Novel N-heterocyclic carbene catalyst and synthesis process thereof
By synthesizing novel nitrogen-heterocyclic carbene catalysts and introducing carbazole groups, the problems of single structure and complex synthesis of existing catalysts are solved, enabling broader substrate applicability and high efficiency in organic synthesis reactions, which are suitable for industrial green synthesis catalytic processes.
Patent Information
- Application Number
- CN202511668881.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-11-14
- Publication Date
- 2026-03-10
AI Technical Summary
Existing nitrogen heterocyclic carbene catalysts have limited structural diversity, narrow substrate applicability, complex synthesis steps, and difficulty in activating distal sites and other inert substrates.
A novel class of nitrogen heterocyclic carbene catalysts was developed. By improving the synthetic route and introducing a carbazole group, a bifunctional carbene catalyst with a carbazole structure was prepared using commercially available raw materials and mild reaction conditions, thus expanding the catalytic activity and substrate applicability.
It enables a wider range of carbon-carbon bond construction and aldehyde-ketone nucleophilic addition reactions, simplifies the synthetic steps, improves the yield, facilitates large-scale production, and broadens the application range of nitrogen heterocyclic carbene catalysis.
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Figure CN121627700A_ABST
Abstract
Description
TECHNICAL FIELD
[0001] The present application relates to the technical field of organic synthesis, in particular to a novel class of N-heterocyclic carbene catalyst and its synthesis process; the catalyst can be widely used in carbon-carbon bond construction, aldehyde and ketone nucleophilic addition and other organic synthesis reactions, and is especially suitable for industrial green synthesis catalytic process. BACKGROUND
[0002] As early as the early 1990s, the Arduengo group isolated an imidazole carbene with two adamantane groups on the ortho nitrogen atom of the carbene, and determined its structure by single crystal diffraction, which provided a solid foundation for the subsequent development of carbene chemistry. In recent decades, N-heterocyclic carbene catalysts have gradually developed into a class of efficient and versatile small organic molecule catalysts due to their low cost, easy availability and less toxicity than metal reagents, and have shown excellent catalytic activity and selectivity in homogeneous catalysis, asymmetric synthesis and other fields. At present, the commonly used N-heterocyclic carbene catalytic structures include imidazole type, thiazole type and triazole type, among which some imidazole type and thiazole type catalysts have been commercialized. In order to further expand the catalytic range of N-heterocyclic carbene, researchers have developed bifunctional carbene catalysts with hydroxyl groups, which can enhance the selectivity of the catalyst by forming hydrogen bonds with the substrate, and achieve the synthesis of chiral lactones and other compounds. However, the existing bifunctional N-heterocyclic carbene catalysts and conventional N-heterocyclic carbene catalysts still have unresolved technical defects: the structure type is single, the functional group modification of the bifunctional catalyst is concentrated in the "hydroxyl-alkyl chain" combination, which limits the catalytic mechanism to "hydrogen bond activation"; the substrate applicability is narrow, and the catalytic activity decreases for remote site activation or other inert substrates; the structural regulation flexibility is poor, and the existing synthesized bifunctional catalysts have complex structures and many steps of substrate synthesis.
[0003] Therefore, developing a catalyst with novel structure, multiple functions and strong substrate universality, as well as a simple synthesis method, is still a key problem to be solved in the current field of organic catalysis.
[0004] The present application provides a novel class of N-heterocyclic carbene catalyst and its synthesis method, which expands the application range of N-heterocyclic carbene catalysis and has important significance. SUMMARY
[0005] In view of the deficiencies of the prior art, the purpose of the present application is to provide a novel class of N-heterocyclic carbene catalyst and its synthesis method, which realizes the synthesis of more kinds of chiral compounds. The catalyst can be widely used in carbon-carbon bond construction, aldehyde and ketone nucleophilic addition and other organic synthesis reactions, and is especially suitable for industrial green synthesis catalytic process.
[0006] To achieve the above technical purpose, the technical scheme of the present application is as follows: A synthesis process of a new type of nitrogen heterocyclic carbene catalyst, the structural formula of which is shown as formula I: ; wherein, R 1 , R 2 , R 3 are independently selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, halogen, methoxy, nitro, cyano, amino, ester, wherein the alkyl, the cycloalkyl, the aryl, the heteroaryl are independently unsubstituted or substituted by a substituent; Y is an anion; The synthesis route of the nitrogen heterocyclic carbene catalyst is as follows:
[0007] wherein the new type of nitrogen heterocyclic carbene catalyst is selected from the compounds with the structural formula as follows:
[0008] A synthesis process of a new type of nitrogen heterocyclic carbene catalyst, comprising the following steps: S1: preparation of (S)-5-(hydroxymethyl)pyrrolidin-2-one ; 1) Take a two-mouth bottle, and under the protection of nitrogen, (S)-5-carboxyl pyrrolidin-2-one is added to a dry tetrahydrofuran solution, and diisobutylaluminum hydride is slowly added under low-temperature stirring. The reaction is continuously carried out in a low-temperature environment, and thin layer chromatography is used to monitor the reaction until the reaction is complete. The reaction is quenched by adding water, extracted with ethyl acetate, and the organic phases are combined and dried with anhydrous sodium sulfate. The filtrate is evaporated and concentrated, and the target product (S)-5-(hydroxymethyl)pyrrolidin-2-one (b) is obtained by column chromatography purification; S2: preparation of (S)-5-(bromomethyl)pyrrolidin-2-one; ; 1) (S)-5-(hydroxymethyl)pyrrolidin-2-one and toluenesulfonyl chloride are dissolved in dichloromethane, and triethylamine is added to the reaction system. Normal temperature stirring is carried out, and high performance liquid chromatography is used to monitor the reaction until the reaction is complete. After the reaction is completed, 1N hydrochloric acid is added to the reaction, dichloromethane is extracted, saturated brine is washed, the organic phases are combined, dried with anhydrous sodium sulfate, and recrystallized to obtain the intermediate (S)-5-((p-tolylsulfonyl)methyl)pyrrolidin-2-one; 2) Add (S)-5-((p-toluenesulfonyl)methyl)pyrrolidin-2-one and lithium bromide into a two-necked flask, vacuumize the reaction system, replace with nitrogen for three times, then add acetone solution under the protection of nitrogen, and place the reaction in an oil bath to reflux overnight. Monitor the reaction by high performance liquid chromatography until the reaction is complete. Cool the reaction to room temperature, extract with dichloromethane and water, combine the organic phases, separate, dry and concentrate. Separate the target product (S)-5-(bromomethyl)pyrrolidin-2-one (c) by column chromatography. S3: Preparation of (S)-5-((9H-carbazol-9-yl)methyl)pyrrolidin-2-one ; Add (S)-5-(bromomethyl)pyrrolidin-2-one into a single-necked flask, add N,N,-dimethylformamide solvent into the flask, then add carbazole and cesium carbonate into the reaction solution, and then place the reaction in an oil bath to heat and reflux. Monitor the reaction by high performance liquid chromatography until the reaction is complete. Cool to room temperature, pour the reaction into a large amount of water, extract with ethyl acetate, combine the organic phases, separate, dry and concentrate to obtain the target product (S)-5-((9H-carbazol-9-yl)methyl)pyrrolidin-2-one (d). S4: Preparation of bifunctional nitrogen heterocyclic carbene catalyst with carbazole structure ; Take a dry two-necked flask, add (S)-5-((9H-carbazol-9-yl)methyl)pyrrolidin-2-one into the flask, replace with nitrogen for three times, then add anhydrous dichloromethane and trimethyloxonium tetrafluoroborate under the protection of nitrogen, and place the reaction in a constant temperature water bath to stir overnight. Monitor the reaction by thin layer chromatography. After the reaction is complete, add an aryl hydrazine compound into the reaction system, continue to stir at room temperature, and monitor the reaction by thin layer chromatography. After the reaction is complete, spin dry and concentrate, and dry under vacuum. Continue to add triethyl orthoformate and chlorobenzene into the reaction system under the condition of nitrogen, and place the reaction in an oil bath to heat. Monitor the reaction by thin layer chromatography. After the reaction is complete, spin dry and concentrate, and separate by column chromatography to obtain the target product I.
[0009] In step S1, the molar ratio of (S)-5-carboxypyrrrolidin-2-one to diisobutylaluminum hydride is 1:1-1:3, and the temperature is -20ºC-20ºC.
[0010] In step 1) of step S2, the molar ratio of (S)-5-(hydroxymethyl)pyrrolidin-2-one to tosyl chloride is 1:1-1:3, and the molar ratio of (S)-5-(hydroxymethyl)pyrrolidin-2-one to triethylamine is 1:1-1:10.
[0011] In step S2, step 2), the molar ratio of (S)-5-((p-toluenesulfonyl)methyl)pyrrolidone-2-one to lithium bromide is 1:1 to 1:5.
[0012] In step S3, the molar ratio of (S)-5-(bromomethyl)pyrrolidone-2-one to carbazole is 1:0.5 to 1:1, and the molar ratio of (S)-5-(bromomethyl)pyrrolidone-2-one to cesium carbonate is 1:1 to 1:3.
[0013] In step S4, the molar ratio of (S)-5-((9H-carbazole-9-yl)methyl)pyrrolidone-2-one to trimethyloxonium tetrafluoroboric acid is 1:1 to 1:3, and the molar ratio of (S)-5-((9H-carbazole-9-yl)methyl)pyrrolidone-2-one to arylhydrazine is 1:1 to 1:5.
[0014] In step S4, the molar ratio of (S)-5-((9H-carbazole-9-yl)methyl)pyrrolidone-2-one to triethyl orthoformate is 1:2 to 1:10, and the temperature is 80ºC to 150ºC.
[0015] A novel class of nitrogen heterocyclic carbene catalysts is produced by the above-mentioned synthesis process.
[0016] Compared with the prior art, the beneficial effects of the present invention are as follows: This invention provides a novel synthetic route by using commercially available raw materials to synthesize a new type of nitrogen heterocyclic carbene catalyst.
[0017] The synthesis method provided by this invention is simple to operate, has mild reaction conditions, and can obtain the target compound in high yield, which is convenient for large-scale production and has important application prospects.
[0018] The novel nitrogen heterocyclic carbene catalyst synthesized in this invention can not only activate distal sites, but also fill the gap in existing nitrogen heterocyclic carbene catalysts and broaden the application scope of nitrogen heterocyclic carbene catalysis. Attached Figure Description
[0019] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.
[0020] Figure 1 The proton NMR spectrum of the novel nitrogen heterocyclic carbene catalyst I-1 prepared in Example 1 of this invention. Figure 2The carbon spectrum of the novel nitrogen heterocyclic carbene catalyst I-1 prepared in Example 1 of this invention. Detailed Implementation
[0021] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.
[0022] In the following embodiments, unless otherwise specified, the raw materials or processing techniques are conventional commercial products or conventional processing techniques in the art.
[0023] The synthetic routes for all the following embodiments of the present invention are as follows: ; Example 1
[0024] This embodiment provides a synthesis process for a novel nitrogen heterocyclic carbene catalyst I-1 with a carbazole group, including the following steps: S1: Preparation of (S)-5-(hydroxymethyl)pyrrolidone-2-one; Under nitrogen protection, 20 mmol of (S)-5-carboxypyrrolidone-2-one was added to a two-necked flask, followed by 60 mL of dry tetrahydrofuran as a solvent. The reaction was stirred at 0°C, and 24 mmol of diisobutylaluminum hydride was slowly added. Stirring continued at low temperature, and the reaction was monitored by thin-layer chromatography until complete. The reaction was quenched with water, extracted with EA, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, evaporated and concentrated, and purified by column chromatography to give (S)-5-(hydroxymethyl)pyrrolidone-2-one in 64% yield.
[0025] S2: Preparation of (S)-5-(bromomethyl)pyrrolidone-2-one; 1) Dissolve 10 mmol of (S)-5-(hydroxymethyl)pyrrolidone-2-one and 10 mmol of toluenesulfonyl chloride in 20 mL of dichloromethane. Add 5 equivalents of triethylamine to the reaction system, and stir at room temperature. Monitor the reaction with high performance liquid chromatography until the reaction is complete. After the reaction is complete, add 1 M hydrochloric acid to the reaction mixture, extract with dichloromethane, wash with saturated brine, combine the organic phases, dry to anhydrous magnesium sulfate, and recrystallize with petroleum ether to give the white intermediate (S)-5-((p-toluenesulfonyl)methyl)pyrrolidone-2-one in 84% yield.
[0026] 2) Add 10 mmol of (S)-5-((p-toluenesulfonyl)methyl)pyrrolidone-2-one and 25 mmol of lithium bromide to a two-necked flask. Evacuate the reaction system under vacuum, replacing the nitrogen atmosphere three times. Add 30 mL of acetone solution under nitrogen protection. Reflux the reaction in an oil bath overnight, monitoring the reaction with high-performance liquid chromatography (HPLC) until complete. Cool the reaction to room temperature, extract with dichloromethane and water, combine the organic phases, separate, dry, and concentrate. Separate by column chromatography (DCM: MeOH = 100:1) to obtain the target product (S)-5-(bromomethyl)pyrrolidone-2-one (c), with a yield of 68%.
[0027] S3: Preparation of (S)-5-((9H-carbazol-9-yl)methyl)pyrrolidone-2-one; 15 mmol of (S)-5-(bromomethyl)pyrrolidone-2-one was added to a single-necked flask, followed by 25 mL of N,N,-dimethylformamide as a solvent. Then, 10 mmol of carbazole and 2 equivalents of cesium carbonate were added to the reaction solution. The reaction was heated under reflux in an oil bath, and the reaction was monitored by high-performance liquid chromatography until complete. The reaction solution was cooled to room temperature, then poured into water, extracted with ethyl acetate, and the organic phases were combined, separated, dried, and concentrated to obtain the target product (S)-5-((9H-carbazole-9-yl)methyl)pyrrolidone-2-one (d) in 50% yield.
[0028] S4: Preparation of nitrogen heterocyclic carbene catalysts with carbazole structures.
[0029] Take a dry two-necked flask and add 5 mmol of (S)-5-((9H-carbazole-9-yl)methyl)pyrrolidine-2-one. Purge the flask three times with nitrogen. Then, under nitrogen protection, add anhydrous dichloromethane and 6 mmol of trimethyloxonium tetrafluoroboric acid. Stir the mixture at room temperature overnight, monitoring the reaction progress using thin-layer chromatography. After the reaction is complete, add 11 mmol of phenylhydrazine to the reaction system and continue stirring at room temperature, monitoring the reaction using thin-layer chromatography. After the reaction is complete, concentrate the solution by rotary evaporation and then dry it under vacuum. Under nitrogen conditions, add 8 equivalents of triethyl orthoformate and 40 mL of chlorobenzene as solvent to the reaction system. Place the reaction in an oil bath at 120°C, monitoring the reaction using thin-layer chromatography. After the reaction is complete, evaporate and concentrate the solution, then separate it by column chromatography (DCM: MeOH = 100:1 ~ 80:1) to obtain the target product I-1.
[0030] I-1 ; The experimental data are as follows: 86%, pale yellow solid. 1 H NMR (400 MHz, Chloroform-d ) δ 9.74 (s, 1H), 7.99 (d, J = 7.7 Hz, 2H), 7.53 – 7.45 (m, 2H), 7.42 (d, J = 8.2 Hz, 2H), 7.29 (t, J = 7.5 Hz, 2H), 7.21 – 7.02 (m, 5H), 5.37 (t, J = 5.9 Hz, 1H), 4.93 – 4.74(m, 2H), 2.85 – 2.73 (m, 1H), 2.62 (qd, J = 13.8, 11.3, 3.5 Hz, 3H). 13C NMR (101 MHz, Chloroform- d ) δ 162.4, 140.1, 136.8, 135.3, 130.5, 129.8, 126.4,123.0, 120.8, 120.4, 120.0, 108.7, 59.9, 44.2, 31.2, 21.0. Example 2
[0031] This embodiment provides a synthesis process for a novel bifunctional carbene catalyst I-2 with a carbazole group, including the following steps: S1: Preparation of (S)-5-(hydroxymethyl)pyrrolidone-2-one; Under nitrogen protection, 20 mmol of (S)-5-carboxypyrrolidone-2-one was added to a two-necked flask, followed by 60 mL of dry tetrahydrofuran as a solvent. The reaction was stirred at -20°C, and 20 mmol of diisobutylaluminum hydride was slowly added. Stirring continued at low temperature, and the reaction was monitored by thin-layer chromatography until complete. The reaction was quenched with water, extracted with EA, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, evaporated and concentrated, and purified by column chromatography to obtain (S)-5-(hydroxymethyl)pyrrolidone-2-one in 60% yield.
[0032] S2: Preparation of (S)-5-(bromomethyl)pyrrolidone-2-one; 1) Dissolve 10 mmol of (S)-5-(hydroxymethyl)pyrrolidone-2-one and 20 mmol of toluenesulfonyl chloride in 20 mL of dichloromethane. Add 1 equivalent of triethylamine to the reaction system and stir at room temperature. Monitor the reaction with high performance liquid chromatography until the reaction is complete. After the reaction is complete, add 1 M hydrochloric acid to the reaction mixture, extract with dichloromethane, wash with saturated brine, combine the organic phases, dry to anhydrous magnesium sulfate, and recrystallize with petroleum ether to give the white intermediate (S)-5-((p-toluenesulfonyl)methyl)pyrrolidone-2-one in 86% yield.
[0033] 2) Add 10 mmol of (S)-5-((p-toluenesulfonyl)methyl)pyrrolidone-2-one and 10 mmol of lithium bromide to a two-necked flask. Evacuate the reaction system under vacuum and replace the nitrogen gas three times. Add 30 mL of acetone solution under nitrogen protection. Reflux the reaction in an oil bath overnight. Monitor the reaction using high-performance liquid chromatography (HPLC) until complete. Cool the reaction to room temperature, extract with dichloromethane and water, combine the organic phases, separate, dry, and concentrate. Separate by column chromatography (DCM: MeOH = 100:1) to obtain the target product (S)-5-(bromomethyl)pyrrolidone-2-one (c), with a yield of 58%.
[0034] S3: Preparation of (S)-5-((9H-carbazol-9-yl)methyl)pyrrolidone-2-one; 15 mmol of (S)-5-(bromomethyl)pyrrolidone-2-one was added to a single-necked flask, followed by 25 mL of N,N,-dimethylformamide as a solvent. Then, 7.5 mmol of carbazole and 1 equivalent of cesium carbonate were added to the reaction solution. The reaction was heated under reflux in an oil bath, and the reaction was monitored by high-performance liquid chromatography until complete. The reaction solution was cooled to room temperature, then poured into water, extracted with ethyl acetate, and the organic phases were combined, separated, dried, and concentrated to obtain the target product (S)-5-((9H-carbazole-9-yl)methyl)pyrrolidone-2-one (d) in 57% yield.
[0035] S4: Preparation of nitrogen heterocyclic carbene catalysts with carbazole structures.
[0036] Take a dry two-necked flask and add 5 mmol of (S)-5-((9H-carbazole-9-yl)methyl)pyrrolidine-2-one. Purge the flask three times with nitrogen. Then, under nitrogen protection, add anhydrous dichloromethane and 5 mmol of trimethyloxonium tetrafluoroboric acid. Stir the mixture at room temperature overnight, monitoring the reaction progress using thin-layer chromatography. After the reaction is complete, add 5 mmol of 1,3,5-trimethylphenylhydrazine to the reaction system and continue stirring at room temperature, monitoring the reaction using thin-layer chromatography. After the reaction is complete, concentrate the solution by rotary evaporation and then dry it under vacuum. Under nitrogen conditions, add 2 equivalents of triethyl orthoformate and 40 mL of chlorobenzene as solvent to the reaction system. Place the reaction in an oil bath at 80°C, monitoring the reaction using thin-layer chromatography. After the reaction is complete, evaporate and concentrate the solution, then separate it by column chromatography (DCM: MeOH = 100:1 ~ 80:1) to obtain the target product I-2.
[0037] I-2 ; The experimental data are as follows: 69%, milky white solid. 1 H NMR (400 MHz, Chloroform- d ) δ 9.14 (s, 1H), 8.05 (d, J = 7.6 Hz, 2H), 7.75 – 7.65 (m, 2H), 7.49 – 7.45(m, 2H), 7.32 – 7.22 (m,2H), 6.97 (s, 2H), 4.39 – 4.14 (m, 2H), 3.36 – 3.16 (m, 1H), 2.58 – 2.43 (m,2H), 2.23 (s, 9H), 2.18 – 1.93 (m, 2H). 13 C NMR (101 MHz, Chloroform- d ) δ159.4, 138.2, 137.8, 137.0, 134.3, 132.5, 127.8, 122.8, 121.6, 120.4, 119.8,109.6, 64.5, 27.3, 24.9, 23.3, 21.0. Example 3
[0038] This embodiment provides a synthetic process for a novel bifunctional carbene catalyst IV-3 with a carbazole group, comprising the following steps: S1: Preparation of (S)-5-(hydroxymethyl)pyrrolidone-2-one; Under nitrogen protection, 20 mmol of (S)-5-carboxypyrrolidone-2-one was added to a two-necked flask, followed by 60 mL of dry tetrahydrofuran as a solvent. The reaction was stirred at 20°C, and 60 mmol of diisobutylaluminum hydride was slowly added. Stirring continued at low temperature, and the reaction was monitored by thin-layer chromatography until complete. The reaction was quenched with water, extracted with EA, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, evaporated and concentrated, and purified by column chromatography to give (S)-5-(hydroxymethyl)pyrrolidone-2-one in 60% yield.
[0039] S2: Preparation of (S)-5-(bromomethyl)pyrrolidone-2-one; 1) Dissolve 10 mmol of (S)-5-(hydroxymethyl)pyrrolidone-2-one and 30 mmol of toluenesulfonyl chloride in 20 mL of dichloromethane. Add 10 equivalents of triethylamine to the reaction system and stir at room temperature. Monitor the reaction with high performance liquid chromatography until the reaction is complete. After the reaction is complete, add 1 M hydrochloric acid to the reaction mixture, extract with dichloromethane, wash with saturated brine, combine the organic phases, dry to anhydrous magnesium sulfate, and recrystallize with petroleum ether to give the white intermediate (S)-5-((p-toluenesulfonyl)methyl)pyrrolidone-2-one in 86% yield.
[0040] 2) Add 10 mmol of (S)-5-((p-toluenesulfonyl)methyl)pyrrolidone-2-one and 50 mmol of lithium bromide to a two-necked flask. Evacuate the reaction system under vacuum, replacing the nitrogen atmosphere three times. Under nitrogen protection, add 30 mL of acetone solution. Reflux the reaction in an oil bath overnight, monitoring the reaction with high-performance liquid chromatography until complete. Cool the reaction to room temperature, extract with dichloromethane and water, combine the organic phases, separate, dry, and concentrate. Separate by column chromatography (DCM: MeOH = 100:1) to obtain the target product (S)-5-(bromomethyl)pyrrolidone-2-one (c), with a yield of 58%.
[0041] S3: Preparation of (S)-5-((9H-carbazol-9-yl)methyl)pyrrolidone-2-one; 15 mmol of (S)-5-(bromomethyl)pyrrolidone-2-one was added to a single-necked flask, followed by 25 mL of N,N,-dimethylformamide as a solvent. Then, 15 mmol of carbazole and 3 equivalents of cesium carbonate were added to the reaction solution. The reaction was heated under reflux in an oil bath, and the reaction was monitored by high-performance liquid chromatography until complete. The reaction solution was cooled to room temperature, then poured into water, extracted with ethyl acetate, and the organic phases were combined, separated, dried, and concentrated to obtain the target product (S)-5-((9H-carbazole-9-yl)methyl)pyrrolidone-2-one (d) in 57% yield.
[0042] S4: Preparation of nitrogen heterocyclic carbene catalysts with carbazole structures.
[0043] Take a dry two-necked flask and add 5 mmol of (S)-5-((9H-carbazole-9-yl)methyl)pyrrolidine-2-one. Purge the flask three times with nitrogen. Then, under nitrogen protection, add anhydrous dichloromethane and 15 mmol of trimethyloxonium tetrafluoroboric acid. Stir the mixture at room temperature overnight, monitoring the reaction progress using thin-layer chromatography. After the reaction is complete, add 25 mmol of pentafluorophenylhydrazine to the reaction system and continue stirring at room temperature, monitoring the reaction using thin-layer chromatography. After the reaction is complete, concentrate the solution by rotary evaporation and then dry it under vacuum. Under nitrogen conditions, add 10 equivalents of triethyl orthoformate and 40 mL of chlorobenzene as solvent to the reaction system. Place the reaction in an oil bath at 150 °C, monitoring the reaction using thin-layer chromatography. After the reaction is complete, evaporate and concentrate the solution, then separate it by column chromatography (DCM: MeOH = 100:1 ~ 80:1) to obtain the target product I-3.
[0044] I-3 ; The experimental data are as follows: 66%, gray solid, 1 H NMR (400 MHz, Chloroform- d ) δ 8.92 (s, 1H), 8.15 (d, J = 7.6 Hz, 2H), 7.75 – 7.55 (m, 2H), 7.49 – 7.45(m, 2H), 7.22 – 7.24 (m,2H), 4.39 – 4.14 (m, 2H), 3.63 – 3.59 (m, 2H), 2.58 – 2.43 (m, 2H), 1.98 –1.48 (m, 2H). 13 C NMR (101 MHz, Chloroform- d ) δ 160.4, 148.6,143.3, 137.8,137.0, 134.1, 122.8, 121.4, 119.8, 111.5, 109.6, 64.5, 64.1, 27.3, 23.3. The foregoing description is intended to provide detailed embodiments for those skilled in the art, ensuring they can accurately grasp and apply the present invention. Any improvements or modifications to the present invention obtained by those skilled in the art through logical analysis, reasoning, or simple enumeration, without creative work, based on existing technology, should be considered within the scope of protection defined by the claims of this invention.
Claims
1. A process for the synthesis of a new class of N-heterocyclic carbene catalysts, characterized in that, The structure of the azaheterocyclic carbene catalyst is shown as formula I: ； wherein R is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, halogen, methoxy, nitro, cyano, amino, ester, wherein the alkyl, the cycloalkyl, the aryl, the heteroaryl are independently from each other unsubstituted or substituted with substituents; 1 , R 2 , R 3 are independently from each other selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, halogen, methoxy, nitro, cyano, amino, ester, wherein the alkyl, the cycloalkyl, the aryl, the heteroaryl are independently from each other unsubstituted or substituted with substituents; Y is an anion; The synthesis route of the azaheterocyclic carbene catalyst is as follows:
2. A process for the synthesis of a new class of N-heterocyclic carbene catalysts according to claim 1, characterized by: The new type of azaheterocyclic carbene catalysts are selected from compounds with the following structural formula:
3. A process for the synthesis of a new class of N-heterocyclic carbene catalysts as claimed in claim 1, wherein The method comprises the following steps: S1: preparation of (S)-5-(hydroxymethyl)pyrrolidin-2-one Take a two-mouth bottle, and add (S)-5-carboxy pyrrolidin-2-one into a dry tetrahydrofuran solution under nitrogen protection, then slowly add diisobutylaluminum hydride under low-temperature stirring, continue to react in a low-temperature environment, monitor the reaction by thin layer chromatography until the reaction is completed; quench the reaction by adding water, extract with ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate, evaporate and concentrate the filtrate, and purify by column chromatography to obtain the target product (S)-5-(hydroxymethyl)pyrrolidin-2-one (b); S2: preparation of (S)-5-(bromomethyl)pyrrolidin-2-one 1) Dissolve (S)-5-(hydroxymethyl)pyrrolidin-2-one and toluenesulfonyl chloride in dichloromethane, add triethylamine to the reaction system, stir at room temperature, monitor the reaction by high performance liquid chromatography until the reaction is completed; after the reaction is completed, add 1N hydrochloric acid to the reaction, extract with dichloromethane, wash with saturated brine, combine the organic phases, dry with anhydrous sodium sulfate, and recrystallize to obtain the intermediate (S)-5-((p-toluenesulfonyl)methyl)pyrrolidin-2-one; 2) Add (S)-5-((p-toluenesulfonyl)methyl)pyrrolidin-2-one and lithium bromide into a two-mouth bottle, vacuumize the reaction system, replace with nitrogen three times, add an acetone solution under nitrogen protection, and reflux the reaction in an oil bath overnight; monitor the reaction by high performance liquid chromatography until the reaction is completed; cool the reaction to room temperature, extract with dichloromethane and water, combine the organic phases, separate, dry and concentrate, and separate by column chromatography to obtain the target product (S)-5-(bromomethyl)pyrrolidin-2-one (c); S3: preparation of (S)-5-((9H-carbazol-9-yl)methyl)pyrrolidin-2-one Add (S)-5-(bromomethyl)pyrrolidin-2-one into a single-mouth bottle, add N,N,-dimethylformamide solvent into the bottle, then add carbazole and cesium carbonate to the reaction solution, heat and reflux the reaction in an oil bath, monitor the reaction by high performance liquid chromatography until the reaction is completed, cool to room temperature, pour the reaction liquid into a large amount of water, extract with ethyl acetate, combine the organic phases, separate, dry and concentrate to obtain the target product (S)-5-((9H-carbazol-9-yl)methyl)pyrrolidin-2-one (d); S4: preparation of a bifunctional azaheterocyclic carbene catalyst with a carbazole structure Take a dry two mouth bottle, add (S)-5-((9H-carbazol-9-yl)methyl)pyrrolidin-2-one to the bottle, replace nitrogen three times, then add anhydrous dichloromethane and trimethyloxonium tetrafluoroborate under the protection of nitrogen, and stir at room temperature overnight. Monitor the reaction progress by thin layer chromatography. After the reaction is completed, add an aryl hydrazine compound to the reaction system, continue to stir at room temperature, and monitor the reaction by thin layer chromatography. After the reaction is completed, spin dry and concentrate, and vacuum dry. Continue to add triethyl orthoformate and chlorobenzene to the reaction system under the condition of nitrogen, and heat the reaction in an oil bath. Monitor the reaction by thin layer chromatography. After the reaction is completed, spin dry and concentrate, and separate the target product I by column chromatography.
4. A process for the synthesis of a new class of N-heterocyclic carbene catalysts according to claim 3, characterized in that, In step S1, the molar ratio of (S)-5-carboxypyrrrolidin-2-one to diisobutylaluminum hydride is 1:1-1:3, and the temperature is -20ºC-20ºC.
5. A process for the synthesis of a new class of N-heterocyclic carbene catalysts as claimed in claim 3, wherein the process comprises the steps of: In step 1) of step S2, the molar ratio of (S)-5-(hydroxymethyl)pyrrrolidin-2-one to tosyl chloride is 1:1-1:3, and the molar ratio of (S)-5-(hydroxymethyl)pyrrrolidin-2-one to triethylamine is 1:1-1:
10.
6. A process for the synthesis of a new class of N-heterocyclic carbene catalysts according to claim 3, characterized in that, In step 2) of step S2, the molar ratio of (S)-5-((p-toluenesulfonyl)methyl)pyrrrolidin-2-one to lithium p-bromide is 1:1-1:
5.
7. A process for the synthesis of a new class of N-heterocyclic carbene catalysts as claimed in claim 3, wherein the process comprises the steps of: In step S3, the molar ratio of (S)-5-(bromomethyl)pyrrrolidin-2-one to carbazole is 1:0.5-1:1, and the molar ratio of (S)-5-(bromomethyl)pyrrrolidin-2-one to cesium carbonate is 1:1-1:
3.
8. A process for the synthesis of a new class of N-heterocyclic carbene catalysts as claimed in claim 3, wherein the process comprises the steps of: In step S4, the molar ratio of (S)-5-((9H-carbazol-9-yl)methyl)pyrrrolidin-2-one to trimethyloxonium tetrafluoroborate is 1:1-1:3, and the molar ratio of (S)-5-((9H-carbazol-9-yl)methyl)pyrrrolidin-2-one to aryl hydrazine is 1:1-1:
5.
9. A process for the synthesis of a new class of N-heterocyclic carbene catalysts as claimed in claim 3, wherein, In step S4, the molar ratio of (S)-5-((9H-carbazol-9-yl)methyl)pyrrrolidin-2-one to triethyl orthoformate is 1:2-1:10, and the temperature is 80ºC-150ºC.
10. A new type of nitrogen heterocyclic carbene catalyst synthesized by the process of any one of claims 1-9.