WO2023023880A1

WO2023023880A1 - Nitrogen heterocyclic carbene-urea bifunctional catalyst and preparation method therefor

Info

Publication number: WO2023023880A1
Application number: PCT/CN2021/113935
Authority: WO
Inventors: 陈杰安; 李恩
Original assignee: 深圳湾实验室坪山生物医药研发转化中心; 深圳湾实验室
Priority date: 2021-08-23
Filing date: 2021-08-23
Publication date: 2023-03-02

Abstract

The present application belongs to the technical field of catalytic materials, and in particular relates to a nitrogen heterocyclic carbene-urea bifunctional catalyst and a preparation method therefor. The general formula of the molecular structure of the metal complex is as shown in formula I in the description, wherein Ar¹ and Ar² in formula I are each independently selected from any one of an aryl, a substituted aryl, a heteroaryl and a substituted heteroaryl. The bifunctionality of the nitrogen heterocyclic carbene-urea is to introduce another active site urea group on the basis of an amino indenol-derived nitrogen heterocyclic carbene skeleton, such that a variety of bifunctional urea-nitrogen heterocyclic carbene catalysts can be formed, and thus same has potential application in the field of organic asymmetric catalysis and can expand organic asymmetric catalytic reactions.

Description

Nitrogen heterocyclic carbene-urea bifunctional catalyst and preparation method thereof

technical field

The present application relates to the technical field of catalytic materials, in particular to a nitrogen-heterocyclic carbene-urea bifunctional catalyst and a preparation method thereof.

Background technique

Bifunctional organic small molecule catalysts consist of Bronsted bases and hydrogen bond donors, which play an important role in asymmetric synthesis. However, there are few reports on bifunctional NHC catalysts. Among them, nitrogen heterocyclic carbene is mainly used for covalent catalytic reactions.

At present, nitrogen heterocyclic carbene derived from aminoindanol skeleton has developed rapidly as a skeleton catalyst in recent years, and has been widely used in the field of covalent and noncovalent asymmetric catalysis. Urea groups, as hydrogen bond donors, play an important role in numerous organocatalytic reactions. At present, there is no report on the connection of urea groups to nitrogen heterocyclic carbene catalysts, which limits the wide application of bifunctional organic small molecule catalysts with nitrogen heterocyclic carbene skeletons.

application content

The purpose of the embodiments of the present application is to provide a nitrogen-heterocyclic carbene-urea bifunctional catalyst and its preparation method, including but not limited to solving the problem of bifunctional catalysts obtained by combining nitrogen-heterocyclic carbene and urea groups that are not disclosed in the prior art. question.

The technical scheme that the embodiment of the present application adopts is:

In the first aspect, a nitrogen-heterocyclic carbene-urea bifunctional catalyst is provided, and the molecular structure general formula of the nitrogen-heterocyclic carbene-urea bifunctional catalyst is shown in formula I:

Wherein, Ar ¹ and Ar ² in the formula I are independently selected from any one of aryl, substituted aryl, heteroaryl and substituted heteroaryl.

In a second aspect, a method for preparing a nitrogen-heterocyclic carbene-urea bifunctional catalyst is provided, comprising the steps of:

Provide (1R,2S)-1-amino-2-indenol compound A, react (1R,2S)-1-amino-2-indenol compound A with sodium hydride, and then add ethyl chloroacetate for reaction to obtain compound B;

Reacting compound B through a nitration reaction to obtain nitro compound C;

Reaction of nitro compound C with trimethyloxonium tetrafluoroborate, Ar ² NHNH ₂ , and triethyl orthoformate to obtain compound D;

Compound D is subjected to reductive hydrogenation reaction to obtain amino compound E;

Amino compound E is reacted with isothiocyanate Ar ¹ NCO to obtain the nitrogen heterocyclic carbene-urea bifunctional catalyst shown in formula I;

Wherein, the structural formula of above-mentioned compound is as follows:

Wherein, Ar ¹ and Ar ² are each independently selected from any one of aryl, substituted aryl, heteroaryl and substituted heteroaryl.

The beneficial effect of a nitrogen-heterocyclic carbene-urea bifunctional catalyst provided in the embodiment of the present application is that the compound provided by the application is a nitrogen-heterocyclic carbene-urea bifunctional catalyst, and the metal complex has a typical high-functional group structure , such as containing Ar ¹ and Ar ² are independently selected from any one of aryl, substituted aryl, heteroaryl and substituted heteroaryl, which has a classic double-tube energy structure, which can be extended to organic asymmetric catalysis reaction.

The beneficial effect of the preparation method of a nitrogen-heterocyclic carbene-urea bifunctional catalyst provided by the embodiment of the present application is that: the present application provides a preparation method of the nitrogen-heterocyclic carbene-urea bifunctional catalyst, which firstly (1R, 2S)- 1-amino-2-indanol compound A is condensed with ethyl chloroacetate to obtain compound B, then nitrated to obtain nitro compound C, then reduced to obtain amino compound D, and finally reacted with isocyanate to obtain the nitrogen heterocycle shown in formula I Carbene-urea bifunctional catalyst. The preparation method simplifies the operation process in the production process, has low requirements on the reaction conditions, and the reaction process is safe and controllable, has high atom utilization and production efficiency, and has little pressure on environmental pollution. Therefore, the preparation method significantly improves the nitrogen heterocyclic carbene - The production efficiency of the urea bifunctional catalyst, thereby improving the application versatility.

Detailed ways

In order to make the purpose, technical solution and advantages of the present application clearer, the present application will be further described in detail below in conjunction with the accompanying drawings and embodiments. It should be understood that the specific embodiments described here are only used to explain the present invention, not to limit the present application.

It should be noted that when a component is referred to as being “fixed on” or “disposed on” another component, it may be directly on the other component or indirectly on the other component. When an element is referred to as being "connected to" another element, it can be directly or indirectly connected to the other element. The orientation or positional relationship indicated by the terms "upper", "lower", "left", "right", etc. are based on the orientation or positional relationship shown in the drawings, and are for convenience of description only, rather than indicating or implying the referred device Or elements must have a specific orientation, be constructed and operated in a specific orientation, and thus should not be construed as limiting the application, and those of ordinary skill in the art can understand the specific meanings of the above terms according to specific situations. The terms "first" and "second" are only used for descriptive purposes, and cannot be understood as indicating or implying relative importance or implicitly specifying the quantity of technical features. "Plurality" means two or more, unless otherwise clearly and specifically defined.

In order to illustrate the technical solutions provided by the present application, detailed descriptions will be given below in conjunction with specific drawings and embodiments.

The compounds and their derivatives involved in the examples of the present invention are all named according to the nomenclature system of IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, located in Columbus, Ohio). Therefore, the compound groups specifically involved in the embodiments of the present invention are described and illustrated as follows:

"Aryl" refers to a cyclic aromatic hydrocarbon, which may be monocyclic, polycyclic or condensed ring aromatic hydrocarbons, including but not limited to phenyl, naphthyl, anthracenyl, phenanthrenyl and other similar groups.

"Heteroaryl" means a monocyclic or polycyclic or fused ring aromatic hydrocarbon in which one or more carbon atoms have been replaced by a heteroatom such as nitrogen, oxygen or sulfur. If a heteroaryl group contains more than one heteroatom, these heteroatoms may or may not be the same. Heteroaryl groups include, but are not limited to, such as benzofuryl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzopyranyl, furyl, imidazolyl, indazolyl, Indolyl, indolyl, isobenzofuryl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazinyl, oxazolyl, Phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl[3,4-b]indolyl, pyridyl, pyrimidinyl, pyrrolyl, quinozine group, quinolinyl, quinoxalinyl, thiadiazolyl, thiatriazolyl, thiazolyl, thienyl, triazinyl, triazolyl, xanthenyl and other similar groups.

"Hetero atom" may be oxygen atom, nitrogen atom, sulfur atom, etc.

In the first aspect, the embodiment of the present application provides a nitrogen-heterocyclic carbene-urea bifunctional catalyst. The molecular structure of the nitrogen-heterocyclic carbene-urea bifunctional catalyst is shown in formula I:

Wherein, Ar ¹ and Ar ² in formula I are independently selected from any one of aryl, substituted aryl, heteroaryl and substituted heteroaryl.

The compound provided by the application is a nitrogen-heterocyclic carbene-urea bifunctional catalyst, and the metal complex has a typical high-functional group structure, such as containing Ar ¹ and Ar ² independently selected from aryl, substituted aryl, heteroaryl Any of the radicals and substituted heteroaryls, which have a classic double-tube energy structure, can be extended to organic asymmetric catalytic reactions.

In one embodiment, in formula I, Ar ¹ and Ar ² are selected from any one of the same aryl, substituted aryl, heteroaryl and substituted heteroaryl.

In another embodiment, in formula I, Ar ¹ and Ar ² are selected from any one of different aryl groups, substituted aryl groups, heteroaryl groups and substituted heteroaryl groups.

In some embodiments, when Ar ¹ or Ar ² is selected from aryl, the aryl is selected from at least one of monocyclic aryl, polycyclic aryl, and condensed ring aryl.

In some embodiments, the aryl group is selected from at least one of phenyl, naphthyl, fluorenyl, anthracenyl, and phenanthrenyl.

In a specific embodiment, the aryl group is selected from monocyclic aryl groups.

In some embodiments, when Ar ¹ or Ar ² is selected from a substituted aryl group, the substituted aryl group includes but not limited to ortho, meta, para substituted phenyl in single or multiple positions.

In some embodiments, in the substituted aryl group, the substituent is selected from alkyl, substituted alkyl, aryl, substituted aryl, acyl, halogen, alkoxy, nitro, -NR ₁ R ₂ , - Any one of NR ₁ -CO-NR ₂ , -OCONR ₁ , -PR ₁ R ₂ , -SOR ₁ , -SO ₂ -R ₂ , -SiR ₁ R ₂ R ₃ , -BR ₁ R ₂ , wherein, -NR ₁ R ₂ , -NR ₁ -CO-NR ₂ , -OCONR ₁ , -PR ₁ R ₂ , -SOR ₁ , -SO ₂ -R ₂ , -SiR ₁ R ₂ R ₃ , -BR ₁ R ₂ , R ₁ and R ₂ are selected from the same or different alkyl groups.

In some embodiments, when the substituent is selected from an alkyl group, the alkyl group is selected from any one of methyl, ethyl, propyl, butyl, and isobutyl.

In some embodiments, when the substituent is selected from substituted alkyl, the substituted alkyl is selected from any one of trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.

In some embodiments, when the substituent is selected from halogen, the halogen is selected from any one of fluorine, chlorine, bromine, and iodine.

In some embodiments, the substituent is selected from alkoxy, and the alkoxy is selected from any one of methyloxy, ethyloxy, and propyloxy.

In some embodiments, the substituted aryl is selected from substituted (C ₄ -C ₁₄ )aryl. Further, the substituted (C ₄ -C ₁₄ )aryl is selected from cyano(C ₁ -C ₁₀ )alkyl(C ₄ -C ₈ )aryl or substituted (C ₄ -C ₈ )aryl.

In some embodiments, when Ar ¹ or Ar ² is selected from heteroaryl, the heteroaryl is selected from at least one of monocyclic heteroaryl and condensed ring heteroaryl.

In some embodiments, the monocyclic heteroaryl is selected from furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyranyl, pyrimidinyl, and pyrazinyl at least one of .

In some embodiments, the fused ring heteroaryl is selected from the group consisting of benzofuryl, benzothienyl, benzopyrrolyl, benzimidazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, At least one of benzopyranyl, quinoline and acridine.

In some embodiments, when Ar ¹ or Ar ² is selected from substituted heteroaryl, the substituted heteroaryl is selected from at least one of substituted monocyclic heteroaryl and substituted fused-ring heteroaryl.

In some embodiments, the substituted monocyclic heteroaryl is selected from substituted furyl, substituted thienyl, substituted pyrrolyl, substituted imidazolyl, substituted pyrazolyl, substituted oxazolyl, substituted thiazole At least one of a group, a substituted pyridyl group, a substituted pyranyl group, a substituted pyrimidinyl group and a substituted pyrazinyl group.

In some embodiments, the substituted fused ring heteroaryl is selected from substituted benzofuryl, substituted benzothienyl, substituted benzopyrrolyl, substituted benzimidazolyl, substituted benzoxazolyl , at least one of substituted benzopyrazolyl, substituted benzothiazolyl, substituted benzopyranyl, substituted quinoline and substituted acridine.

In some embodiments, in the substituted heteroaryl, the substituent is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, acyl, halogen, alkoxy, nitro, -NR ₁ R ₂ , Any one of -NR ₁ -CO-NR ₂ , -OCONR ₁ , -PR ₁ R ₂ , -SOR ₁ , -SO ₂ -R ₂ , -SiR ₁ R ₂ R ₃ , -BR ₁ R ₂ , wherein , R ₁ and R ₂ are selected from the same or different alkyl groups.

In some embodiments, the substituted heteroaryl is selected from but not limited to any one of alkoxy substituted furan, (C3-C8) heteroaryl substituted furan, and aliphatic chain substituted thiophene.

In some embodiments, in the azacyclic carbene-urea bifunctional catalyst, Ar ¹ is selected from (C ₁ -C ₅ ) heteroalkyl substituted phenyl, Ar ² is selected from (C ₁ -C ₅ ) alkyl substituted phenyl or halophenyl.

In a specific embodiment, the nitrogen-heterocyclic carbene-urea bifunctional catalyst is shown in the following formula II. The bifunctional catalyst skeleton contains a urea group, a triazole heterocyclic group, and has a Bronsted base and a hydrogen bond donor. active catalytic sites, greatly expanding the designability and application prospects of such compounds.

In the second aspect, the embodiment of the present application provides a method for preparing a nitrogen-heterocyclic carbene-urea bifunctional catalyst, comprising the following steps:

S01. Provide (1R,2S)-1-amino-2-indenol compound A, react (1R,2S)-1-amino-2-indenol compound A with sodium hydride, and then add ethyl chloroacetate for reaction Obtain compound B;

S02. reacting compound B through a nitration reaction to obtain nitro compound C;

S03. Reaction of nitro compound C with trimethyloxonium tetrafluoroborate, Ar ² NHNH ₂ , and triethyl orthoformate to obtain compound D;

S04. Compound D is subjected to reductive hydrogenation reaction to obtain amino compound E;

S05. Amino compound E is reacted with isothiocyanate Ar ¹ NCO to obtain the nitrogen heterocyclic carbene-urea bifunctional catalyst shown in formula I;

Wherein, the structural formula of above-mentioned compound is as follows:

This application provides a preparation method of nitrogen heterocyclic carbene-urea bifunctional catalyst, which first condenses (1R,2S)-1-amino-2-indenol compound A with ethyl chloroacetate to obtain compound B, and then performs nitration reaction to obtain The nitro compound C is then reduced to obtain the amino compound D, and finally reacted with isocyanate to obtain the azacyclic carbene-urea bifunctional catalyst represented by formula I. The preparation method simplifies the operation process in the production process, has low requirements on the reaction conditions, and the reaction process is safe and controllable, has high atom utilization and production efficiency, and has little pressure on environmental pollution. Therefore, the preparation method significantly improves the nitrogen heterocyclic carbene - The production efficiency of the urea bifunctional catalyst, thereby improving the application versatility.

In step S01, (1R,2S)-1-amino-2-indenol compound A is provided, (1R,2S)-1-amino-2-indenol compound A is reacted with sodium hydride, and ethyl chloroacetate is added The reaction affords Compound B.

In some embodiments, (1R,2S)-1-amino-2-indanol compound A is dissolved in an organic solvent, cooled to 0-3°C, and then added with sodium hydride to react to obtain a mixed solution, and then ethyl acetate Solution extraction and drying, recrystallization to obtain compound B, the reaction formula is as follows:

In some embodiments, the step of dissolving (1R,2S)-1-amino-2-indanol compound A in an organic solvent comprises: dissolving (1R,2S)-1-amino-2-indanol compound A in tetrahydrofuran middle.

In step S02, compound B is reacted through a nitration reaction to obtain nitro compound C.

In some embodiments, compound B is dissolved in nitromethane solution, cooled to -10°C to -5°C for reaction, then mixed with concentrated nitric acid, concentrated sulfuric acid and water for reaction, and then filtered, and the filter residue is mixed with water and acetic acid The mixed solution of ethyl ester is washed, can obtain white solid product compound C, and reaction formula is as follows:

In some embodiments, the volume ratio of concentrated sulfuric acid, concentrated nitric acid and water is (0.1-100):(0.1-100):(0.1-20).

In step S03, the nitro compound C is reacted with trimethyloxonium tetrafluoroborate, Ar ² NHNH ₂ , and triethyl orthoformate to obtain compound D, and the reaction formula is as follows:

In some embodiments, Ar in Ar ² NHNH ₂ corresponds to Ar ² in the finally obtained azacyclic carbene-squaramide bifunctional catalyst shown ^{in formula I, and the specific selection of Ar 2} ^has been described in detail above, I won't repeat them here.

In some embodiments, the nitro compound C and trimethyloxonium tetrafluoroborate are dissolved and reacted at room temperature under an inert atmosphere for 12-14 hours to obtain the first mixed solution, ensuring complete reaction of the two.

In some implementations, the inert atmosphere is at least one selected from helium, neon, argon, krypton, xenon, and radon.

In some embodiments, trimethylphenylhydrazine is dissolved and then reacted with the first mixed solution for 24 to 28 hours to obtain the second mixture; then the second mixed solution is mixed with triethyl orthoformate and then heated to reflux, The reaction solution was concentrated and separated and purified to obtain compound D.

Step S04. Compound D is subjected to reductive hydrogenation reaction to obtain amino compound E. The reaction formula is as follows:

In some embodiments, after compound D is dissolved, it is mixed with 5% palladium carbon, subjected to reduction treatment with hydrogen for 12-14 hours, and then purified to obtain amino compound E.

Step S05. Reacting the amino compound E with the isothiocyanate Ar ¹ NCO to obtain the azacyclic carbene-urea bifunctional catalyst represented by formula I.

In some embodiments, Ar ¹ in the isothiocyanate Ar ¹ NCO corresponds to Ar ¹ in the azacyclic carbene-square amide bifunctional catalyst shown in the final formula I, and the Ar ¹ is specifically selected from the above It has already been described in detail, and will not be repeated here.

The preparation method of the above-mentioned chiral nitrogen heterocyclic carbene-urea bifunctional catalyst is through the steps of (1R,2S)-1-amino-2-indenol compound A condensation, nitration, cyclization, reduction and other steps; the preparation method is simple in process, The requirements for reaction conditions are low, the reaction process is safe and controllable, the utilization rate of atoms and production efficiency are high, and the enantioselectivity of the product is efficiently guaranteed. Moreover, the operation process in the preparation and production process is simplified, so that the toxicity of the reaction residue is minimized, the pollution to the environment produced by the production process is reduced, and the steps and operations for removing the residue after the reaction can be simplified. In addition, the raw material of the reactant is very easy to obtain, and the reactant of this type does not need to be additionally modified before the reaction, and can be directly used in the preparation and production, which simplifies the operation steps, shortens the reaction route, and significantly reduces the production cost. The preparation method for constructing nitrogen-heterocyclic carbene-urea bifunctional catalyst can be widely used in the fields of organic synthesis chemistry, asymmetric catalysis, pesticide and medicine research. Such a nitrogen-heterocyclic carbene-urea bifunctional catalyst has a good application in the synthesis of drug intermediates, functional materials and metal ligands or complexes, and can effectively reduce the concentration of drug intermediates, functional materials and metal ligands or Economical cost of compound preparation.

The following will be described in conjunction with specific embodiments.

Example 1

A nitrogen heterocyclic carbene-urea bifunctional catalyst, its molecular structure is as follows:

The preparation method of this nitrogen heterocyclic carbene-urea bifunctional catalyst comprises the steps:

(1) Synthesis of intermediate (4aR,9aS)-4,4a,9,9a-tetrahydroindeno[2,1-b][1,4]oxazin-3(2hydrogen)-one, reaction formula and the synthesis steps are as follows:

Add 9.0g (1R,2S)-1-amino-2-indanol to 300mL tetrahydrofuran solution, cool to 0 degrees, then add 2.52g 60% sodium hydride, stir for half an hour, then add 7.1mL ethyl chloroacetate . After stirring for 4 hours, samples were taken to monitor the reaction progress (TLC detection). After the reaction was complete, the reaction system was quenched with saturated sodium bicarbonate, then extracted with ethyl acetate solution, and then the combined organic phase was dried with anhydrous sodium sulfate, and the product was obtained by recrystallization. Compound B was obtained as a solid product.

(2) Intermediate (4aR, 9aS)-6-nitro-4,4a,9,9A tetrahydroindeno[2,1-B][1,4]oxazin-3(2hydrogen)-one Synthesis, reaction formula and synthetic steps are as follows:

Dissolve 5.67 g of intermediate (4aR,9aS)-4,4a,9,9a-tetrahydroindeno[2,1-b][1,4]oxazin-3(2hydro)-one in 56 mL of nitro In the methane solution, cool to -10°C, then add the mixture of 1.6mL concentrated nitric acid, 11mL water, and 40mL concentrated sulfuric acid pre-cooled to -10°C to the above solution drop by drop in one hour, and place the reaction in - The reaction was continued for 2 hours at 10°C to monitor the progress of the reaction (TLC detection). Then pour into 1000mL of ice water, continue to stir for 1 hour, filter, and wash the filter residue with a large amount of water and a small amount of cold ethyl acetate. The washed filter residue is the target product. Compound C was obtained as a white solid product.

(3) Intermediate (5aS,10bR)-2-Mesityl-9-nitro-5a,10b-dihydro-4H,6H-indeno[2,1-b][1,2,4] The synthesis of triazolo[4,3-d][1,4]oxazin-2-ium tetrafluoroborate, the reaction formula and synthesis steps are as follows:

2.34g (4aR, 9aS)-6-nitro-4,4a,9,9A tetrahydroindeno[2,1-B][1,4]oxazin-3(2hydrogen)-one and 1.6g Trimethyloxytetrafluoroborate was dissolved in 100 mL of dichloromethane solution. Stir at room temperature for 12 hours under an atmosphere of nitrogen protection, and monitor the progress of the reaction. 1.8 g of s-trimethylphenylhydrazine was dissolved in 20 mL of dichloromethane solution, and the solution was added to the above solution, and stirring was continued for 24 hours. The mixture was spin-dried, dissolved in 100 mL of chlorobenzene and 16 mL of trimethyl orthoformate, heated to 110°C, and refluxed for 48 hours. After the reaction was completed, it was directly spin-dried and purified by column chromatography to obtain compound D as a white solid.

(4) Intermediate (5aS,10bR)-2-Mesityl-9-amino-5a,10b-dihydro-4H,6H-indeno[2,1-b][1,2,4]tri The synthesis of azolo[4,3-d][1,4]oxazin-2-ium tetrafluoroborate, the reaction formula and synthesis steps are as follows:

0.9g (5aS,10bR)-2-Mesityl-9-nitro-5a,10b-dihydro-4H,6H-indeno[2,1-b][1,2,4]triazole And[4,3-d][1,4]oxazin-2-ium tetrafluoroborate was dissolved in 100mL of methanol, 98mg of 5% palladium carbon was added, and it was reduced with hydrogen for 12 hours, and the reaction was monitored by sampling (TLC detection). . After filtering off the palladium carbon, the filtrate was spin-dried and purified by column chromatography to obtain compound E as a white solid.

(5) Final product: (5aS,10bR)-9-(3-(3,5-bis(trifluoromethyl)phenyl)ureido)-2-mesitylacetone-5a,10bdihydro- Synthesis of 4H,6H-indeno[2,1-b][1,2,4]triazolo[4,3-d][1,4]oxazin-2-ium tetrafluoroborate, reaction The formula and synthesis steps are as follows:

The 467 mg intermediate (5aS,10bR)-2-mesityl-9-amino-5a,10b-dihydro-4H,6H-indeno[2,1-b][1,2,4 ] Triazolo[4,3-d][1,4]oxazin-2-ium tetrafluoroborate was dissolved in 6mL of dichloromethane, and 515mg of 3,5-bis(trifluoromethyl)phenyl Isocyanate was stirred at room temperature for 12 hours, and samples were taken to monitor the reaction (TLC detection). After the reaction was complete, the reaction system was spin-dried and purified by column chromatography to obtain a white solid. Compound I1 was obtained as a solid.

Correlation characterization analysis, the results are: ¹ H NMR (500MHz, DMSO) δ11.32(s,1H),9.50(s,1H),9.09(s,1H),8.15(s,2H),7.90(s, 1H),7.62(s,1H),7.35(d,J=8.1Hz,1H),7.20(d,J=7.4Hz,1H),7.16(s,2H),6.08(d,J=3.7Hz, 1H), 5.27(d, J=16.0Hz, 1H), 5.07(d, J=16.0Hz, 1H), 4.99(s, 1H), 3.44(dd, J=16.7, 4.4Hz, 1H), 3.11( s,1H),2.36(s,3H),2.15(s,6H) ^.13C NMR(126MHz,DMSO)δ153.27,150.77,144.97,144.97,142.49,142.27,138.84,137.22,135.56,135.24,131.81,131.3 (q, J=32.5Hz), 129.93, 126.37, 125.01 (q, J=273.4Hz), 121.24, 118.51, 115.76, 114.92, 77.96, 61.84, 60.31, 37.09, 21.29, 17.47. ¹⁹ F NMR (376MHz, DMSO )δ-61.75(s),-148.25(s).HRMS(ESI-TOF)[M]calculated for[C ₃₀ H ₂₆ F ₆ N ₅ O ₂ ] ⁺ Exact Mass:602.1985, observed 602.1980.

Example 2

Its preparation method refers to the preparation method of compound I1 in Example 1, except that 2,4-dimethyl-p-bromophenylhydrazine (2.57 g) is used instead of mesitylene trap. The reaction solution was directly separated and purified by silica gel column chromatography (methanol and dichloromethane as eluents) to obtain the target product as a white solid. Yield 54%

The prepared product I2 was subjected to correlation characterization analysis, and the result was ¹ H NMR (400MHz, DMSO) δ11.45 (s, 1H), 10.57 (s, 1H), 9.73 (s, 1H), 7.86 (s, 1H) ,7.64(d,J=5.8Hz,3H),7.36(d,J=8.2Hz,1H),7.27(dd,J=8.2,1.4Hz,1H),6.13(d,J=3.9Hz,1H) ,5.28(d,J=16.1Hz,1H),5.09(d,J=16.0Hz,1H),5.00(t,J=4.3Hz,1H),3.44(dd,J=16.9,4.6Hz,1H) , 3.11 (d, J=16.8Hz, 1H), 2.21 (s, 6H). ¹³ C NMR (101MHz, DMSO) δ153.25, 150.89, 145.05, 142.43, 138.79, 138.43, 137.05, 134.91, 133.41, 131.94, 131.23 ( q,J=33.3Hz),126.26,125.27,123.78(q ^, J=273.7Hz),120.71,117.87,117.85,115.21,114.71,114.67,114.64,77.72,61.77,60.14,36.86,17.31 NMR.19 376MHz, DMSO) δ-61.70.

The above are only optional embodiments of the application, and are not intended to limit the application. For those skilled in the art, various modifications and changes may occur in this application. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present application shall be included within the scope of the claims of the present application.

Claims

A nitrogen-heterocyclic carbene-urea bifunctional catalyst, characterized in that the molecular structure general formula of the nitrogen-heterocyclic carbene-urea bifunctional catalyst is as shown in formula I:

Wherein, Ar 1 and Ar 2 in the formula I are independently selected from any one of aryl, substituted aryl, heteroaryl and substituted heteroaryl.
The nitrogen-heterocyclic carbene-urea bifunctional catalyst according to claim 1, wherein the aryl group is selected from at least one of monocyclic aryl groups, polycyclic aryl groups, and condensed ring aryl groups.
The nitrogen heterocyclic carbene-urea bifunctional catalyst according to claim 1, wherein the heteroaryl is selected from at least one of monocyclic heteroaryl and condensed ring heteroaryl.
nitrogen heterocyclic carbene-urea bifunctional catalyst according to claim 3, is characterized in that, described monocyclic heteroaryl is selected from furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, At least one of thiazolyl, pyridyl, pyranyl, pyrimidinyl and pyrazinyl.
nitrogen heterocyclic carbene-urea bifunctional catalyst according to claim 3, is characterized in that,

The condensed ring heteroaryl is selected from benzofuryl, benzothienyl, benzopyrrolyl, benzimidazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, benzopyranyl At least one of radical, quinoline and acridine.
nitrogen heterocycle carbene-urea bifunctional catalyst according to claim 1, is characterized in that, described substituted aryl is selected from substituted monocyclic aryl, substituted polycyclic aryl, substituted condensed ring aryl any of the
The nitrogen heterocyclic carbene-urea bifunctional catalyst according to claim 6, characterized in that, in the substituted aryl, the substituent is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, acyl , Halogen, Alkoxy, Nitro, -NR 1 R 2 , -NR 1 -CO-NR 2 , -OCONR 1 , -PR 1 R 2 , -SOR 1 , -SO 2 -R 2 , -SiR 1 R Any one of 2 R 3 , -BR 1 R 2 , wherein R 1 and R 2 are selected from the same or different alkyl groups.
The nitrogen heterocyclic carbene-urea bifunctional catalyst according to claim 1, wherein the substituted heteroaryl is selected from at least one of substituted monocyclic heteroaryl and substituted condensed ring heteroaryl .
The nitrogen heterocyclic carbene-urea bifunctional catalyst according to claim 8, wherein the substituted monocyclic heteroaryl is selected from substituted furyl, substituted thienyl, substituted pyrrolyl, substituted imidazole At least one of a group, a substituted pyrazolyl group, a substituted oxazolyl group, a substituted thiazolyl group, a substituted pyridyl group, a substituted pyranyl group, a substituted pyrimidinyl group and a substituted pyrazinyl group.
The nitrogen heterocyclic carbene-urea bifunctional catalyst according to claim 8, wherein the substituted condensed ring heteroaryl is selected from substituted benzofuryl, substituted benzothienyl, substituted benzo Pyrrolyl, substituted benzimidazolyl, substituted benzoxazolyl, substituted benzopyrazolyl, substituted benzothiazolyl, substituted benzopyranyl, substituted quinoline, and substituted acridine at least one of the
nitrogen heterocyclic carbene-urea bifunctional catalyst according to claim 8, characterized in that, in the substituted heteroaryl, the substituent is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, Acyl, halogen, alkoxy, nitro, -NR 1 R 2 , -NR 1 -CO-NR 2 , -OCONR 1 , -PR 1 R 2 , -SOR 1 , -SO 2 -R 2 , -SiR 1 Any one of R 2 R 3 , -BR 1 R 2 , wherein R 1 and R 2 are selected from the same or different alkyl groups.
The nitrogen heterocyclic carbene-urea bifunctional catalyst according to claim 1, characterized in that, in the formula I, Ar 1 is a substituted phenyl group, and Ar 2 is a substituted phenyl group.
The nitrogen heterocyclic carbene-urea bifunctional catalyst according to claim 12, characterized in that, in the formula I, Ar 1 is a phenyl group substituted by (C 1 -C 5 ) heteroalkyl, and Ar 2 is (C 1 -C 5 ) alkyl-substituted phenyl or halophenyl.
A preparation method of nitrogen heterocyclic carbene-urea bifunctional catalyst, is characterized in that, comprises the steps:

Provide (1R,2S)-1-amino-2-indenol compound A, react (1R,2S)-1-amino-2-indenol compound A with sodium hydride, and then add ethyl chloroacetate for reaction to obtain compound B;

Reacting compound B through a nitration reaction to obtain nitro compound C;

Reaction of nitro compound C with trimethyloxonium tetrafluoroborate, Ar 2 NHNH 2 , and triethyl orthoformate to obtain compound D;

Compound D is subjected to reductive hydrogenation reaction to obtain amino compound E;

Amino compound E is reacted with isothiocyanate Ar 1 NCO to obtain the nitrogen heterocyclic carbene-urea bifunctional catalyst shown in formula I;

Wherein, the structural formula of above-mentioned compound is as follows:

Wherein, Ar 1 and Ar 2 are each independently selected from any one of aryl, substituted aryl, heteroaryl and substituted heteroaryl.