, extracting for three times, combining the organic phases to obtain extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V) on the crude product_{Ethyl acetate}∶V_{Petroleum ether}3: 1) to yield 70mg of product, calculated yield 80%.

The main physicochemical properties are as follows:

a white solid.¹H NMR(400MHz,CDCl₃):δ7.94-7.96(m,2H),7.83-7.85(m,2H),7.32-7.44(m,6H),4.27-4.34(m,2H),1.24-1.30(m,3H).¹³C{¹H}NMR(100MHz,CDCl₃):δ161.1,.147.6,132.3,129.8,129.4,128.9,128.6,127.8,126.1,61.0,14.2.HRMS(ESI-TOF):m/z calcd for C₁₈H₁₇N₂O₂[M+H]⁺293.1284,found:293.1289。

Example 19: the synthesis of 5- (4-nitrophenyl) -2-phenyl-1H-imidazole-4-carboxylic acid ethyl ester (2s) has the following specific structural formula:

0.3mmol of enamine ester (1s), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate were added to 6mL of N, N-dimethylformamide, refluxed for 12 hours, and after completion of the reaction, 110mL of organic phase (PE: EA. RTM.10: 1) and 50mL of water were added in three portions (5:3:3) in total, and the organic phases were combined after extraction for three timesDrying the extract with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing rapid silica gel column chromatography (V) on the crude product_{Ethyl acetate}∶V_{Petroleum ether}3: 1) to yield 35mg of product, calculated yield 35%.

The main physicochemical properties are as follows:

yellow solid. H NMR (400MHz, CDCl)₃):δ8.21-8.32(m,4H)7.96-7.98(m,2H),7.46-7.52(m,3H),4.39(q,J＝7.1Hz,2H),1.36(t,J＝7.1Hz,3H).¹³C{¹H}NMR(100MHz,CDCl₃):δ159.8,148.1,147.5,130.4,130.2,129.4,129.1,128.2,128.0,126.6,126.0,123.1,61.6,14.3.HRMS(ESI-TOF):m/z calcd for C₁₈H₁₆N₃O₄[M+H]⁺338.1135,found:338.1142。

Example 20: the synthesis of 2-phenyl-5- (trifluoromethyl) -1H-imidazole-4-carboxylic acid ethyl ester (2t) has the following structural formula:

adding 0.3mmol of enamine ester (1t), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate into 6mL of N, N-dimethylformamide, refluxing for 12h, adding organic phase 110mL (PE: EA ═ 10:1) into three times (5:3:3) after reaction, extracting for three times, combining the organic phases to obtain extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V) on the crude product_{Ethyl acetate}∶V_{Petroleum ether}3: 1) to give 56mg of product, calculated yield 58%.

The main physicochemical properties are as follows:

yellow solid.¹H NMR(400MHz,CDCl₃):δ12.00(b,1H),8.19-8.21(m,2H),7.57-7.60(m,2H),7.29-7.42(m,3H),7.12-8.15(m,3H),7.05-7.09(m,5H).¹³C{¹H}NMR(100MHz,CDCl₃):δ187.7,150.8,149.9,137.2,133.7,132.3,130.1,129.9,129.6,128.8,128.0,127.9,127.8,127.6,126.7.HRMS(ESI-TOF):m/z calcd for C₂₂H₁₇N₂O[M+H]⁺325.1341,found:308.1394。

Example 21: the synthesis of (2, 5-diphenyl-1H-imidazol-4-yl) (phenyl) methanone (2u) has the following structural formula:

adding 0.3mmol of enamine ester (1u), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate into 6mL of N, N-dimethylformamide, refluxing for 12h, adding organic phase 110mL (PE: EA ═ 10:1) into three times (5:3:3) after reaction, extracting for three times, combining the organic phases to obtain extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V) on the crude product_{Ethyl acetate}∶V_{Petroleum ether}3: 1) to give 56mg of product, calculated yield 58%.

The main physicochemical properties are as follows:

yellow solid.¹H NMR(400MHz,CDCl₃):δ12.00(b,1H),8.19-8.21(m,2H),7.57-7.60(m,2H),7.29-7.42(m,3H),7.12-8.15(m,3H),7.05-7.09(m,5H).¹³C{¹H}NMR(100MHz,CDCl₃):δ187.7,150.8,149.9,137.2,133.7,132.3,130.1,129.9,129.6,128.8,128.0,127.9,127.8,127.6,126.7.HRMS(ESI-TOF):m/z calcd for C₂₂H₁₇N₂O[M+H]⁺325.1341,found:308.1394。

Example 22: the synthesis of 2-phenylchromium [3,4-d ] imidazole-4 (1H) -ketone (2v) has the following structural formula:

0.3mmol of enamine ester (1v), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate were added to 6mL of N, N-dimethylformamide, refluxed for 12 hours, and after completion of the reaction, 110mL of organic phase (PE: EA ═ 3:3) were added in three portions in total10:1) and 50mL of water, extracting for three times, combining organic phases to obtain an extract, drying the extract by using anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing rapid silica gel column chromatography (V) on a crude product_{Ethyl acetate}∶V_{Petroleum ether}3: 1) to yield 67mg of product, calculated in 85% yield.

The main physicochemical properties are as follows:

yellow solid.¹H NMR(400MHz,DMSO-d₆):δ13.81(b,1H),8.07-8.17(m,3H),7.38-7.55(m,6H).¹³C{¹H}NMR(100MHz,DMSO-d₆):δ169.5,152.3,140.0,130.7,130.0,129.4,128.7,127.7,127.1,126.9,125.0,122.7,117.4.HRMS(ESI-TOF):m/z calcd for C₁₆H₁₀N₂O₂[M+H]⁺263.0815,found:263.0811。

Example 23: the synthesis of 2-methyl-5-phenyl-1H-4-carboxylic acid methyl ester (4a) has the following structural formula:

adding 0.3mmol of enamine ester (3a), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate into 6mL of N, N-dimethylformamide, refluxing for 12h, adding organic phase 110mL (PE: EA ═ 10:1) into three times (5:3:3) after reaction, extracting for three times, combining the organic phases to obtain extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V) on the crude product_{Ethyl acetate}∶V_{Petroleum ether}3: 1) to yield 33mg of product, calculated yield 51%.

The main physicochemical properties are as follows:

yellow oil.¹H NMR(400MHz,CDCl₃):δ10.27(b,1H),7.66-7.68(m,2H),7.29-7.33(m,3H),3.74(s,3H),2.25(s,3H).¹³C{¹H}NMR(100MHz,CDCl₃):δ162.2,146.3,142.8,131.2,129.1,128.6,128.0,121.3,51.6,13.6.HRMS(ESI-TOF):m/z calcd for C₁₂H₁₃N₂O₂[M+H]⁺217.0971,found:217.0967。

Example 24: the synthesis of 2-ethyl-5-phenyl-1H-4-carboxylic acid methyl ester (4b) has the following structural formula:

adding 0.3mmol of enamine ester (3b), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate into 6mL of N, N-dimethylformamide, refluxing for 12h, adding organic phase 110mL (PE: EA ═ 10:1) into three times (5:3:3) after reaction, extracting for three times, combining the organic phases to obtain extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V) on the crude product_{Ethyl acetate}∶V_{Petroleum ether}3: 1) to yield 35mg of product, calculated yield 51%.

The main physicochemical properties are as follows:

yellow oil.¹H NMR(400MHz,CDCl₃):δ7.72-7.74(m,2H),7.31-7.37(m,3H),3.78(s,3H),2.68-2.74(m,2H),1.27(t,J＝7.7Hz,3H).¹³C{¹H}NMR(100MHz,CDCl₃):δ161.8,151.4,131.9,129.1,128.5,127.5,120.2,51.6,21.7,12.3.HRMS(ESI-TOF):m/z calcd for C₁₃H₁₅N₂O₂[M+H]⁺231.1128,found:231.1127。

Example 25: the synthesis of 2-propyl-5-phenyl-1H-4-carboxylic acid methyl ester (4c) has the following structural formula:

adding 0.3mmol of enamine ester (3c), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate into 6mL of N, N-dimethylformamide, refluxing for 12h, adding organic phase 110mL (PE: EA ═ 10:1) into three times (5:3:3) after reaction, extracting for three times, combining the organic phases to obtain extract, and drying with anhydrous sodium sulfateFiltering, concentrating under reduced pressure, and performing rapid silica gel column chromatography (V) on the crude product_{Ethyl acetate}∶V_{Petroleum ether}3: 1) to yield 30mg of product, calculated in 41% yield.

The main physicochemical properties are as follows:

yellow oil.¹H NMR(400MHz,CDCl₃):δ7.72-7.75(m,2H),7.31-7.37(m,3H),3.78(s,3H),2.60-2.64(m,2H),1.65-1.74(m,2H),0.90(t,J＝7.3Hz,3H).¹³C{¹H}NMR(100MHz,CDCl₃):δ161.9,150.4,131.9,129.1,128.5,127.9,51.6,30.3,21.9,13.7.HRMS(ESI-TOF):m/z calcd for C₁₄H₁₇N₂O₂[M+H]⁺245.1284,found:245.1232。

Example 26: the synthesis of 2-n-butyl-5-phenyl-1H-4-carboxylic acid methyl ester (4d) has the following structural formula:

adding 0.3mmol of enamine ester (3d), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate into 6mL of N, N-dimethylformamide, refluxing for 12h, adding organic phase 110mL (PE: EA ═ 10:1) into three times (5:3:3) after reaction, extracting for three times, combining the organic phases to obtain extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V) on the crude product_{Ethyl acetate}∶V_{Petroleum ether}3: 1) to yield 35mg of product, calculated yield 45%.

The main physicochemical properties are as follows:

yellow oil.¹H NMR(400MHz,CDCl₃):δ9.72(b,1H),7.68-7.70(m,2H),7.29-7.34(m,3H),3.75(s,3H),2.56-2.59(m,2H),1.53-1.61(m,2H),1.19-1.29(m,2H),0.81(t,J＝7.47Hz,3H).¹³C{¹H}NMR(100MHz,CDCl₃):δ162.1,150.6,143.3,131.6,129.1,128.5,127.9,120.8,51.6,30.4,28.0,22.3,13.7.HRMS(ESI-TOF):m/z calcd for C₁₅H₁₉N₂O₂[M+H]⁺259.1441,found:259.1388。

Example 27: synthesis of methyl 2-pentyl-5-phenyl-1H-4-carboxylate (4e), the structural formula of which is specifically as follows:

adding 0.3mmol of enamine ester (3e), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate into 6mL of N, N-dimethylformamide, refluxing for 12h, adding organic phase 110mL (PE: EA ═ 10:1) into three times (5:3:3) after reaction, extracting for three times, combining the organic phases to obtain extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V) on the crude product_{Ethyl acetate}∶V_{Petroleum ether}3: 1) to yield 29mg of product, calculated yield 36%.

The main physicochemical properties are as follows:

yellow oil.¹H NMR(400MHz,CDCl₃):δ7.72-7.74(m,2H),7.30-7.36(m,3H),3.77(s,3H),2.61-2.65(m,2H),1.62-1.69(m,2H),1.23-1.27(m,4H),0.82-0.85(m,3H).¹³C{¹H}NMR(100MHz,CDCl₃):δ161.9,150.6,131.9,129.1,128.5,127.9,51.6,31.4,28.4,28.0,22.3,13.9.HRMS(ESI-TOF):m/z calcd for C₁₆H₂₁N₂O₂[M+H]⁺273.1597,found:273.1600。

Example 28: synthesis of methyl 2-hexyl-5-phenyl-1H-4-carboxylate (4f), the structural formula is as follows:

0.3mmol of enamine ester (3f), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate were added to 6mL of N, N-dimethylformamide, refluxed for 12 hours, and after completion of the reaction, 110mL of organic phase (PE: EA. RTM.10: 1) and 50mL of water were added in three portions (5:3:3) in total, and the organic phase was combined after extraction three timesDrying the organic phase with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing rapid silica gel column chromatography (V)_{Ethyl acetate}∶V_{Petroleum ether}3: 1) to yield 37mg of product, calculated yield 43%.

The main physicochemical properties are as follows:

yellow oil.¹H NMR(400MHz,CDCl₃):δ7.70-7.73(m,2H),7.30-7.36(m,3H),3.77(s,3H),2.60(t,J＝7.9Hz,2H),1.58-1.66(m,2H),1.21-1.27(m,6H),0.82(t,J＝6.7Hz,3H).¹³C{¹H}NMR(100MHz,CDCl₃):δ162.0,150.6,131.8,129.9,129.1,128.5,128.2,127.9,51.6,31.4,29.0,28.4,28.3,22.5,14.0.HRMS(ESI-TOF):m/z calcd for C₁₇H₂₃N₂O₂[M+H]⁺287.1754,found:287.1757。

Example 29: synthesis of methyl 2-heptyl-5-phenyl-1H-4-carboxylate (4g), having the following specific structural formula:

adding 0.3mmol of enamine ester (3g), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate into 6mL of N, N-dimethylformamide, refluxing for 12h, adding organic phase 110mL (PE: EA ═ 10:1) into three times (5:3:3) after reaction, extracting for three times, combining the organic phases to obtain extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V) on the crude product_{Ethyl acetate}∶V_{Petroleum ether}3: 1) to yield 36mg of product, calculated yield 40%.

The main physicochemical properties are as follows:

yellow oil.¹H NMR(400MHz,CDCl₃):δ7.74-7.76(m,2H),7.33-7.39(m,3H),3.80(s,3H),2.65-2.69(m,2H),1.64-1.71(m,2H),1.21-1.28(m,8H),0.84(t,J＝6.7Hz,1H).¹³C{¹H}NMR(100MHz,CDCl₃):δ131.7,150.6,132.9,131.8,130.0,129.1,128.3,128.0,51.7,31.6,29.3,28.9,28.5,28.3,22.6,14.1.HRMS(ESI-TOF):m/z calcd for C₁₈H₂₅N₂O₂[M+H]⁺301.1910,found:301.1897。

Example 30: the synthesis of 2-benzyl-5-phenyl-1H-4-carboxylic acid methyl ester (4H) has the following structural formula:

adding 0.3mmol of enamine ester (3h), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate into 6mL of N, N-dimethylformamide, refluxing for 12h, adding organic phase 110mL (PE: EA ═ 10:1) into three times (5:3:3) after reaction, extracting for three times, combining the organic phases to obtain extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V) on the crude product_{Ethyl acetate}∶V_{Petroleum ether}3: 1) to yield 44mg of product, calculated yield 50%.

The main physicochemical properties are as follows:

yellow oil.¹H NMR(400MHz,CDCl₃):δ7.70-7.72(m,2H),7.31-7.37(m,3H),7.22-7.29(m,3H),7.15-7.18(m,2H),4.01(s,2H),3.74(s,3H).¹³C{¹H}NMR(100MHz,CDCl₃):δ161.8,148.6,136.1,131.5,129.3,129.1,128.9,128.8,128.6,128.0,127.9,127.2,51.6,34.8.HRMS(ESI-TOF):m/z calcd for C₁₈H₁₇N₂O₂[M+H]⁺293.1284,found:293.1279。

Example 31: synthesis of methyl 2- (methoxymethyl) -5-phenyl-1H-4-carboxylate (4i), the structural formula of which is specifically as follows:

0.3mmol of enamine ester (3i), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate were added to 6mL of N, N-dimethylformamide, refluxed for 12 hours, and reactedAdding organic phase 110mL (PE: EA is 10:1) and water 50mL in three times (5:3:3) for three times, extracting for three times, mixing organic phases to obtain extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V) on the crude product_{Ethyl acetate}∶V_{Petroleum ether}3: 1) to yield 31mg of product, calculated yield 42%.

The main physicochemical properties are as follows:

yellow oil.¹H NMR(400MHz,CDCl₃):δ7.74-7.77(m,2H),7.34-7.40(m,3H),4.56(s,2H),3.81(s,3H),3.42(s,3H).¹³C{¹H}NMR(100MHz,CDCl₃):δ161.7,146.5,131.3,129.2,129.0,128.7,128.1,127.9,67.6,59.0,51.7.HRMS(ESI-TOF):m/z calcd for C₁₃H₁₅N₂O₃[M+H]⁺247.1077,found:247.1072。

Example 32: synthesis of methyl 2- ((benzyloxy) methyl) -5-phenyl-1H-4-carboxylate (4j), having the following specific structural formula:

adding 0.3mmol of enamine ester (3j), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate into 6mL of N, N-dimethylformamide, refluxing for 12h, adding organic phase 110mL (PE: EA ═ 10:1) into three times (5:3:3) after reaction, extracting for three times, combining the organic phases to obtain extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V) on the crude product_{Ethyl acetate}∶V_{Petroleum ether}3: 1) to yield 67mg of product, calculated in 69%.

The main physicochemical properties are as follows:

yellow oil.¹H NMR(400MHz,CDCl₃):δ7.73-7.76(m,2H),7.29-7.40(m,8H),4.63(s,2H),4.57(s,2H),3.81(s,3H).¹³C{¹H}NMR(100MHz,CDCl₃):δ161.6,146.5,136.9,129.4,129.1,128.7,128.6,128.2,128.1,127.7,73.4,65.3,51.7.HRMS(ESI-TOF):m/z calcd for C₁₉H₁₉N₂O₃[M+H]⁺323.1390,found:323.1379。

Example 33: synthesis of methyl 2- (phenoxymethyl) -5-phenyl-1H-4-carboxylate (4k), having the following specific structural formula:

adding 0.3mmol of enamine ester (3k), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate into 6mL of N, N-dimethylformamide, refluxing for 12h, adding organic phase 110mL (PE: EA ═ 10:1) into three times (5:3:3) after reaction, extracting for three times, combining the organic phases to obtain extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V) on the crude product_{Ethyl acetate}∶V_{Petroleum ether}3: 1) to yield 53mg of product, calculated yield 57%.

The main physicochemical properties are as follows:

yellow solid.¹H NMR(400MHz,CDCl₃):δ7.79-7.81(m,2H),7.38-7.44(m,3H),7.28-7.32(m,2H),5.22(s,2H),3.84(s,3H).¹³C{¹H}NMR(100MHz,CDCl₃):δ157.5,129.8,129.1,129.0,128.2,122.1,114.6,63.4,51.9.HRMS(ESI-TOF):m/z calcd for C₁₈H₁₇N₂O₃[M+H]⁺309.1233,found:309.1227。

Example 34: synthesis of methyl 2-azidomethyl-5-phenyl-1H-4-carboxylate (4l), the structural formula of which is specifically as follows:

0.3mmol of enamine ester (3l), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate were added to 6mL of N, N-dimethylformamide, refluxed for 12 hours, and after the reaction was completed, 110mL of organic phase (PE:EA 10:1), 50mL water, extracting for three times, combining organic phases to obtain an extract, drying the extract with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V) on a crude product_{Ethyl acetate}∶V_{Petroleum ether}3: 1) to give 9mg of product, calculated yield 13%.

The main physicochemical properties are as follows:

yellow oil.¹H NMR(400MHz,CDCl₃):δ87.69-7.72(m,2H),7.34-7.39(m,3H),4.41(s,2H),3.79(s,3H).¹³C{¹H}NMR(100MHz,CDCl₃):δ161.8,143.8,130.9,129.1,128.9,128.8,128.1,120.0,51.8,47.5.HRMS(ESI-TOF):m/z calcd for C₁₂H₁₂N₅O₂[M+H]⁺258.0985,found:258.0973。

Example 35: synthesis of methyl 2-phenyl-5- (trifluoromethyl) -1H-4-carboxylate (4m), the structural formula is specifically as follows:

adding 0.3mmol of enamine ester (3m), 0.9mmol of azidotrimethylsilane, 0.9mmol of iodine, 0.9mmol of potassium carbonate and 0.3mmol of sodium acetate into 6mL of N, N-dimethylformamide, refluxing for 12h, adding organic phase 110mL (PE: EA ═ 10:1) into three times (5:3:3) after reaction, extracting for three times, combining the organic phases to obtain extract, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing flash silica gel column chromatography (V) on the crude product_{Ethyl acetate}∶V_{Petroleum ether}3: 1) to yield 71mg of product, calculated yield 83%.

The main physicochemical properties are as follows:

a white solid.¹H NMR(400MHz,CDCl₃):δ7.94-7.97(m,2H),7.44-7.47(m,3H),4.41(q,J＝7.1Hz,2H),1.39(t,J＝7.1Hz,3H).¹³C{¹H}NMR(100MHz,CDCl₃):δ159.2,147.8,130.6,129.0,127.9,126.3,122.0,119.4,62.3,13.9.HRMS(ESI-TOF):m/z calcd for C₁₃H₁₂F₃N₂O₂[M+H]⁺285.0845,found:285.0847。

The chemical structures of the enamine esters used as starting materials in examples 1 to 35 are as follows: