WO2022104599A1 - 氮杂环卡宾催化剂及其制备方法 - Google Patents

氮杂环卡宾催化剂及其制备方法 Download PDF

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WO2022104599A1
WO2022104599A1 PCT/CN2020/129804 CN2020129804W WO2022104599A1 WO 2022104599 A1 WO2022104599 A1 WO 2022104599A1 CN 2020129804 W CN2020129804 W CN 2020129804W WO 2022104599 A1 WO2022104599 A1 WO 2022104599A1
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substituted
group
formula
heterocyclic carbene
heteroaryl
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陈杰安
黄湧
郭芳芳
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深圳湾实验室坪山生物医药研发转化中心
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Priority to PCT/CN2020/129804 priority Critical patent/WO2022104599A1/zh
Priority to US18/037,621 priority patent/US20230398526A1/en
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    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
    • B01J31/0235—Nitrogen containing compounds
    • B01J31/0244—Nitrogen containing compounds with nitrogen contained as ring member in aromatic compounds or moieties, e.g. pyridine
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
    • B01J31/0235—Nitrogen containing compounds
    • B01J31/0245—Nitrogen containing compounds being derivatives of carboxylic or carbonic acids
    • B01J31/0247—Imides, amides or imidates (R-C=NR(OR))
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/0215—Sulfur-containing compounds
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    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/0231—Halogen-containing compounds
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    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
    • B01J31/0235—Nitrogen containing compounds
    • B01J31/0245—Nitrogen containing compounds being derivatives of carboxylic or carbonic acids
    • B01J31/0249—Ureas (R2N-C(=O)-NR2)
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
    • B01J31/0271—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds also containing elements or functional groups covered by B01J31/0201 - B01J31/0231
    • B—PERFORMING OPERATIONS; TRANSPORTING
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    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J37/00—Processes, in general, for preparing catalysts; Processes, in general, for activation of catalysts
    • B01J37/16—Reducing
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/16—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/30—Addition reactions at carbon centres, i.e. to either C-C or C-X multiple bonds
    • B01J2231/34—Other additions, e.g. Monsanto-type carbonylations, addition to 1,2-C=X or 1,2-C-X triplebonds, additions to 1,4-C=C-C=X or 1,4-C=-C-X triple bonds with X, e.g. O, S, NH/N
    • B01J2231/348—1,4-additions, e.g. conjugate additions

Definitions

  • the present application relates to the technical field of catalytic materials, in particular to a nitrogen heterocyclic carbene catalyst and a preparation method thereof.
  • bifunctional bicatalytic sites have been designed and successfully applied in organic asymmetric catalysis.
  • the most widely used bifunctional catalysts are chiral catalysts containing thiourea (urea) groups, which achieve good catalytic activity and stereoselectivity because the thiourea groups in their structure form hydrogen bonds with various substrates .
  • thiourea thiourea
  • Bifunctional thiourea catalysts have been widely used in asymmetric azaMichael reactions.
  • N-Heterocyclic Carbenes are an important class of organic small molecule catalysts, which have been widely used in the field of asymmetric organic catalysis.
  • the currently developed bifunctional azacarbene catalysts have not been successfully applied to asymmetric azaMichael addition reactions.
  • One of the purposes of the embodiments of the present application is to provide a nitrogen heterocyclic carbene catalyst and a preparation method thereof, aiming at solving the technical problem of the limited reaction types catalyzed by the existing bifunctional nitrogen heterocyclic carbene.
  • a nitrogen heterocyclic carbene catalyst is provided, and the general structural formula of the nitrogen heterocyclic carbene catalyst is shown in the following formula I:
  • Ar 1 and Ar 2 in the formula I are independently selected from any one of aryl, substituted aryl, heteroaryl and substituted heteroaryl, and X is an oxygen atom or a sulfur atom.
  • a method for preparing a nitrogen heterocyclic carbene catalyst comprising the steps of:
  • Ar 1 and Ar 2 are each independently selected from any one of an aryl group, a substituted aryl group, a heteroaryl group and a substituted heteroaryl group, and X is an oxygen atom or a sulfur atom.
  • the beneficial effects of the nitrogen heterocyclic carbene catalysts are: the present application introduces another active site thiourea (urea) group on the basis of the nitrogen heterocyclic carbene skeleton, and by adjusting the Ar 1 in formula I
  • the selection of various groups of aryl, substituted aryl, heteroaryl and substituted heteroaryl with Ar 2 can form various types of bifunctional thiourea (urea) azacyclic carbene catalysts.
  • Cyclic carbene catalysts have good catalytic activity in catalyzing asymmetric aza-Michael reactions, so they have potential applications in the field of organic asymmetric catalysis.
  • the preparation method has the advantages of easy availability of raw materials, low cost, convenient operation, mild reaction conditions and easy control, and can be prepared into a bifunctional thiourea ( urea) azacyclic carbene catalysts have good catalytic activity in catalyzing asymmetric aza-Michael reactions, and have potential applications in the field of organic asymmetric catalysis.
  • FIG. 1 is a schematic flow diagram of a method for preparing a nitrogen heterocyclic carbene catalyst according to an embodiment of the present application.
  • Aryl refers to an aromatic hydrocarbon having an aromatic cyclic structure, including but not limited to groups such as phenyl, naphthyl, anthracenyl, phenanthryl, etc., and other similar groups.
  • Substituted aryl refers to an aryl derivative in which the hydrogen atom on the above-mentioned aryl ring is substituted by other functional groups, wherein the substituted functional groups may be one or more.
  • Heteroaryl refers to a monocyclic or polycyclic or fused-ring aromatic hydrocarbon in which one or more carbon atoms have been replaced by heteroatoms such as nitrogen, oxygen or sulfur. If the heteroaryl group contains more than one heteroatom, these may or may not be the same. Heteroaryl groups include, but are not limited to, groups such as benzofuranyl, benzothienyl, benzimidazolyl, thiazolyl, thienyl, and the like, as well as other similar groups. "Substituted heteroaryl” refers to the heteroaryl derivative that the hydrogen atom on the above-mentioned heteroaryl ring is substituted by other functional groups, wherein the substituted functional groups may be one or more.
  • the application provides a nitrogen heterocyclic carbene catalyst
  • the general structural formula of the nitrogen heterocyclic carbene catalyst is shown in the following formula I:
  • Ar 1 and Ar 2 in the formula I are independently selected from any one of aryl, substituted aryl, heteroaryl and substituted heteroaryl, and X is an oxygen atom or a sulfur atom.
  • the nitrogen heterocyclic carbene catalyst provided in the examples of the present application is to introduce another active site thiourea (urea) group on the basis of the nitrogen heterocyclic carbene skeleton, and by performing an aryl group on Ar 1 and Ar 2 in formula I
  • thiourea urea
  • the selection of various groups of , substituted aryl, heteroaryl and substituted heteroaryl can form various types of bifunctional thiourea (urea) azacyclic carbene catalysts, which are in the catalytic
  • the symmetric azaMichael reaction has good catalytic activity, so it has potential applications in the field of organic asymmetric catalysis.
  • Ar 1 and Ar 2 can be the same or different aryl, substituted aryl, heteroaryl, and substituted heteroaryl.
  • the aryl group is selected from at least one of phenyl, naphthyl, anthracenyl, phenanthryl and fluorenyl.
  • the substituted aryl is the above-mentioned aryl introduced substituent, specifically, the substituted aryl is selected from substituted phenyl, substituted naphthyl, substituted anthracenyl, substituted phenanthryl and substituted fluorenyl at least one of them.
  • the substituent group is selected from halogen atom, hydroxyl group, amino group, nitro group, sulfo group, cyano group, acyl group, ester group, (C 1 -C 10 ) alkyl group, (C 6 -C 14 ) At least one of aryl and (C 4 -C 14 )heteroaryl.
  • the heteroaryl group is selected from at least one of a monocyclic heteroaryl group and a fused-ring heteroaryl group.
  • the monocyclic heteroaryl group is selected from at least furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyranyl, pyrimidinyl and pyrazinyl
  • the fused ring heteroaryl is selected from benzofuranyl, benzothienyl, benzopyrrolyl, benzimidazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, benzene at least one of pyranyl, quinoline and acridine.
  • the substituted heteroaryl group is the substituent introduced into the above-mentioned heteroaryl group.
  • the substituted heteroaryl group is selected from at least one of a substituted monocyclic heteroaryl group and a substituted fused-ring heteroaryl group.
  • the substituted monocyclic heteroaryl is selected from substituted furyl, substituted thienyl, substituted pyrrolyl, substituted imidazolyl, substituted pyrazolyl, substituted oxazolyl, substituted thiazolyl, At least one of substituted pyridyl, substituted pyranyl, substituted pyrimidinyl and substituted pyrazinyl;
  • the substituted fused ring heteroaryl is selected from substituted benzofuranyl, substituted benzothiophene base, substituted benzopyrrolyl, substituted benzimidazolyl, substituted benzoxazolyl, substituted benzopyrazolyl, substituted benzothiazolyl, substituted benzopyranyl, substituted quinoline at least one of phenoline and substituted acridine.
  • the substituent is selected from halogen atom, hydroxyl, amino, nitro, sulfo, cyano, acyl, ester, (C 1 -C 10 ) alkyl, (C 6 -C 14 ) ) at least one of aryl and (C 4 -C 14 )heteroaryl.
  • Ar 1 is a substituted phenyl group
  • Ar 2 is a substituted phenyl group.
  • Ar 2 is a halogen atom-substituted (C 1 -C 10 ) alkyl substituted phenyl group, such as a halogenated C 1 -C 10 alkyl mono- or polysubstituted phenyl group, etc., wherein the halogen atom may be fluorine , chlorine, bromine, iodine;
  • Ar 1 is (C 1 -C 10 ) alkyl substituted phenyl, such as methyl mono- or poly-substituted phenyl, ethyl mono- or poly-substituted phenyl and the like.
  • Ar 1 is mes-trimethylphenyl
  • Ar 2 is 3,5-bis(trifluoromethyl)phenyl
  • X is a sulfur atom or an oxygen atom
  • the structure of the azacyclic carbene catalyst is as follows :
  • Ar 1 being mesityl phenyl can improve the ⁇ electron-donating ability of nitrogen heterocyclic carbene to improve its Bronsted basicity, while Ar 2 being 3,5-bis(trifluoromethyl)phenyl can greatly improve the The acidity of the thiourea group makes it easier to form hydrogen bonds with the substrate, thereby exerting catalytic activity and stereoselectivity. In this way, through the joint action of these two unique groups, a general catalytic model with better catalytic effect can be formed.
  • the present application also provides a preparation method of a nitrogen heterocyclic carbene catalyst, as shown in Figure 1, the preparation method comprises the following steps:
  • Ar 1 and Ar 2 are independently selected from any one of an aryl group, a substituted aryl group, a heteroaryl group and a substituted heteroaryl group, and X is an oxygen atom or a sulfur atom.
  • the preparation method has the advantages of easy availability of raw materials, low cost, convenient operation, mild reaction conditions and easy control, and can be prepared into a bifunctional thiourea ( urea) azacyclic carbene catalysts have good catalytic activity in catalyzing asymmetric aza-Michael reactions, and have potential applications in the field of organic asymmetric catalysis.
  • Ar 1 in Ar 1 NHNH 2 ⁇ HCl and Ar 2 in Ar 2 NCX correspond to Ar 1 and Ar 2 in the finally obtained nitrogen heterocyclic carbene catalyst represented by formula I respectively, and the Ar 1 and Ar 2 are specifically selected It has been elaborated above.
  • step S01 the preparation method of (S)-2-(azidomethyl)-5-methoxy-3,4-dihydro-2H-pyrrole represented by formula V comprises the following steps:
  • L-pyroglutamine shown in formula II is protected by hydroxyl group with p-toluenesulfonyl chloride to obtain (S)-5-hydroxymethyl-2-pyrrolidone p-toluenesulfonate shown in formula III;
  • L-pyroglutamine is a simple and readily available chemical raw material.
  • the preparation method has the advantages of easily available raw materials, low cost, convenient operation, and potential application activity in the field of organic asymmetric catalysis.
  • the synthetic route consisted of 7 steps, and the final product was obtained in 11% yield.
  • This route has the advantages of easy availability of raw materials, low cost, convenient operation, mild reaction conditions and easy control.
  • Ar 1 is mes-trimethylphenyl, that is, Ar 1 NHNH 2 ⁇ HCl is mes-trimethylphenylhydrazine hydrochloride
  • Ar 2 is 3,5-bis(trifluoromethyl)phenyl
  • X is a sulfur atom
  • Ar 2 NCX 3,5-bis(trifluoromethyl) phenyl isothiocyanate as an example
  • the synthesis method includes the following steps:
  • Step 1 using L-pyroglutamine as a raw material, protecting the hydroxyl group with p-toluenesulfonyl chloride (reactants include: p-toluenesulfonyl chloride, triethylamine, 4-lutidine, dichloromethane solution) to obtain Intermediate (S)-5-hydroxymethyl-2-pyrrolidone p-toluenesulfonate.
  • reactants include: p-toluenesulfonyl chloride, triethylamine, 4-lutidine, dichloromethane solution
  • step 2 the above intermediate (S) 5-hydroxymethyl-2-pyrrolidone p-toluenesulfonate is reacted with sodium azide to obtain the intermediate (S)-5-azidomethyl-2-pyrrolidone.
  • Step 3 the above intermediate (S)-5-azidomethyl-2-pyrrolidone and trimethyl oxonium tetrafluoroborate to obtain intermediate (S)-2-(azidomethyl)-5 -Methoxy-3,4-dihydro-2H-pyrrole.
  • step 4 the above intermediate (S)-2-(azidomethyl)-5-methoxy-3,4-dihydro-2H-pyrrole is reacted with mesityl phenylhydrazine hydrochloride to obtain the intermediate
  • Step 5 the above intermediate 1-((5S)-5-(azidomethyl)pyrrolidin-2-yl)-2-mestrimethylphenylhydrazine hydrochloride is reacted with trimethyl orthoformate and hydrochloric acid , to give the intermediate (S)-5-(azidomethyl)-2-methanesulfonyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole -2-Onium hydrochloride.
  • Step 6 the above intermediate (S)-5-(azidomethyl)-2-methanesulfonyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4 ] Triazole-2-onium hydrochloride was reductive hydrogenation with palladium carbon to give intermediate (S)-5-(aminomethyl)-2-tolyl-6,7-dihydro-5H-pyrrolo[2, 1-c][1,2,4]triazol-2-onium hydrochloride.
  • the azacyclic carbene catalyst provided in this application and the azacyclic carbene catalyst prepared by the preparation method have good catalytic activity in catalyzing asymmetric azaMichael reactions, such as: nucleophile compound NR 1 R 2 and conjugated alkene Ketones
  • asymmetric azaMichael addition reaction can be catalyzed to obtain a ⁇ -carbonyl chiral amino compound, and the reaction formula is as follows:
  • R 1 and R 2 in the nucleophile compound NR 1 R 2 may be the same or different C 1 -C 20 alkyl, C 1 -C 20 alkoxy, C 1 -C 20 alkyloxycarbonyl, aryl aryloxy, aryloxycarbonyl, aryl(C 1 -C 20 )alkyl, aryl(C 1 -C 20 )alkoxy and aryl(C 1 -C 20 )alkoxycarbonyl any of the .
  • R in the conjugated ketene compounds can be C 1 -C 20 alkyl, C 1 -C 20 heteroalkyl, C 3 -C 20 cycloalkyl, C 3 -C 20 heterocycloalkyl, C 2 - C 20 alkenyl, C 2 -C 20 heteroalkenyl, C 3 -C 20 cycloalkenyl, C 3 -C 20 heterocycloalkenyl, C 2 -C 20 alkynyl, C 2 -C 20 heteroalkynyl, C 3 -C 20 cycloalkynyl, C 3 -C 20 heterocycloalkynyl, C 1 -C 20 alkoxy, C 1 -C 20 alkyloxycarbonyl, C 1 -C 20 alkyloxycarbonyl (C 1 -C 20 alkyloxycarbonyl -C 20 ) alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, aryl
  • a bifunctional nitrogen heterocyclic carbene catalyst the molecular structure of which is as follows:
  • the preparation method of this bifunctional nitrogen heterocyclic carbene catalyst comprises the following steps:
  • the solid obtained in the previous step was placed in a reaction flask, 38.0 mL of trimethyl orthoformate, 28.0 mL of chlorobenzene solution and 7.0 mL of concentrated hydrochloric acid were added thereto, and the gas was replaced with nitrogen three times. It was then refluxed at 100 degrees for 1 hour, and the reaction system was monitored (TLC detection). After the reaction was completed, the reaction was returned to room temperature, spin-dried, and purified by column chromatography to obtain a brown solid. Purification by column chromatography gave a brown solid. 4.45 g of brown solid was obtained in 50% yield.
  • the 250mg solid obtained in the previous step was placed in a reaction flask, 230mg 3,5-bis(trifluoromethyl)phenyl isothiocyanate and 2.5mL dichloromethane solution were added, stirred at room temperature for 12 hours, and the reaction was monitored by sampling ( TLC detection). After the reaction was completed, the reaction system was spin-dried and purified by column chromatography to obtain a white solid. 440 mg of solid product was obtained in 95% yield.
  • a bifunctional nitrogen heterocyclic carbene catalyst the molecular structure of which is as follows:
  • the preparation method of this bifunctional nitrogen heterocyclic carbene catalyst comprises the following steps:
  • reaction solution was filtered through a glass dropper containing silica gel, washed with ether, the filtrate was spin-dried, and separated by column chromatography to obtain the target product as a white solid with a yield of 87%, 92% ee.

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Abstract

一种氮杂环卡宾催化剂，该氮杂环卡宾催化剂的结构通式如式I所示，式I中的Ar 1和Ar 2分别独立选自芳基、取代的芳基、杂芳基和取代的杂芳基中的任意一种。该氮杂环卡宾催化剂是在氮杂环卡宾骨架的基础上引入另一活性位点硫脲(脲)基团，可以形成多种双功能硫脲(脲)氮杂环卡宾催化剂，该氮杂环卡宾催化剂在催化不对称氮杂迈克尔反应具有很好的催化活性，因此在有机不对称催化领域具有潜在的应用。

Description

氮杂环卡宾催化剂及其制备方法 技术领域
本申请涉及催化材料技术领域，具体涉及一种氮杂环卡宾催化剂及其制备方法。
背景技术
近些年来，具有双功能团双催化位点的催化剂被设计并成功应在有机不对称催化中。其中，应用最广泛的双官能团催化剂是含有硫脲(脲)基团的手性催化剂，由于其结构中的硫脲基团与多种底物形成氢键从而实现良好的催化活性和立体选择性。例如奎宁硫脲催化剂，手性环己二胺硫脲催化剂，膦酰亚胺硫脲催化剂等。双功能硫脲催化剂已广泛地应用于不对称氮杂迈克尔反应中。
氮杂环卡宾(N-Heterocyclic Carbenes,NHCs)是一类重要的有机小分子催化剂，其在有机不对称催化领域得到了广泛的应用。但是，目前发展的双功能团的氮杂卡宾催化剂还没有成功应用于不对称氮杂迈克尔加成反应中。
技术问题
本申请实施例的目的之一在于：提供一种氮杂环卡宾催化剂及其制备方法，旨在解决现有双功能团的氮杂环卡宾催化的反应类型有限的技术问题。
技术解决方案
为解决上述技术问题，本申请实施例采用的技术方案是：
第一方面，提供了一种氮杂环卡宾催化剂，所述氮杂环卡宾催化剂的结构通式如下式I所示：
Figure PCTCN2020129804-appb-000001
其中，所述式I中的Ar 1和Ar 2分别独立选自芳基、取代的芳基、杂芳基和取代的杂芳基中的任意一种，X为氧原子或硫原子。
第二方面，提供了一种氮杂环卡宾催化剂的制备方法，包括如下步骤：
将式V所示的(S)-2-(叠氮甲基)-5-甲氧基-3,4-二氢-2H-吡咯与Ar 1NHNH 2·HCl进行反应得到式VI所示的化合物；
将式VI所示的化合物与原甲酸三甲酯和盐酸反应，得到式VII所示的化合物；
将式VII所示的化合物进行还原氢化反应，得到式VIII所示的化合物；
将式VIII所示的化合物与异硫氰酸酯Ar 2NCX反应，得到式I所示的氮杂环卡宾催化剂；
其中，上述化合物的结构式如下：
Figure PCTCN2020129804-appb-000002
Ar 1和Ar 2分别独立选自芳基、取代的芳基、杂芳基和取代的杂芳基中的任意一种，X为氧原子或硫原子。
有益效果
本申请实施例提供的氮杂环卡宾催化剂的有益效果在于：本申请在氮杂环卡宾骨架的基础上引入另一活性位点硫脲(脲)基团，并且通过对式I中的Ar 1和Ar 2进行芳基、取代的芳基、杂芳基和取代的杂芳基的多种基团的选择，可以形成多种类的双功能硫脲(脲)氮杂环卡宾催化剂，该氮杂环卡宾催化剂在催化不对称氮杂迈克尔反应具有很好的催化活性，因此在有机不对称催化领域具有潜在的应用。
本申请实施例提供的氮杂环卡宾催化剂的制备方法的有益效果在于：该制备方法具有原料易得，成本低，操作方便，反应条件温和易于控制的优点，而且可以制备成双功能硫脲(脲)氮杂环卡宾催化剂，在催化不对称氮杂迈克尔反应具有很好的催化活性，其在有机不对称催化领域具有潜在的应用。
附图说明
为了更清楚地说明本申请实施例中的技术方案，下面将对实施例或示范性技术描述中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图仅仅是本申请的一些实施例，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其它的附图。
图1是本申请实施例的氮杂环卡宾催化剂的制备方法的流程示意图。
本发明的实施方式
为了使本申请的目的、技术方案及优点更加清楚明白，以下结合附图及实施例，对本申请进行进一步详细说明。应当理解，此处所描述的具体实施例仅用以解释本申请，并不用于限定本申请。
本申请实施例中所涉及的化合物及其衍生物均是按照IUPAC(国际纯粹与应用化学联合会)或CAS(化学文摘服务社)命名系统命名的。因此，本申请实施例中具体涉及到的化合物基团做如下阐述与说明：
“芳基”是指一种具有芳香性的环状结构的芳香烃，包括但不限于如苯基、萘基、蒽基、菲基等以及其它类似基团。“取代的芳基”即指上述芳基环上的氢原子被其他官能团取代的芳基衍生物，其中取代 的官能团可以是一个或多个。
“杂芳基”是指单环或多环或稠环芳香烃，其中的一个或多个碳原子已被如氮、氧或硫等杂原子取代。如果杂芳基含有不止一个杂原子，则这些杂原子可能是相同，也可能是不同的。杂芳基包括但不限于如苯并呋喃基、苯并噻吩基、苯并咪唑基、噻唑基、噻吩基等以及其它类似基团。“取代的杂芳基”即指上述杂芳基环上的氢原子被其他官能团取代杂芳基衍生物，其中取代的官能团可以是一个或多个。
一方面，本申请提供了一种氮杂环卡宾催化剂，所述氮杂环卡宾催化剂的结构通式如下式I所示：
Figure PCTCN2020129804-appb-000003
其中，所述式I中的Ar 1和Ar 2分别独立选自芳基、取代的芳基、杂芳基和取代的杂芳基中的任意一种，X为氧原子或硫原子。
本申请实施例提供的氮杂环卡宾催化剂是在氮杂环卡宾骨架的基础上引入另一活性位点硫脲(脲)基团，并且通过对式I中的Ar 1和Ar 2进行芳基、取代的芳基、杂芳基和取代的杂芳基的多种基团的选择，可以形成多种类的双功能硫脲(脲)氮杂环卡宾催化剂，该氮杂环卡宾催化剂在催化不对称氮杂迈克尔反应具有很好的催化活性，因此在有机不对称催化领域具有潜在的应用。
在一些实施例中，Ar 1和Ar 2可以是相同或不同的芳基、取代的芳基、杂芳基和取代的杂芳基。
具体地，所述芳基选自苯基、萘基、蒽基、菲基和芴基中的至少一种。所述取代的芳基即为上述芳基引入取代基，具体地，所述取代的芳基选自取代的苯基、取代的萘基、取代的蒽基、取代的菲基和取代的芴基中的至少一种。所述取代的芳基中，取代基选自卤素原子、羟基、氨基、硝基、磺基、氰基、酰基、酯基、(C 1-C 10)烷基、(C 6-C 14)芳基和(C 4-C 14)杂芳基中的至少一种。
所述杂芳基选自单环杂芳基和稠环杂芳基中的至少一种。其中，所述单环杂芳基选自呋喃基、噻吩基、吡咯基、咪唑基、吡唑基、恶唑基、噻唑基、吡啶基、吡喃基、嘧啶基和吡嗪基中的至少一种；所述稠环杂芳基选自苯并呋喃基、苯并噻吩基、苯并吡咯基、苯并咪唑基、苯并恶唑基、苯并吡唑基、苯并噻唑基、苯并吡喃基、喹啉和吖啶中的至少一种。所述取代的杂芳基即为上述杂芳基引入取代基，具体地，所述取代的杂芳基选自取代的单环杂芳基和取代的稠环杂芳基中的至少一种。其中，所述取代的单环杂芳基选自取代的呋喃基、取代的噻吩基、取代的吡咯基、取代的咪唑基、取代的吡唑基、取代的恶唑基、取代的噻唑基、取代的吡啶基、取代的吡喃基、取代的嘧啶基和取代的吡嗪基中的至少一种；所述取代的稠环杂芳基选自取代的苯并呋喃基、取代的苯并噻吩基、取代的苯并吡咯基、取代的苯并咪 唑基、取代的苯并恶唑基、取代的苯并吡唑基、取代的苯并噻唑基、取代的苯并吡喃基、取代的喹啉和取代的吖啶中的至少一种。所述取代的杂芳基中，取代基选自卤素原子、羟基、氨基、硝基、磺基、氰基、酰基、酯基、(C 1-C 10)烷基、(C 6-C 14)芳基和(C 4-C 14)杂芳基中的至少一种。
在一些实施例中，所述式I中，Ar 1为取代的苯基，Ar 2为取代的苯基。具体地，Ar 2为卤素原子取代(C 1-C 10)烷基取代的苯基，例如卤代C 1-C 10烷基单取代或多取代的苯基等等，其中卤素原子可以是氟、氯、溴、碘；Ar 1为(C 1-C 10)烷基取代的苯基，例如甲基单取代或多取代的苯基、乙基单取代或多取代的苯基等。
在一个实施例中，Ar 1为均三甲基苯基，Ar 2为3,5-双(三氟甲基)苯基，X为硫原子或氧原子；该氮杂环卡宾催化剂的结构如下：
Figure PCTCN2020129804-appb-000004
Ar 1为均三甲基苯基可提升氮杂环卡宾的σ电子供体能力从而提高其布朗斯特碱性，而Ar 2为3,5-双(三氟甲基)苯基则大大提高了硫脲基团的酸性，使之与底物更易形成氢键，从而发挥催化活性和立体选择性。这样，通过这两个特有的基团共同作用，可组建成为一个具有更好催化效果的催化通用模式。
另方面，本申请还提供了一种氮杂环卡宾催化剂的制备方法，如图1所示，该制备方法包括如下步骤：
S01：将式V所示的(S)-2-(叠氮甲基)-5-甲氧基-3,4-二氢-2H-吡咯与Ar 1NHNH 2·HCl进行反应得到式VI所示的化合物；
S02：将式VI所示的化合物与原甲酸三甲酯和盐酸反应，得到式VII所示的化合物；
S03：将式VII所示的化合物进行还原氢化反应，得到式VIII所示的化合物；
S04：将式VIII所示的化合物与异硫氰酸酯Ar 2NCX反应，得到式I所示的氮杂环卡宾催化剂；
其中，上述化合物的结构式如下：
Figure PCTCN2020129804-appb-000005
其中，Ar 1和Ar 2分别独立选自芳基、取代的芳基、杂芳基和取代的杂芳基中的任意一种，X为氧原子或硫原子。
本申请实施例提供的氮杂环卡宾催化剂的制备方法的有益效果在于：该制备方法具有原料易得，成本低，操作方便，反应条件温和易于控制的优点，而且可以制备成双功能硫脲(脲)氮杂环卡宾催化剂，在催化不对称氮杂迈克尔反应具有很好的催化活性，其在有机不对称催化领域具有潜在的应用。
对于Ar 1NHNH 2·HCl中的Ar 1和Ar 2NCX中的Ar 2分别对应最终得到的式I所示的氮杂环卡宾催化剂中的Ar 1和Ar 2，该Ar 1和Ar 2具体选择上文已经详细阐述。
其中，步骤S01中，式V所示的(S)-2-(叠氮甲基)-5-甲氧基-3,4-二氢-2H-吡咯的制备方法包括如下步骤：
将式II所示的L-焦谷氨醇用对甲基苯磺酰氯进行羟基保护，得到式III所示的(S)-5-羟甲基-2-吡咯烷酮对甲苯磺酸酯；
将式III所示的(S)-5-羟甲基-2-吡咯烷酮对甲苯磺酸酯与叠氮化钠反应得到式IV所示的(S)-5-叠氮甲基-2-吡咯烷酮；
将式IV所示的(S)-5-叠氮甲基-2-吡咯烷酮与三甲基氧嗡四氟硼酸盐反应得到式V所示的(S)-2-(叠氮甲基)-5-甲氧基-3,4-二氢-2H-吡咯；
其中，上述化合物的结构式如下：
Figure PCTCN2020129804-appb-000006
上述步骤以L-焦谷氨醇为原料合成双功能氮杂环卡宾催化剂的方法。L-焦谷氨醇是一种简单易得的化学原料。使得该制备方法具有原料易得，成本低，操作方便，其在有机不对称催化领域具有潜在的应 用活性。
具体地，以L-焦谷氨醇为原料合成氮杂环卡宾催化剂的合成路线为：
Figure PCTCN2020129804-appb-000007
合成路线共7步，以11％的产率获得最终产物。该路线具有原料易得，成本低，操作方便，反应条件温和易于控制的优点。具体的，以Ar 1为均三甲基苯基，即Ar 1NHNH 2·HCl为均三甲基苯肼盐酸盐，Ar 2为3,5-双(三氟甲基)苯基，X为硫原子，即Ar 2NCX为3,5-双(三氟甲基)苯基异硫氰酸酯为例，该合成方法，包括如下步骤：
步骤1，以L-焦谷氨醇为原料，用对甲基苯磺酰氯保护羟基(反应物包括：对甲苯磺酰氯，三乙胺，4-二甲基吡啶，二氯甲烷溶液)，得到中间体(S)-5-羟甲基-2-吡咯烷酮对甲苯磺酸酯。
步骤2，将上述中间体(S)5-羟甲基-2-吡咯烷酮对甲苯磺酸酯与叠氮化钠反应，得到中间体(S)-5-叠氮甲基-2-吡咯烷酮。
步骤3，将上述中间体(S)-5-叠氮甲基-2-吡咯烷酮与三甲基氧嗡四氟硼酸盐，得到中间体(S)-2-(叠氮甲基)-5-甲氧基-3,4-二氢-2H-吡咯。
步骤4，将上述中间体(S)-2-(叠氮甲基)-5-甲氧基-3,4-二氢-2H-吡咯与均三甲基苯肼盐酸盐反应，得到中间体1-((5S)-5-(叠氮甲基)吡咯烷-2-基)-2-均三甲基苯肼盐酸盐。
步骤5，将上述中间体1-((5S)-5-(叠氮甲基)吡咯烷-2-基)-2-均三甲基苯肼盐酸盐与原甲酸三甲酯和盐酸反应，得到中间体(S)-5-(叠氮甲基)-2-甲磺酰基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]三唑-2-鎓盐酸盐。
步骤6，将上述中间体(S)-5-(叠氮甲基)-2-甲磺酰基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]三唑-2-鎓盐酸盐用钯碳还原氢化，得到中间体(S)-5-(氨基甲基)-2-甲苯基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4] 三唑-2-鎓盐酸盐。
步骤7，将上述中间体(S)-5-(氨基甲基)-2-甲苯基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]三唑-2-鎓盐酸盐与3,5-双(三氟甲基)苯基异硫氰酸酯反应，得到终产物：(S)-5-((3-(3,5-双(三氟甲基)苯基)硫脲基)甲基)-2-甲磺酰基-6,7-二氢-5H-吡咯烷[2,1-c][1,2,4]三唑-2-鎓盐酸盐即(S)-5-((3-(3,5-bis(trifluoromethyl)phenyl)thioureido)methyl)-2-mesityl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]tri azol-2-ium chloride，结构式如下：
Figure PCTCN2020129804-appb-000008
本申请提供的氮杂环卡宾催化剂以及该制备方法制备得到的氮杂环卡宾催化剂在催化不对称氮杂迈克尔反应具有很好的催化活性，例如：亲核试剂化合物NR 1R 2和共轭烯酮类化合物
Figure PCTCN2020129804-appb-000009
在本申请的氮杂环卡宾催化剂的催化条件下可以催化不对称氮杂迈克尔加成反应，得到β-羰基手性氨基化合物，反应式如下所示：
Figure PCTCN2020129804-appb-000010
亲核试剂化合物NR 1R 2中的R 1和R 2可以是相同或不相同的C 1-C 20烷基、C 1-C 20烷氧基、C 1-C 20烷基氧羰基、芳基、芳氧基、芳氧基羰基、芳基(C 1-C 20)烷基、芳基(C 1-C 20)烷氧基和芳基(C 1-C 20)烷氧基羰基中的任意一种。共轭烯酮类化合物中的R可以是C 1-C 20烷基、C 1-C 20杂烷基、C 3-C 20环烷基、C 3-C 20杂环烷基、C 2-C 20烯基、C 2-C 20杂烯基、C 3-C 20环烯基、C 3-C 20杂环烯基、C 2-C 20炔基、C 2-C 20杂炔基、C 3-C 20环炔基、C 3-C 20杂环炔基、C 1-C 20烷氧基、C 1-C 20烷基氧羰基、C 1-C 20烷基氧羰基(C 1-C 20)烷基、芳基、取代的芳基、杂芳基、取代的杂芳基、芳氧基、芳氧基羰基、杂芳氧基、杂芳氧基羰基、芳基(C 1-C 20)烷基、芳基(C 1-C 20)烷氧基、杂芳基(C 1-C 20)烷基、C 2-C 20烯基(C 1-C 20)烷基、C 2-C 20炔基(C 1-C 20)烷基、氰基(C 1-C 20)烷基和卤代(C 1-C 20)烷基中的任意一种。通过本申请的氮杂环卡宾催化剂的催化作用，从而得到多种类的β-羰基手性氨基化合物。
本申请先后进行过多次试验，现举一部分试验结果作为参考对申请进行进一步详细描述，下面结合具体实施例进行详细说明。
实施例1
一种双功能氮杂环卡宾催化剂，其分子结构如下所示：
Figure PCTCN2020129804-appb-000011
该双功能氮杂环卡宾催化剂的制备方法包括如下步骤：
(1)中间体(S)-5-羟甲基-2-吡咯烷酮对甲苯磺酸酯的合成，反应式和合成步骤如下：
Figure PCTCN2020129804-appb-000012
在300mL二氯甲烷溶液中加入10g L-焦谷氨醇和对21g甲苯磺酰氯，冷却至0度，加入2.2g 4-二甲基吡啶和16mL三乙胺，然后恢复至室温，搅拌12小时取样监测反应进程(TLC检测)。反应完全后反应体系用水淬灭，然后二氯甲烷溶液萃取，之后合并的有机相，用无水硫酸钠干燥，通过重结晶得到产物。得到固体产物21.7g，产率93％。
(2)中间体(S)-5-叠氮甲基-2-吡咯烷酮的合成，反应式和合成步骤如下：
Figure PCTCN2020129804-appb-000013
将15g(S)-5-羟甲基-2-吡咯烷酮对甲苯磺酸酯溶解在200mL N,N-二甲基甲酰胺溶液中，用塑料勺小心加入4g叠氮化钠固体，将反应置于55度中加热9小时监测反应进程(TLC检测)。然后用过滤，滤渣用乙酸乙酯洗涤。旋蒸滤液，用柱层析纯化，得到淡黄色油状液体。得到液体产物7.0g，产率90％。
(3)中间体(S)-2-(叠氮甲基)-5-甲氧基-3,4-二氢-2H-吡咯的合成，反应式和合成步骤如下：
Figure PCTCN2020129804-appb-000014
将6.0g(S)-5-叠氮甲基-2-吡咯烷酮和7.0g三甲基氧嗡四氟硼酸盐溶解在300mL二氯甲烷溶液中。室温，在氮气保护的氛围下搅拌17小时，监测反应进程。将反应降至0度，用饱和碳酸氢钠溶液淬灭，继续搅拌1小时，然后萃取。将有机相干燥旋干，所得产品直接下一步投料。
(4)中间体1-((5S)-5-(叠氮甲基)吡咯烷-2-基)-2-均三甲基苯肼盐酸盐的合成，反应式和合成步骤如下：
Figure PCTCN2020129804-appb-000015
将5.5g(S)-2-(叠氮甲基)-5-甲氧基-3,4-二氢-2H-吡咯置于反应瓶中，加入6.6g均三甲基苯肼盐酸盐，加入140mL甲醇溶液，将反应置于50度条件下搅拌1小时，取样监测反应进程(TLC检测)。将反应冷却至室温，旋干得到固体。然后固体用乙酸乙酯溶解，抽滤。滤液浓缩旋干，所得产品直接下一步投料。
(5)中间体Ⅴ(S)-5-(叠氮甲基)-2-甲磺酰基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]三唑-2-鎓盐酸盐的合成，反应式和合成步骤如下：
Figure PCTCN2020129804-appb-000016
将上一步所的固体置于反应瓶中，向其中加入38.0mL原甲酸三甲酯，28.0mL氯苯溶液以及7.0mL浓盐酸，用氮气置换气体三次。接着在100度下回流1个小时，监测反应体系(TLC检测)。玩应完全后将反应恢复至室温，旋干，用柱层析纯化，得到褐色固体。用柱层析纯化，得到褐色固体。得到褐色固体4.45g，产率50％。
(6)中间体(S)-5-(氨基甲基)-2-甲苯基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]三唑-2-鎓盐酸盐的合成，合成步骤如下：
将1.5g(S)-5-(氨基甲基)-2-甲苯基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]三唑-2-鎓盐酸盐置于反应瓶中，加入148mg 10％钯碳，用氢气还原12小时，取样监测反应(TLC检测)发现。过滤掉钯碳后，将滤液旋干，用柱层析纯化，得到黄褐色固体。得到1.34g黄褐色固体，产率91％。
(7)终产物(S)-5-((3-(3,5-双(三氟甲基)苯基)硫脲基)甲基)-2-甲磺酰基-6,7-二氢-5H-吡咯烷[2,1-c][1,2，4]三唑-2-鎓盐酸盐的合成，反应式和合成步骤如下：
Figure PCTCN2020129804-appb-000017
将上一步所得250mg固体置于反应瓶中，加入230mg 3,5-双(三氟甲基)苯基异硫氰酸酯和2.5mL二氯甲烷溶液，室温下搅拌12小时，取样监测反应(TLC检测)。反应完全后反应体系旋干，用柱层析纯化，得到白色固体。得到固体产物440mg，产率95％。
相关表征分析，其结果为： 1H NMR(400MHz,CDCl 3)δ10.91(s,1H),10.77(s,1H),9.45(t,J＝6.0Hz,1H),8.23(d,J＝1.6Hz,2H),7.53(s,1H),6.89(s,2H),5.32(dq,J＝10.2,6.7,5.3Hz,1H),4.27(tt,J＝14.5, 8.1Hz,2H),3.43(ddd,J＝17.5,9.3,5.8Hz,1H),3.35–3.16(m,1H),3.05(dtd,J＝14.2,8.5,6.0Hz,1H),2.84–2.59(m,1H),2.28(s,3H),2.05(s,6H). 13C NMR(101MHz,Chloroform-d)δ182.52,161.72,142.21,141.66,141.09,134.73,131.60,131.31(q,J＝33.5Hz),129.78,123.22(q,J＝272.8Hz),122.50,117.35,61.09,45.43,30.98,21.69,21.12,17.74. 19F NMR(376MHz,CDCl 3)δ-62.85.HRMS(ESI-TOF)[M +]calculated for[C 24H 24F 6N 5S] +528.1651,observed 528.1645.[α] D 25＝7.3(c＝0.80in CHCl 3)。
实施例2
一种双功能氮杂环卡宾催化剂，其分子结构如下所示：
Figure PCTCN2020129804-appb-000018
该双功能氮杂环卡宾催化剂的制备方法包括如下步骤：
(1)～(6)的步骤过程与实施例1相同；
(7)终产物(S)-5-((3-(3,5-双(三氟甲基)苯基)脲基)甲基)-2-甲磺酰基-6,7-二氢-5H-吡咯烷[2,1-c][1,2，4]三唑-2-鎓盐酸盐的合成，反应式和合成步骤如下：
Figure PCTCN2020129804-appb-000019
将上一步所得250mg固体置于反应瓶中，加入230mg 3,5-双(三氟甲基)苯基异氰酸酯和2.5mL二氯甲烷溶液，室温下搅拌12小时，取样监测反应(TLC检测)。反应完全后反应体系旋干，用柱层析纯化，得到白色固体。得到固体产物448mg，产率93％。
相关表征分析，其结果为： 1H NMR(400MHz,Chloroform-d)δ10.78(s,1H),9.67(s,1H),7.98(d,J＝6.3Hz,1H),7.92(s,2H),7.39(s,1H),6.88(s,2H),5.21–5.09(m,1H),3.93(dt,J＝14.8,4.5Hz,1H),3.74(dt,J＝15.1,7.6Hz,1H),3.47–3.33(m,1H),3.23(ddd,J＝17.5,9.4,5.6Hz,1H),3.03(ddd,J＝16.9,14.2,8.0Hz,1H),2.71(ddq,J＝14.6,9.3,5.4Hz,1H),2.25(s,3H),2.03(s,6H). 13C NMR(101MHz,Chloroform-d)δ161.66,155.95,142.18,141.81,141.37,134.76,131.70(q,J＝33.2Hz), 131.62,129.68,123.35(q,J＝272.6Hz),117.81,114.79,61.95,41.84,30.60,21.74,21.06,17.50. 19F NMR(376MHz,Chloroform-d)δ-62.96.HRMS(ESI-TOF)[M+H]calculated for[C 24H 24F 6N 5O] +512.1880,observed 512.1880.[α] 25 D＝8.5(c＝0.80in CHCl 3)。
实施例3
用实施例1的双功能氮杂环卡宾催化剂催化不对称氮杂迈克尔反应，反应式和步骤如下：
Figure PCTCN2020129804-appb-000020
在干燥的10mL试管中加入实施例1的双功能氮杂环卡宾催化剂(0.02mmol,0.2equiv.)，0.6mL无水甲苯，氩气置换三次，加入碱(0.02mmol,0.2eq)反应试管密封后在室温下搅拌30min。亲核试剂氨基甲酸叔丁酯(0.12mmol,1.2eq)缓慢加入反应体系中，于室温下搅拌0.5小时。对应的β-三氟甲基烯酮(0.1mmol,1.0equiv.)缓慢加入反应体系中，所得混合物在室温下搅拌12小时。反应完毕后，反应液通过含硅胶的玻璃滴管过滤，乙醚冲洗后，滤液旋干，柱层析分离，得目标产物，无色油状液体。
相关表征分析，其结果为： 1H NMR(400MHz,Chloroform-d)δ7.93–7.84(m,2H),7.56(t,J＝7.4Hz,1H),7.42(t,J＝7.7Hz,2H),7.37–7.27(m,5H),5.48–5.32(m,1H),4.89(dd,J＝27.1,9.7Hz,2H),3.74(dd,J＝17.7,9.7Hz,1H),3.17(dd,J＝17.7,3.4Hz,1H),1.57(s,9H). 13C NMR(101MHz,CDCl 3)δ194.57,156.17,136.15,135.15,133.62,129.40,128.74,128.65,128.53,128.28,125.24(q,J＝282.1Hz),83.07,78.15,56.47(q,J＝31.1Hz),33.68,28.26. 19F NMR(376MHz,CDCl 3)δ-73.22.HRMS(ESI-TOF)[M+Na]calculated for[C 22H 24F 3NO 4Na] +446.1550,observed 446.1547.HPLC(Chiralpak-OJ column,98:2hexane/ethanol,flow rate:1.0mL/min):t major＝10.433min；t minor＝7.081min.[α] D 25＝-19.9(c＝0.80in CHCl 3)。
实施例4
用实施例2的双功能氮杂环卡宾催化剂催化不对称氮杂迈克尔反应，反应式和步骤如下：
Figure PCTCN2020129804-appb-000021
在干燥的10mL试管中加入实施例2的双功能氮杂环卡宾催化剂(0.02mmol,0.2equiv.)，0.6mL无 水甲苯，氩气置换三次，加入碱(0.02mmol,0.2eq)反应试管密封后在室温下搅拌30min。亲核试剂氨基甲酸叔丁酯(0.12mmol,1.2eq)缓慢加入反应体系中，于室温下搅拌0.5小时。对应的β-甲酸酯烯酮(0.1mmol,1.0equiv.)缓慢加入反应体系中，所得混合物在室温下搅拌12小时。反应完毕后，反应液通过含硅胶的玻璃滴管过滤，乙醚冲洗后，滤液旋干，柱层析分离，得目标产物，白色固体，产率87％，92％ee。
相关表征分析，其结果为： 1H NMR(400MHz,Chloroform-d)δ7.86(d,J＝7.7Hz,3H),7.48–7.35(m,4H),7.35–7.28(m,3H),5.34(s,1H),5.26–5.21(m,1H),4.91(dd,J＝47.0,10.5Hz,2H),4.71–4.63(m,1H),3.71(ddd,J＝16.8,7.3,2.7Hz,1H),3.18(dd,J＝16.4,4.8Hz,1H),2.40–2.24(m,2H),2.03–1.91(m,2H),1.89–1.78(m,3H),1.59(d,J＝34.8Hz,5H),1.53(s,9H),1.49–1.39(m,4H),1.37–1.22(m,5H),1.18–1.04(m,7H),0.95(s,3H),0.91(d,J＝6.5Hz,3H),0.87(d,J＝1.8Hz,3H),0.85(d,J＝1.8Hz,3H),0.66(s,3H). 13C NMR(101MHz,Chloroform-d)δ191.08(d,J＝2.6Hz),168.95(d,J＝2.8Hz),156.74,143.15,142.63,139.41,139.05,135.73,129.59(d,J＝3.8Hz),128.48,128.41,127.50,126.00,125.02,122.98,122.83(d,J＝2.4Hz),82.43,77.68(d,J＝2.0Hz),75.77,59.69(d,J＝4.6Hz),56.67,56.14,49.98,42.31,39.72,39.52,38.56(d,J＝3.7Hz),37.96,37.88,36.90(d,J＝2.0Hz),36.55,36.19,35.79,31.86(d,J＝5.1Hz),28.26,28.23,28.09,28.02,27.68,27.59,24.28,23.84,22.83,22.57,21.02,19.24,18.72,11.85.HRMS(ESI-TOF)[M+Na]calculated for[C 51H 69NO 6SNa] +846.4738observed 846.4740.HPLC(Chiralpak-IA column,97.5:2.5hexane/ethanol,flow rate:1.0mL/min):t major＝11.946min；t minor＝10.781min.[α] D 25＝-21.1(c＝0.80in CHCl 3)。
以上仅为本申请的可选实施例而已，并不用于限制本申请。对于本领域的技术人员来说，本申请可以有各种更改和变化。凡在本申请的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本申请的权利要求范围之内。

Claims (15)

  1. 一种氮杂环卡宾催化剂，其特征在于，所述氮杂环卡宾催化剂的结构通式如下式I所示：
    Figure PCTCN2020129804-appb-100001
    其中，所述式I中的Ar 1和Ar 2分别独立选自芳基、取代的芳基、杂芳基和取代的杂芳基中的任意一种，X为氧原子或硫原子。
  2. 如权利要求1所述的氮杂环卡宾催化剂，其特征在于，所述芳基选自苯基、萘基、蒽基、菲基和芴基中的至少一种。
  3. 如权利要求1所述的氮杂环卡宾催化剂，其特征在于，所述杂芳基选自单环杂芳基和稠环杂芳基中的至少一种。
  4. 如权利要求3所述的氮杂环卡宾催化剂，其特征在于，所述单环杂芳基选自呋喃基、噻吩基、吡咯基、咪唑基、吡唑基、恶唑基、噻唑基、吡啶基、吡喃基、嘧啶基和吡嗪基中的至少一种；和/或，
    所述稠环杂芳基选自苯并呋喃基、苯并噻吩基、苯并吡咯基、苯并咪唑基、苯并恶唑基、苯并吡唑基、苯并噻唑基、苯并吡喃基、喹啉和吖啶中的至少一种。
  5. 如权利要求1所述的氮杂环卡宾催化剂，其特征在于，所述取代的芳基选自取代的苯基、取代的萘基、取代的蒽基、取代的菲基和取代的芴基中的至少一种。
  6. 如权利要求5所述的氮杂环卡宾催化剂，其特征在于，所述取代的芳基中，取代基选自卤素原子、羟基、氨基、硝基、磺基、氰基、酰基、酯基、(C 1-C 10)烷基、(C 6-C 14)芳基和(C 4-C 14)杂芳基中的至少一种。
  7. 如权利要求1所述的氮杂环卡宾催化剂，其特征在于，所述取代的杂芳基选自取代的单环杂芳基和取代的稠环杂芳基中的至少一种。
  8. 如权利要求7所述的氮杂环卡宾催化剂，其特征在于，所述取代的单环杂芳基选自取代的呋喃基、取代的噻吩基、取代的吡咯基、取代的咪唑基、取代的吡唑基、取代的恶唑基、取代的噻唑基、取代的吡啶基、取代的吡喃基、取代的嘧啶基和取代的吡嗪基中的至少一种；和/或，
    所述取代的稠环杂芳基选自取代的苯并呋喃基、取代的苯并噻吩基、取代的苯并吡咯基、取代的苯并咪唑基、取代的苯并恶唑基、取代的苯并吡唑基、取代的苯并噻唑基、取代的苯并吡喃基、取代的喹啉和取代的吖啶中的至少一种。
  9. 如权利要求7所述的氮杂环卡宾催化剂，其特征在于，所述取代的杂芳基中，取代基选自卤素原子、羟基、氨基、硝基、磺基、氰基、酰基、酯基、(C 1-C 10)烷基、(C 6-C 14)芳基和(C 4-C 14)杂芳基中的至少一种。
  10. 如权利要求1所述的氮杂环卡宾催化剂，其特征在于，所述式I中，Ar 1为取代的苯基，Ar 2为取代的苯基。
  11. 如权利要求10所述的氮杂环卡宾催化剂，其特征在于，所述式I中，Ar 1为(C 1-C 10)烷基取代的苯基，Ar 2为卤素原子取代(C 1-C 10)烷基取代的苯基。
  12. 如权利要求11所述的氮杂环卡宾催化剂，其特征在于，所述式I中，Ar 1为均三甲基苯基，Ar 2为3,5-双(三氟甲基)苯基。
  13. 一种氮杂环卡宾催化剂的制备方法，其特征在于，包括如下步骤：
    将式V所示的(S)-2-(叠氮甲基)-5-甲氧基-3,4-二氢-2H-吡咯与Ar 1NHNH 2·HCl进行反应得到式VI所示的化合物；
    将式VI所示的化合物与原甲酸三甲酯和盐酸反应，得到式VII所示的化合物；
    将式VII所示的化合物进行还原氢化反应，得到式VIII所示的化合物；
    将式VIII所示的化合物与异硫氰酸酯Ar 2NCX反应，得到式I所示的氮杂环卡宾催化剂；
    其中，上述化合物的结构式如下：
    Figure PCTCN2020129804-appb-100002
    Ar 1和Ar 2分别独立选自芳基、取代的芳基、杂芳基和取代的杂芳基中的任意一种，X为氧原子或硫原子。
  14. 如权利要求13所述的氮杂环卡宾催化剂的制备方法，其特征在于，式V所示的(S)-2-(叠氮甲基)-5-甲氧基-3,4-二氢-2H-吡咯的制备方法包括如下步骤：
    将式II所示的L-焦谷氨醇用对甲基苯磺酰氯进行羟基保护，得到式III所示的(S)-5-羟甲基-2-吡咯烷酮对甲苯磺酸酯；
    将式III所示的(S)-5-羟甲基-2-吡咯烷酮对甲苯磺酸酯与叠氮化钠反应得到式IV所示的(S)-5-叠氮甲基-2-吡咯烷酮；
    将式IV所示的(S)-5-叠氮甲基-2-吡咯烷酮与三甲基氧嗡四氟硼酸盐反应得到式V所示的(S)-2-(叠氮甲基)-5-甲氧基-3,4-二氢-2H-吡咯；
    其中，上述化合物的结构式如下：
    Figure PCTCN2020129804-appb-100003
  15. 如权利要求13所述的氮杂环卡宾催化剂的制备方法，其特征在于，所述芳基选自苯基、萘基、蒽基、菲基和芴基中的至少一种；和/或，
    所述杂芳基选自单环杂芳基和稠环杂芳基中的至少一种；和/或，
    取代的芳基选自取代的苯基、取代的萘基、取代的蒽基、取代的菲基和取代的芴基中的至少一种；且所述取代的芳基中，取代基选自卤素原子、羟基、氨基、硝基、磺基、氰基、酰基、酯基、(C 1-C 10)烷基、(C 6-C 14)芳基和(C 4-C 14)杂芳基中的至少一种；和/或，
    所述取代的杂芳基选自取代的单环杂芳基和取代的稠环杂芳基中的至少一种；且所述取代的杂芳基中，取代基选自卤素原子、羟基、氨基、硝基、磺基、氰基、酰基、酯基、(C 1-C 10)烷基、(C 6-C 14)芳基和(C 4-C 14)杂芳基中的至少一种。
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