Nothing Special   »   [go: up one dir, main page]

CN107011218B - A kind of fluorine nitrogen type amination reagent, preparation method and application - Google Patents

A kind of fluorine nitrogen type amination reagent, preparation method and application Download PDF

Info

Publication number
CN107011218B
CN107011218B CN201710283728.3A CN201710283728A CN107011218B CN 107011218 B CN107011218 B CN 107011218B CN 201710283728 A CN201710283728 A CN 201710283728A CN 107011218 B CN107011218 B CN 107011218B
Authority
CN
China
Prior art keywords
formula
compound shown
substituted
preparation
unsubstituted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201710283728.3A
Other languages
Chinese (zh)
Other versions
CN107011218A (en
Inventor
刘国生
王定海
陈品红
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Institute of Organic Chemistry of CAS
Original Assignee
Shanghai Institute of Organic Chemistry of CAS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shanghai Institute of Organic Chemistry of CAS filed Critical Shanghai Institute of Organic Chemistry of CAS
Priority to CN201710283728.3A priority Critical patent/CN107011218B/en
Publication of CN107011218A publication Critical patent/CN107011218A/en
Application granted granted Critical
Publication of CN107011218B publication Critical patent/CN107011218B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)

Abstract

The invention discloses a kind of fluorine nitrogen type amination reagent, preparation method and applications.The application includes the following steps: under gas shield; in organic solvent; under the action of copper catalyst and dinitrogen ligand and alkali; fluorine nitrogen type amination reagent shown in formula I, such as Formula II compound represented and such as formula III compound represented are subjected to reaction as follows, such as formula IV compound represented is made.Fluorine nitrogen type amination reagent of the invention is under copper catalyst and the effect of dinitrogen ligand, and using alkene as substrate, by the asymmetric amine arylation reaction of alkene, with good yield, outstanding corresponding selection obtains optically active 2,2- diaryl ethylamine compounds.

Description

Fluorine-nitrogen type amination reagent, preparation method and application thereof
Technical Field
The invention relates to a fluorine-nitrogen type amination reagent, a preparation method and application thereof.
Background
N-fluoro-N-alkylsulfonamides are generally used as electrophilic fluorinating agents which are highly effective in fluorinating carbanions (J.Am.chem.Soc.1984,106, 454; U.S. Pat. No. 4479901), and the amine moiety is used as a by-product in the form of N-alkylsulfonamide, which is not highly atom-economical. N-fluoro-N-alkylsulfonamides have never been reported as aminating agents.
Optically active 2, 2-diarylethylamine compounds are widely present in drugs, active molecules and natural products. The development of asymmetric synthetic methods for such compounds is of great interest, however, relatively little research is currently being conducted in this area.
In documents j.am.chem.soc.2004,126,1954, asymmetric addition of aryl lithium reagents to β -nitroethylene compounds is reported, for styrenic substrates, ee values of 91% to 95% are obtained, excess ligand is added, while at the same time, coordinated oxygen atoms are required at the ortho position of the aromatic ring of the substrate, thus limiting the substrate universality, in angelw.chem.int.ed.2010, 49,5780, asymmetric arylboronic acids are reported as ligands, under rhodium catalysis, aryl boronic acids are used as aryl sources, achieving asymmetric arylation of β -nitroethylene, and optically active diarylnitroethane compounds are obtained with ee values of 61% to 97%, in documents org.lett.2015,17,2250, chiral isoquinolinium oxazoline is reported as a ligand, under palladium catalysis, achieving asymmetric arylation of β -nitroethylene, achieving optical active diarylethenes, 81% to 96% optically active diarylethenes, 2.999, and aromatic dienoic acids are directly obtained from aryl alkene derivatives through hydrogenation reactions of chiral amino alcohols, β -nitroalkene compounds, 2.
Therefore, in view of the above-mentioned current reaction situation, there is a need for developing an amination reagent and simultaneously developing a method capable of synthesizing chiral 2, 2-diarylethylamine compounds from simple substrates such as olefins with high efficiency and high selectivity.
Disclosure of Invention
The invention aims to solve the technical problem that in the synthetic method of 2, 2-diaryl ethylamine compounds in the prior art, the application range of a substrate is narrow, the chiral 2, 2-diaryl ethylamine compounds can be converted only through hydrogenation reaction, or the requirements on the substrate are strict, highly functionalized diaryl enamine is required to be used as the substrate, and the like, and provides a fluorine nitrogen type amination reagent, a preparation method and application thereof. Under the action of a copper catalyst and a dinitrogen ligand, the fluorine nitrogen type amination reagent takes olefin as a substrate, and obtains the optically active 2, 2-diarylethylamine compound with good yield and excellent corresponding selectivity through the asymmetric amine arylation reaction of the olefin.
The invention mainly solves the technical problems through the following technical scheme.
The invention provides an application of a fluorine nitrogen type amination reagent shown as a formula I in preparation of 2, 2-diaryl ethylamine compound intermediates;
wherein,
R1is substituted or unsubstituted C6-C30An aryl group; said substituted C6-C30The substituents in the aryl group are selected from halogen, C1-C10Alkyl, halogen substituted C1-C10Alkyl radical, C1-C10Alkoxy andone or more of R1’Is C1-C10An alkyl group; when the substituent is plural (e.g., 1 to 6, preferably 1 to 3), the substituents may be the same or different;
R2is C1-C10Straight chain alkyl orWherein R is1aDefinition of (A) and R1The same is true.
A fluoro-nitrogen form of formula IIn the amination reagent, R1In (b), said substituted C6-C30The substituents in the aryl group are preferably selected from the group consisting of F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, n-pentyl (and isomers thereof), n-hexyl (and isomers thereof), trifluoromethyl, pentafluoroethyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and mixtures thereof,And when the number of the substituents is plural, the substituents may be the same or different (for example, 1 to 6, preferably 1 to 3, more preferably 1 to 2).
In the fluorine nitrogen type amination reagent shown as the formula I, R1Wherein said substituted or unsubstituted C6-C30Aryl is preferably substituted or unsubstituted C6-C14And (4) an aryl group. Said substituted or unsubstituted C6-C14The aryl group is preferably a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, a substituted or unsubstituted anthryl group, or a substituted or unsubstituted phenanthryl group. Said substituted C6-C30Aryl is preferred
In the fluorine nitrogen type amination reagent shown as the formula I, R2In (b), the C1-C10The straight-chain alkyl group is preferably C1-C6A linear alkyl group. Said C1-C6The straight-chain alkyl group is preferably methyl, ethyl, n-propyl, n-butyl, n-pentyl or n-hexyl.
Said application preferably comprises the following steps: under the protection of gas, under the action of a copper catalyst, a dinitrogen ligand and alkali, carrying out the following reaction on a fluorine nitrogen type amination reagent shown as a formula I, a compound shown as a formula II and a compound shown as a formula III in an organic solvent to prepare a compound shown as a formula IV;
wherein,
R1and R2The definitions are the same as those in the previous step;
R3and R4Independently is substituted or unsubstituted C6-C30Aryl, or, substituted or unsubstituted C2-C30A heteroaryl group; said C2-C30The heteroatom in heteroaryl is selected from one or more of N, O and S (e.g., 1-6, preferably 1-3, more preferably 1-2); when there are a plurality of heteroatoms, the heteroatoms may be the same or different; said substituted C6-C30Aryl and said substituted C2-C30The substituents in the heteroaryl group are independently selected from nitro and C2-C6Heteroaryl of (A), C1-C10Alkyl, halogen substituted C1-C10Alkyl radical, C6-C14Aryl, halogen,And one or more of cyano (e.g., 1-6, preferably 1-3); wherein, said C2-C6The heteroaryl group of (A) is C with 1-4 heteroatoms selected from N, O and S2-C6Heteroaryl (e.g., pyridyl, imidazolyl, pyrazolyl, pyrrolyl, pyrimidinyl, thienyl, furyl, quinolyl, indolyl, etc.); r5Is C1-C10Alkyl, halogen substituted C1-C10Alkyl orR6And R7Independently is C1-C10Alkyl orWhen the substituent is plural, the substituents may be the same or different.
In the preparation method of the compound shown in the formula IV, the gas in the gas protection is preferably nitrogen or argon.
In the preparation method of the compound shown in the formula IV, the organic solvent is preferably one or more of a nitrile solvent, an aromatic hydrocarbon solvent, a halogenated alkane solvent, a ketone solvent and an amide solvent. The nitrile solvent is preferably acetonitrile. The aromatic hydrocarbon solvent is preferably toluene. The halogenated aromatic hydrocarbon solvent is preferably one or more of chlorobenzene, fluorobenzene and trifluorotoluene. The halogenated alkane solvent is preferably dichloromethane and/or dichloroethane. The ketone solvent is preferably acetone. The amide solvent is preferably N, N-dimethylformamide and/or N, N-dimethylacetamide. The organic solvent is preferably a mixed solvent of a halogenated alkane solvent and an amide solvent, and the volume ratio of the halogenated alkane solvent to the amide solvent is preferably 9:1-1: 4.
In a preferred embodiment of the present invention, in the preparation method of the compound represented by formula IV, the organic solvent is preferably dried. The drying method can be a method which is conventional in the field of organic solvent drying.
In the preparation method of the compound shown in the formula IV, the copper catalyst can be a copper catalyst which is conventional in the reaction in the field, and preferably copper powder, cuprous iodide, cuprous chloride, cuprous bromide, cupric chloride, cupric bromide, cupric acetate, cuprous acetate, copper tetraacetonitrile hexafluorophosphate, copper tetraacetonitrile tetrafluoroborate, copper tetraacetonitrile trifluoromethanesulfonate, copper trifluoromethanesulfonate or cuprous thiophenecarboxylate; more preferred is copper tetraacetonitrile hexafluorophosphate, copper tetraacetonitrile tetrafluoroborate, copper tetraacetonitrile trifluoromethanesulfonate or copper trifluoromethanesulfonate, and most preferred is copper tetraacetonitrile hexafluorophosphate.
In the preparation method of the compound shown in the formula IV, the double-nitrogen ligand is preferably a chiral double-nitrogen ligand. The chiral double nitrogen ligand is preferably a chiral double oxazoline ligand
One or more of, R3a、R3b、R3cAnd R3dIndependently is C1-C10Alkyl or C6-C30Aryl substituted C1-C10An alkyl group; r4a、R5a、R4bAnd R5bIndependently of one another is hydrogen, C1-C10Alkyl radical, C6-C30Aryl, or R4aAnd R5a、R4bAnd R5bTogether with the carbon atom to which they are attached form C3-C10A cycloalkyl group; r6a、R6bAnd R6cIndependently of one another is hydrogen, C1-C10Alkyl, halogen,Cyano, trifluoromethyl or C6-C30An aryl group; r8Is C1-C10An alkyl group; n is 1, 2, 3 or 4; when n is 2, 3 or 4, R6aAnd R6bThe same or different.
In the preparation method of the compound shown in the formula IV, the alkali is preferably alkali metal salt of alcohol or sodium phenolate, preferably Ra-ONa、Rb-OK、Rc-OLi andwherein R isa、RbAnd RcIndependently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl; ra1、Ra2、Ra3、Ra4And Ra5Independently of one another hydrogen, halogen, C1-C10Alkyl orR9Is C1-C10An alkyl group.
In the preparation method of the compound shown as the formula IV, the reaction temperature can be the temperature which is conventional in the field, preferably-40-30 ℃, and more preferably-10-0 ℃.
In the preparation method of the compound shown in the formula IV, the progress of the reaction can be monitored by a detection method (such as TLC, GC, HPLC, or HNMR) which is conventional in the art, and the end point of the reaction is generally determined when the compound shown in the formula II or the formula III disappears.
In the preparation method of the compound shown in the formula IV, the dosage of the organic solvent is not particularly limited as long as the reaction is not affected. The copper catalyst and the bis-nitrogen ligand may be used in amounts conventional in the art for such reactions, preferably in a molar ratio of from 2:1 to 1:3, more preferably 1: 2. The dosage of the copper catalyst is preferably 1 to 100 percent of the molar equivalent of the compound shown in the formula II; more preferably from 5% to 10% molar equivalents; the dosage of the dinitrogen ligand is preferably 1 to 100 percent of the molar equivalent of the compound shown in the formula II; more preferably 10-20% molar equivalents; the molar ratio of the compound shown in the formula II to the compound shown in the formula III is preferably 1:1-1:3, and more preferably 1: 2. The usage amount of the fluorine nitrogen type amination reagent shown in the formula I is preferably 100 to 400 percent of the molar equivalent of the compound shown in the formula II, and more preferably 200 percent of the molar equivalent. The amount of the base used may be 20 to 200% molar equivalents, preferably 50% molar equivalents, of the compound of formula II.
In a preferred embodiment of the present invention, the preparation method of the compound represented by formula IV preferably comprises the following steps: under the protection of gas, mixing a mixture of a copper catalyst, a dinitrogen ligand and an organic solvent with a fluorine nitrogen type amination reagent shown as a formula I, a compound shown as a formula II, a compound shown as a formula III and alkali, and carrying out the reaction to obtain a compound shown as a formula IV.
Wherein, the mixture of the copper catalyst, the dinitrogen ligand and the organic solvent is carried out under the protection of gas in the preparation process. The temperature of said mixing is preferably between-20 ℃ and 30 ℃ (for example-20 ℃).
In the preparation method of the compound shown as the formula IV, after the reaction is finished, the operation of post-treatment can be further included. The post-treatment method is a conventional post-treatment method in the field of organic synthesis. In the present invention, the post-treatment preferably comprises the steps of: diluting the reaction solution after the reaction with ethyl acetate, and washing with water; the organic phase is dried (e.g., anhydrous magnesium sulfate), filtered, and the filtrate is concentrated and then further purified by flash column chromatography. The conditions and methods of column chromatography described therein are conventional in the art, and the eluent (eluent) employed may be selected according to TLC.
The invention also provides application of the fluorine nitrogen type amination reagent shown in the formula I in preparation of 2, 2-diaryl ethylamine compounds.
Said application preferably comprises the following steps:
(1) under the protection of gas, under the action of a copper catalyst, a dinitrogen ligand and alkali, carrying out the following reaction on a fluorine nitrogen type amination reagent shown as a formula I, a compound shown as a formula II and a compound shown as a formula III in an organic solvent to prepare a compound shown as a formula IV;
(2) under the protection of gas, in an organic solvent, under the action of a reducing agent, carrying out a reaction of removing a sulfonyl protecting group on the compound shown as the formula IV to prepare a 2, 2-diaryl ethylamine compound shown as the formula V;
wherein R is1、R2、R3And R4The definitions of (A) and (B) are the same as described above; r2’Is C1-C10Straight chain alkyl or R1a；R1aDefinition of (A) and R1The same is true.
In the preparation method of the 2, 2-diaryl ethyl amine compound shown in the formula V, all the conditions of the reaction in the step (1) are the same as those described above.
In the process for preparing 2, 2-diarylethylamine compounds represented by formula V, the method and conditions for the reaction for removing the sulfonyl protecting group in step (2) may be those conventional in the art, and the following methods and conditions are preferred in the present invention: the organic solvent is preferably an alcohol solvent. The alcohol solvent is preferably methanol. The reducing agent is preferably magnesium powder. The temperature of the reaction is preferably room temperature. The progress of the reaction can be monitored by detection methods conventional in the art (e.g., TLC, GC, HPLC, or HNMR, etc.), and is generally determined as the end point of the reaction when the compound of formula IV disappears. The amount of the organic solvent to be used is not particularly limited as long as the reaction is not affected. The reducing agent is generally used in an excess amount, preferably in a molar ratio of 2:1 to 100:1, more preferably 5:1 to 50:1 (e.g., 47:1) to the compound of formula IV.
In the step (2), after the reaction is finished, a post-treatment step may be further included. The post-treatment method can be a conventional post-treatment method in the field of organic synthesis. In the present invention, the post-treatment preferably comprises the steps of: carrying out solid-liquid separation (reduced pressure concentration or suction filtration) on the reaction solution after the reaction is finished, filtering a filter cake by using kieselguhr, and leaching by using ethyl acetate/methanol (10: 1); concentrating the filtrate, and separating by flash column chromatography (the eluent/eluent can be selected according to TLC condition of compound).
The invention also provides a fluorine nitrogen type amination reagent shown as the formula I:
wherein R is1And R2The definitions are the same as those described above.
The aminating agent of the fluoro-nitrogen type represented by formula I is preferably any one of the following compounds:
the invention also provides a preparation method of the fluorine nitrogen type amination reagent shown in the formula I, which comprises the following steps: in an organic solvent, carrying out a fluorination reaction on a compound shown as a formula A and fluorine gas as shown in the specification to prepare a fluorine-nitrogen type amination reagent shown as a formula I;
wherein R is1And R2The definitions are the same as those described above.
The organic solvent may be a solvent conventional in the art for such reactions, preferably a haloalkane solvent. The halogenated alkane solvent is preferably a mixed solvent of trichlorofluoromethane and chloroform. In the mixed solvent, the volume ratio of trichlorofluoromethane to chloroform is preferably 1: 1. The amount of fluorine gas to be used is not particularly limited, and it is preferable to continuously introduce the fluorine gas into the reaction mixture during the reaction. The temperature of the fluorination reaction may be that conventional in the art for such reactions, preferably-78 ℃. The fluorination reaction can be monitored by detection methods conventional in the art (e.g., TLC, GC, HPLC, or HNMR, etc.), and is typically terminated when the compound of formula A is eliminated. The time for the fluorination reaction is preferably 3 hours.
In a preferred embodiment of the present invention, the preparation method of the fluorinated nitrogen type amination reagent shown in formula I is performed under the protection of gas (such as nitrogen or inert gas).
In the preparation method of the fluorine-nitrogen type amination reagent shown in the formula I, after the fluorination reaction is finished, the operation of post-treatment can be further included. The post-treatment method can be a conventional post-treatment method in the field of organic synthesis. The present invention preferably comprises the following steps: and (2) carrying out solid-liquid separation on the reaction solution after the fluorination reaction is finished at room temperature (preferably, carrying out solid-liquid separation through a short silica gel short column, and leaching the short silica gel column by using a halogenated alkane solvent), removing the organic solvent in the filtrate (preferably, carrying out reduced pressure concentration), and separating by using flash column chromatography (petroleum ether/ethyl acetate is 20: 1).
R3And R4In (b), said substituted C6-C30Aryl and said substituted C2-C30The substituents in the heteroaryl group are preferably independently selected from nitro, or,Methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, n-pentyl (and isomers), n-hexyl (and isomers), chloromethyl, trifluoromethyl, phenyl, naphthyl, anthryl, phenanthryl, F, Cl, Br, I,And cyano (e.g., 1-6, preferably 1-3, more preferably 1-2); wherein R is5Is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, n-pentyl (or an isomer), n-hexyl (or an isomer),Trifluoromethyl orR7Independently is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, n-pentyl (or isomers), n-hexyl (or isomers) orWhen the substituent is plural, thenThe substitutions mentioned may be identical or different.
R3And R4Wherein said substituted or unsubstituted C6-C30Aryl is preferably substituted or unsubstituted C6-C14And (4) an aryl group. Said substituted or unsubstituted C6-C14The aryl group is preferably a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, a substituted or unsubstituted anthryl group, or a substituted or unsubstituted phenanthryl group.
R3And R4Wherein said substituted or unsubstituted C2-C30C in heteroaryl2-C30Heteroaryl is preferably C2-C12Heteroaryl (e.g. C)4-C12Heteroaryl group of (a). Said C2-C12The heteroaryl group of (a) is preferably pyridyl, thienyl, acridine, carbazole, cinnoline, carboline, quinoxaline, imidazole, pyrazole, pyrrole, indole, indoline, benzotriazole, benzimidazole, furan, thiophene, isothiazole, benzothiophene, dihydrobenzothiophene, benzofuran, isobenzofuran, benzoxazole, benzofurazan, benzopyrazole, quinoline, isoindole, isoquinoline, oxazole, oxadiazole, isoxazole, indole, pyrazine, pyridopyridine, tetrazolopyridine, pyridazine, pyridine, naphthyridine, pyrimidine, pyrrole, tetrazole, thiadiazole, thiazole, thiophene, triazole, quinazoline, tetrahydroquinoline, dihydrobenzimidazole, dihydrobenzofuran, dihydrobenzoxazole or dihydroquinoline.
R3And R4Wherein said substituted or unsubstituted C2-C30In heteroaryl groups, when the heteroatom is N and the N atom is sp3 hybridized, the N may be linked to a substituent, preferably C1-C10Alkyl radical, C6-C14Aryl, halogen, More preferably(e.g., Boc (t-butyloxycarbonyl) or Ac (acetyl)).
R3And R4Wherein said substituted or unsubstituted C2-C30The heteroaryl group is more preferably a substituted or unsubstituted group of the following:wherein X is N, O, S, NBoc or NAc.
In a preferred embodiment of the invention, R3And R4Independently is phenylNaphthyl (for example) ) Phenanthryl (e.g.))、
R3a、R3b、R3c、R3d、R4a、R5a、R4b、R5b、R6a、R6b、R6cAnd R8In (b), the C1-C10Alkyl is preferably C1-C6An alkyl group. Said C1-C6The alkyl group is preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a tert-butyl group, an isobutyl group, an n-pentyl groupHexyl and their various isomers. Said C6-C30Aryl substituted C1-C10Alkyl is preferably C6-C14Aryl substituted C1-C6An alkyl group. Said C6-C14Aryl substituted C1-C6The alkyl group is preferably benzyl.
When R is4aAnd R5a、R4bAnd R5bTogether with the carbon atom to which they are attached form C3-C10When there is a cycloalkyl group, said C3-C10Cycloalkyl is preferably C3-C7A cycloalkyl group. Said C3-C7Cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
R6a、R6bAnd R6cIn (1), the halogen is preferably F, Cl, Br or I.
Ra1、Ra2、Ra3、Ra4And Ra5In (1), the halogen is preferably F, Cl, Br or I.
Ra1、Ra2、Ra3、Ra4、Ra5、R9And R2’In (b), the C1-C10Alkyl is preferably C1-C6An alkyl group. Said C1-C6The alkyl group is preferably a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, a tert-butyl group, an isobutyl group, a n-pentyl group, a n-hexyl group or various isomers thereof.
In the present invention, the term "heteroaryl" denotes a stable monocyclic or bicyclic ring of up to 7 atoms in each ring, wherein at least one ring is aromatic and contains 1 to 4 heteroatoms selected from O, N and S. For exampleWithin the definition of heteroaryl.
In the present invention, the term "aryl" refers to any stable monocyclic ring of up to 7 atoms in each ringOr bicyclic carbocycles wherein at least one ring is aromatic. For exampleWithin the definition of aryl.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
In the present invention, room temperature means 10 to 40 ℃.
The positive progress effects of the invention are as follows:
the fluorine nitrogen type amination reagent takes olefin as a substrate under the action of a catalyst and a ligand, and obtains the 2, 2-diaryl ethylamine compound with optical activity by asymmetric amine arylation reaction of the olefin with good yield and excellent corresponding selectivity.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
In the following examples, the specific operation temperature is not limited, and it is referred to that the operation is carried out at room temperature (10 to 40 ℃ C.).
Example 1
In a 500mL three-necked flask, N-methylbenzenesulfonamide (13.5g,78.9mmol) was dissolved in FCCl3/HCCl3(200mL, v/v 1:1) in a mixed solvent, cooling to-78 ℃, and then F2/N2(2:8) gas was slowly introduced into the reaction solution (1-2 bubbles/min). After 3 hours of reaction, TLC showed that most of the starting material had been consumed. Introduction of N2After half an hour later, after the reaction is returned to room temperature, the reaction solution is passed through a short silica gel short column and CH2Cl2The filtrate was rinsed, concentrated and then subjected to flash column chromatography (20: 1 petroleum ether/ethyl acetate) to give 6.7g (45% yield) of a colorless liquid. Rf0.5 (petroleum ether/ethyl acetate 10:1).1H NMR(400MHz,CDCl3)δ7.97(d,J＝8.0Hz,2H),7.77(t,J＝8.0Hz,1H),7.64(t,J＝8.0Hz,2H),3.17(d,J＝31.6Hz,3H).13C NMR(100MHz,CDCl3)δ135.0,131.0,130.1,129.3,40.8(d,J＝12.2Hz).19F NMR(376MHz,CDCl3) δ -37.46(q, J ═ 31.6Hz). HRMS: M/z (esi) calculated value [ M + H]+190.0333, measured value of 190.0332.IR vmax/cm-11449,1368,1181,1087,1029,1000,861,731,686,652,622,578,552,528,484.
Example 2
NaH (3.6g,60mmol,60 wt% in mineral oil) was weighed into a 500mL round-bottomed flask, and anhydrous CH was added2Cl2(250mL) and stirred to a paste. Under the protection of Ar gas, a dichloromethane solution (50mL) of N-alkylbenzenesulfonamide (30mmol) is added dropwise, and a large amount of gas is generated during the addition. After the addition was complete, stirring was continued at room temperature for 30 minutes. N-fluorobisbenzenesulfonylimide (NFSI,56g,180mmol) was added to the reaction system, and the mixture was stirred at room temperature for 6 hours. The reaction solution was slowly poured into ice water to quench the unreacted NaH. Separating organic phase from separating funnel, using CH for aqueous phase2Cl2(200 mL. times.3) extraction with anhydrous MgSO4The organic phase was dried and filtered. After the filtrate is concentrated, the target product is obtained by flash column chromatography separation (PE/EA is 20: 1).
Reaction of N-isopropylbenzenesulfonamide (6.0g,30mmol) gave 3.36g of a red liquid, 52% yieldf＝0.7(PE/EA＝10:1).1H NMR(400MHz,CDCl3)δ7.98(d,J＝7.6Hz,2H),7.71(t,J＝8.0Hz,1H),7.59(t,J＝8.0Hz,2H),4.25–4.01(m,1H),1.33(d,J＝6.4Hz,6H).13C NMR(100MHz,CDCl3)δ135.2,134.5,129.3(d,J＝1.2Hz),129.2,55.4(d,J＝13.9Hz),19.3(d,J＝6.1Hz).19F NMR(376MHz,CDCl3)δ-76.08(d,J＝34.6Hz).HRMS:m/z(ESI)calculated[M+H]+:218.0646,measured:218.0646.IR νmax/cm-12987,2943,1585,1449,1356,1171,1086,892,756,727,685,653,606,573,552.
Reaction of N-ethylbenzenesulfonamide (13.5g,72.9mmol) gave 6.7g of a yellow liquid, 45% yieldf＝0.7(PE/EA＝10:1).1H NMR(400MHz,CDCl3)δ7.96(d,J＝8.0Hz,2H),7.75(t,J＝7.6Hz,1H),7.63(t,J＝7.6Hz,2H),3.31(dq,J＝39.6,7.6Hz,2H),1.34(t,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3)δ134.9,131.9,129.9,129.2,48.8(d,J＝12.9Hz),11.6.19F NMR(376MHz,CDCl3)δ-52.90(t,J＝39.6Hz).HRMS:m/z(ESI)calculated[M+H]+:204.0489,measured:204.0489.IR νmax/cm-12991,1584,1370,1178,1087,1039,935,893,757,731,685,575,557.
Reaction of N-Ethyl-p-toluenesulfonamide (6.0g,30mmol) gave 3.1g of a red solid, 48% yieldf＝0.7(PE/EA＝10:1).1H NMR(400MHz,CDCl3)δ7.82(d,J＝8.4Hz,2H),7.41(d,J＝8.4Hz,2H),3.28(dq,J＝39.6,7.2Hz,2H),2.48(s,3H),1.32(t,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3)δ146.2,130.0,129.9,128.7,48.9(d,J＝12.8Hz),21.7,11.6.19F NMR(376MHz,CDCl3)δ-52.87(t,J＝39.8Hz).HRMS:m/z(ESI)calculated[M+H]+:218.0646,measured:218.0645.IR νmax/cm-12993,1592,1364,1170,1087,1037,937,889,704,638,565,541,477.
The following compounds were synthesized according to the same procedures as in example 2, substituting the corresponding reaction materials:
reaction of N-Ethyl-p-toluenesulfonamide (6.0g,30mmol) gave 4.35g, 63% yield R as a pale yellow liquidf＝0.7(PE/EA＝10:1).1H NMR(400MHz,CDCl3)δ7.99(d,J＝7.6Hz,2H),7.67(t,J＝7.6Hz,1H),7.56(t,J＝7.6Hz,2H),1.47(d,J＝2.0Hz,9H).13C NMR(100MHz,CDCl3)δ137.3,134.2,129.0(d,J＝1.6Hz),128.9,66.6(d,J＝11.4Hz),27.2(d,J＝6.0Hz).19F NMR(376MHz,CDCl3)δ-62.47(s).HRMS:m/z(ESI)calculated[M+H]+:232.0802,measured:232.0802.IR νmax/cm-12986,2939,1478,1449,1402,1351,1166,1089,894,795,755,721,685,627,584,554.
Reaction of N-Ethyl-p-trifluoromethylbenzenesulfonamide (5.06g,20mmol) gave 1.35g of a yellow liquid, 25% yieldf＝0.8(PE/EA＝8:1).1H NMR(400MHz,CDCl3)δ8.10(d,J＝8.4Hz,2H),7.89(d,J＝8.4Hz,2H),3.36(dq,J＝39.6,7.2Hz,2H),1.36(t,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3)δ136.3(q,J＝33.0Hz),135.8,130.5(d,J＝1.5Hz),126.4(q,J＝3.4Hz),122.9(q,J＝271.8Hz),48.7(d,J＝12.6Hz),11.5.19F NMR(376MHz,CDCl3)δ-52.82(t,J＝39.6Hz),-63.44(s).HRMS:m/z(ESI)calculated[M+H]+:272.0363,measured:273.0362.IR νmax/cm-11404,1380,1319,1174,1132,1107,1060,1006,900,843,790,719,680,588,553,426.
Reaction of N-Ethyl-p-methoxybenzenesulphonamide (6.46g,30mmol) gave 2.5g of a red solid, 36% yieldf＝0.4(PE/EA＝8:1).1H NMR(400MHz,CDCl3)δ7.87(d,J＝8.8Hz,2H),7.07(d,J＝8.8Hz,2H),3.91(s,3H),3.28(dq,J＝40.0,7.2Hz,1H),1.32(t,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3)δ164.7,132.2,122.9,114.5,55.8,48.8(d,J＝12.9Hz),11.6.19F NMR(376MHz,CDCl3)δ-52.63(t,J＝40.0Hz).HRMS:m/z(ESI)calculated[M+H]+:234.0595,measured:234.0594.IR νmax/cm-12989,2921,2848,1591,1365,1267,1217,1187,1092,1023,884,831,803,703,551.
Example 3
Step 1: in a 100mL vial, ligands L (82.0mg,0.20mmol) and Cu (CH)3CN)4PF6(37.0mg,0.10mmol) was dissolved in DMA/CH under argon2Cl2(1:4,20mL) and stirred for 0.5 h to obtain a colorless solution for further use.
Step 2: in a 10mL stopcock, the compound of formula III (0.40mmol,2.0equiv) and anhydrous LiOtBu (8.0mg,0.10mmol,0.5equiv) were added. Under the protection of argon, the copper is sequentially added into a reaction tube cooled to-20 DEG CThe catalyst solution (2.0mL), the compound represented by formula II (0.20mmol,1.0equiv), the fluorine nitrogen type amination reagent represented by formula I (0.4mmol,2.0equiv), and the reaction solution turned blue. The reaction was stirred at-10 ℃ and after the specified time, the reaction was diluted with 20mL of ethyl acetate and washed with water (10 mL. times.3). The organic phase was over anhydrous MgSO4Drying, filtering, concentrating the filtrate, separating by flash column chromatography (petroleum ether/ethyl acetate, and selecting the proportion of the two according to the specific TLC condition of the compound) to obtain the target product, and determining ee value by HPLC through chiral column resolution.
Wherein, the structure of the fluorine nitrogen type amination reagent shown as the formula I is
Compound P1
After 5 days of reaction, 65.2mg (81% yield, 92% ee) of a colorless viscous liquid are obtainedf＝0.4(PE/EA＝5:1).1H NMR(400MHz,CDCl3)δ8.11–8.02(m,1H),7.87–7.81(m,1H),7.80–7.70(m,3H),7.59–7.40(m,7H),7.37–7.20(m,5H),5.12(t,J＝8.0Hz,1H),3.92(dd,J＝13.6,7.6Hz,1H),3.57(dd,J＝13.6,8.4Hz,1H),2.59(s,3H).13C NMR(100MHz,CDCl3) Delta 141.6,137.3,136.6,134.0,132.5,131.6,129.0,128.9,128.6,128.4,127.6,127.3,126.8,126.2,125.5,125.3,125.0,123.3,54.8,45.0,35.6 HRMS M/z (ESI) calculated [ M + H ]]+402.1522, measured 405.1524.IR vmax/cm-12962,1446,1335,1260,1161,1088,1025,796,745,695,577.[α] D 27.445.02(c 1.07,CHCl3) HPLC (AD-H,0.46 × 25cm,5 μm, n-hexane/isopropanol 7/3, flow rate 0.7mL/min, detection range wavelength 214nm) retention time 8.95min (bulk) and 11.53min (small).
Compound P2
After 5.5 days of reaction, 76.8mg (80% yield, 92% ee), R, of a pale yellow viscous liquid are obtainedf＝0.5(PE/EA＝5:1).1H NMR(400MHz,CDCl3)δ8.28(dd,J＝8.8,1.6Hz,1H),8.08(d,J＝8.0Hz,1H),7.81(d,J＝7.6Hz,1H),7.77–7.69(m,2H),7.62–7.41(m,6H),7.32–7.18(m,5H),5.08(t,J＝8.4Hz,1H),3.96(dd,J＝13.2,8.0Hz,1H),3.46(dd,J＝13.6,8.0Hz,1H),2.59(s,3H).13CNMR(100MHz,CDCl3)δ141.1,137.1,136.5,133.0,132.6,132.3,129.4,129.1,128.7,128.3,128.1,127.3,127.0,127.0,126.9,125.6,123.7,122.3,54.7,44.9,35.7.HRMS:m/z(ESI)calculated[M+H]+:480.0627,measured:480.0631.IR νmax/cm-12962,1259,1015,796,694,576.[α] D 27.659.16(c 0.83,CHCl3) HPLC (AD-H,0.46 × 25cm,5 μm, n-hexane/isopropanol 7/3, flow rate 0.7mL/min, detection range wavelength 214nm) retention time 9.11min (small) and 9.97min (large).
Compound P3
After 5.5 days of reaction, 46.9mg (47% yield, 90% ee), R, of a pale yellow viscous liquid are obtainedf＝0.5(PE/EA＝4:1).1H NMR(400MHz,CDCl3)δ8.35–8.29(m,1H),8.06–7.99(m,1H),7.77–7.70(m,2H),7.60–7.45(m,6H),7.33–7.26(m,4H),7.25–7.17(m,1H),6.84(d,J＝8.0Hz,1H),5.03(t,J＝8.0Hz,1H),4.53(q,J＝8.0Hz,2H),3.99(dd,J＝13.2,8.0Hz,1H),3.45(dd,J＝13.2,8.0Hz,1H),2.61(s,3H).13C NMR(100MHz,CDCl3)δ152.3,141.6,137.1,132.7,132.6,130.3,129.1,128.7,128.3,127.3,127.2,126.9,125.8,125.5,124.8,123.4(q,J＝276.3Hz),123.1,122.5,104.8,65.9(q,J＝35.6Hz),54.7,44.5,35.4.19F NMR(376MHz,CDCl3)δ-73.71(t,J＝8.0Hz).HRMS:m/z(ESI)calculated[M+NH4]+:517.1767,measured:517.1775.IR νmax/cm-12960,1636,1260,1155,1088,1020,797,744,695,668,666,576.[α] D 27.851.67(c0.78,CHCl3) HPLC (IG,0.46 × 25cm,5 μm, n-hexane/isopropanol 8/2, flow rate 0.7mL/min, detection range wavelength 214nm) retention time 16.81min (bulk) and 18.28min (small).
Compound P4
After 5.5 days of reaction, 68.9mg (75% yield, 89% ee), R, of a pale yellow viscous liquid are obtainedf＝0.3(PE/EA＝10:3).1H NMR(400MHz,CDCl3)δ7.79(d,J＝8.8Hz,1H),7.76–7.66(m,4H),7.54–7.35(m,5H),7.31–7.26(m,4H),7.23–7.19(m,2H),4.44(t,J＝8.0Hz,1H),3.78(dd,J＝13.2,8.4Hz,1H),3.67(dd,J＝13.2,8.4Hz,1H),2.58(s,3H),2.33(s,3H).13C NMR(100MHz,CDCl3)δ169.6,148.2,141.2,138.8,137.3,132.6,132.5,131.4,129.3,129.0,128.6,128.2,128.0,127.3,127.2,126.9,126.5,121.4,118.2,54.4,49.9,35.4,21.1.HRMS:m/z(ESI)calculated[M+H]+:460.1577,measured:460.1579.IR νmax/cm-11750,1507,1473,1446,1334,1197,1161,744,696,577.[α] D 28.211.74(c 1.07,CHCl3) HPLC (AD-H,0.46 × 25cm,5 μm, n-hexane/isopropanol 7/3, flow rate 0.7mL/min, detection range wavelength 214nm) retention time 23.46min (small) and 26.78min (large).
Compound P5
After 3days of reaction, 62.8mg (77% yield, 84% ee), R, of a pale yellow viscous liquid are obtainedf＝0.5(PE/EA＝8:1).1H NMR(400MHz,CDCl3)δ7.74–7.66(m,2H),7.55(t,J＝6.8Hz,1H),7.46(t,J＝7.6Hz,2H),7.34–7.26(m,6H),7.26–7.16(m,3H),4.24(t,J＝8.0Hz,1H),3.74–3.54(m,2H),2.56(s,3H),1.28(s,9H).13C NMR(100MHz,CDCl3)δ149.5,141.6,138.4,137.5,132.5,129.0,128.6,128.2,127.7,127.4,126.7,125.5,54.6,49.6,35.3,34.4,31.3.HRMS:m/z(ESI)calculated[M+H]+:408.1992,measured:408.1993.IR νmax/cm-12960,1446,1337,1260,1163,1089,936,739,690,577.[α] D 28.82.85(c 0.79,CHCl3) HPLC (AD-H,0.46 × 25cm,5 μm, n-hexane/isopropanol 96/4, flow rate 0.7mL/min, detection range wavelength 214nm) retention time 15.95min (small) and 22.80min (large).
Compound P6
After 3days of reaction, 59.0mg (72% yield, 83% ee) of after 3days, R.sub.3 days, are obtained as a pale yellow viscous liquidf＝0.4(PE/EA＝3:1).1H NMR(400MHz,CDCl3)δ7.74–7.68(m,2H),7.60–7.52(m,1H),7.51–7.44(m,2H),7.33–7.19(m,7H),7.05–6.99(m,2H),4.29(t,J＝8.0Hz,1H),3.60(d,J＝8.0Hz,2H),2.56(s,3H),2.27(s,3H).13C NMR(100MHz,CDCl3)δ169.4,149.3,141.0,138.9,137.2,132.5,129.1,129.0,128.6,128.1,127.3,126.9,121.6,54.6,49.4,35.3,21.1.HRMS:m/z(ESI)calculated[M+H]+:410.1421,measured:410.1422.IR νmax/cm-12922,1760,1506,1446,1337,1197,1163,1089,1017,747,696,577.[α] D 28.9-0.75(c 1.02,CHCl3) HPLC (IC,0.46 × 25cm,5 μm, n-hexane/isopropanol 6/4, flow rate 0.7mL/min, detection range wavelength 214nm) retention time 28.91min (small amount) and 31.29min (large amount).
Compound P7
After 7.5 days of reaction, 45.0mg (63% yield, 88% ee), R, of a pale yellow viscous liquid are obtainedf＝0.5(PE/EA＝5:1).1H NMR(400MHz,CDCl3)δ7.71(d,J＝8.0Hz,2H),7.58(t,J＝7.2Hz,1H),7.49(t,J＝7.6Hz,2H),7.35–7.18(m,9H),4.26(t,J＝8.0Hz,1H),3.68(dd,J＝13.6,8.8Hz,1H),3.51(dd,J＝13.6,7.6Hz,1H),2.58(s,3H).13C NMR(100MHz,CDCl3)δ141.0,139.8,137.2,132.6,129.6,129.1,128.7,128.0,127.3,127.0,54.5,49.3,35.3.HRMS:m/z(ESI)calculated[M+H]+:386.0976,measured:386.0977.IR νmax/cm-12922,1490,1446,1337,1260,1162,1089,1004,935,743,690,577,553.[α] D 27.95.85(c 0.84,CHCl3) HPLC (AD-H,0.46 × 25cm,5 μm, n-hexane/isopropanol 9/1, flow rate 0.7mL/min, detection range wavelength 214nm) retention time 20.23min (small) and 21.89min (large).
Compound P8
After 7.5 days of reaction, 62.0mg (74% yield, 87% ee), R, of a colorless viscous liquid are obtainedf＝0.4(PE/EA＝5:1).1H NMR(400MHz,CDCl3)δ7.75–7.67(m,2H),7.60–7.53(m,3H),7.52–7.45(m,2H),7.42(d,J＝8.0Hz,2H),7.33-7.30(m,2H),7.26-7.22(m,3H),4.36(t,J＝8.0Hz,1H),3.77(dd,J＝13.6,8.8Hz,1H),3.52(dd,J＝13.6,7.6Hz,1H),2.59(s,3H).13C NMR(100MHz,CDCl3)δ145.4,140.6,137.1,132.7,129.1,128.8,128.6,128.1,127.3,127.2,125.5(q,J＝3.7Hz),124.1(q,J＝270.3Hz),54.3,49.8,35.4.19F NMR(376MHz,CDCl3)δ-62.43(s).HRMS:m/z(ESI)calculated[M+H]+:420.1240,measured:420.1243.IR νmax/cm-11447,1323,1161,1188,1068,1018,936,831,746,691,577,550.[α] D 29.09.14(c 1.19,CHCl3) HPLC (AD-H,0.46 × 25cm,5 μm, n-hexane/isopropanol 7/3, flow rate 0.7mL/min, detection range waveLong 214nm) retention time 7.69min (small) and 8.20min (large).
Compound P9
After 4 days of reaction, 53.2mg (65% yield, 90% ee), R, of a yellow, viscous liquid are obtainedf＝0.3(PE/EA＝7:2).1H NMR(400MHz,CDCl3)δ7.98(d,J＝8.0Hz,2H),7.74–7.67(m,2H),7.57(t,J＝7.2Hz,1H),7.49(t,J＝7.2Hz,2H),7.37(d,J＝8.4Hz,2H),7.34–7.28(m,2H),7.27–7.19(m,3H),4.35(t，J＝8.0Hz，1H)，3.89(s，3H)，3.72(dd，J＝13.6，8.4Hz，1H)，3.57(dd，J＝13.6，7.6Hz，1H),2.57(s,3H).13C NMR(100MHz,CDCl3)δ166.8,146.6,140.7,137.2,132.6,129.9,129.1,128.8,128.7,128.3,128.1,127.3,127.1,54.4,52.1,50.0,35.5.HRMS:m/z(ESI)calculated[M+H]+:410.1421,measured:410.1423.IR νmax/cm-11761,1446,1339,1279,1162,1112,937,742,691,577,554.[α] D 29.19.60(c 1.33,CHCl3) HPLC (AD-H,0.46 × 25cm,5 μm, n-hexane/isopropanol 7/3, flow rate 0.7mL/min, detection range wavelength 214nm) retention time 15.76min (small) and 16.89min (large).
Compound P10
After 5.5 days of reaction, 66.6mg (78% yield, 90% ee), R, of a colorless viscous liquid are obtainedf＝0.5(PE/EA＝5:1).1H NMR(400MHz,CDCl3)δ7.71(d,J＝8.0Hz,2H),7.58–7.50(m,5H),7.48-7.39(m,4H),7.36-7.30(m,7H),7.25-7.20(m,1H),4.32(t,J＝8.0Hz,1H),3.67(m,2H),2.59(s,3H).13CNMR(100MHz,CDCl3)δ141.4,140.6,140.5,139.6,137.4,132.5,129.0,128.7,128.7,128.6,128.2,127.3,127.3,127.2,126.9,126.9,54.5,49.7,35.3.HRMS:m/z(ESI)calculated[M+H]+:428.1679,measured:428.1686.IR νmax/cm-12922,1558,1473,1338,1260,1162,1088,936,798,745,634,577.[α] D 28.92.69(c 0.73,CHCl3) HPLC (IE-3,0.46 × 25cm,5 μm, n-hexane/isopropanol 9/1, flow rate 0.7mL/min, detection range wavelength 214nm) retention time 50.50min (bulk) and 55.87min (small).
Compound P11
After 5.5 days of reaction, 49.2mg (53% yield, 91% ee), R, of a yellow solid are obtainedf＝0.6(PE/EA＝5:1).1HNMR(400MHz,CDCl3)δ7.72(d,J＝7.6Hz,2H),7.54(m,4H),7.37–7.17(m,7H),4.77(t,J＝8.0Hz,1H),3.67(dd,J＝13.2,8.0Hz,1H),3.49(dd,J＝13.2,8.0Hz,1H),2.65(s,3H).13CNMR(100MHz,CDCl3)δ140.7,139.1,137.0,133.1,132.7,132.1,131.2,131.2,129.1,128.2,128.5,127.4,127.3,120.9,53.2,45.0,34.8.HRMS:m/z(ESI)calculated[M+H]+:464.0081,measured:464.0085.IR νmax/cm-12922,1260,1018,797.[α] D 28.738.84(c 0.96,CHCl3) HPLC (AD-H,0.46 × 25cm,5 μm, n-hexane/isopropanol 94/6, flow rate 0.7mL/min, detection range wavelength 214nm) retention time 16.67min (small) and 20.76min (large).
Compound P12
After 7.5 days of reaction, 68.6mg (70% yield, 92% ee), R, of a pale yellow viscous liquid are obtainedf＝0.5(PE/EA＝10:3).1H NMR(400MHz,CDCl3)δ7.71(d,J＝7.6Hz,2H),7.57(t,J＝7.6Hz,1H),7.49(t,J＝7.6Hz,2H),7.34–7.19(m,5H),7.09(s,1H),6.99(s,1H),4.68(dd,J＝10.0,7.2Hz,1H),3.93(s,3H),3.92–3.86(m,1H),3.85(s,3H),3.22(dd,J＝13.2,6.8Hz,1H),2.68(s,3H).13CNMR(100MHz,CDCl3)δ148.6,148.3,140.2,136.9,132.6,131.3,129.0,128.6,128.3,127.3,126.9,115.5,114.8,112.2,56.2,56.0,53.2,46.8,34.1.HRMS:m/z(ESI)calculated[M+H]+:490.0682,measured:490.0692.IR νmax/cm-11540,1504,1457,1260,1209,1161,1089,1027,942,744,694,603,577.[α] D 28.732.81(c 0.93,CHCl3) HPLC (AD-H,0.46 × 25cm,5 μm, n-hexane/isopropanol 7/3, flow rate 0.7mL/min, detection range wavelength 214nm) retention time 12.90min (bulk) and 16.49min (small).
Compound P14
After 7.5 days of reaction, 60.8mg (47% yield, 87% ee), R, of a white solid are obtainedf＝0.5(PE/EA＝5:3).1HNMR(400MHz,CDCl3)δ8.14(d,J＝8.0Hz,2H),7.73(d,J＝8.0Hz,2H),7.64–7.48(m,3H),7.44(d,J＝8.0Hz,2H),7.39–7.19(m,6H),7.00–6.86(m,2H),4.39(t,J＝8.0Hz,1H),3.78(dd,J＝13.6,8.8Hz,1H),3.55(dd,J＝13.6,7.6Hz,1H),2.94–2.93(m,2H),2.60(s,3H),2.59–1.93(m,8H),1.68–1.39(m,5H),0.92(s,3H).13C NMR(100MHz,CDCl3)δ220.9,165.1,148.7,147.3,140.6,138.0,137.3,137.1,132.6,130.4,129.1,128.8,128.5,128.1,128.0,127.3,127.1,126.4,121.6,118.8,54.3,50.3,50.0,47.9,44.1,37.9,35.8,35.4,31.5,29.4,26.3,25.7,21.5,13.8.HRMS:m/z(ESI)calculated[M+H]+:648.2778,measured:648.2800.IRνmax/cm-12925,1731,1493,1340,1262,1163,1072,746,691,578,554.[α] D 28.851.70(c 0.59,CHCl3) HPLC (AD-H,0.46 × 25cm,5 μm, n-hexane/isopropanol 5/5, flow rate 0.7mL/min, detection range wavelength 214nm) retention time 46.83min (small) and 52.73min (large).
Compound P15
After 3days of reaction, 41.2mg (42% yield, 84% ee), R, of a colorless viscous liquid are obtainedf＝0.5(PE/EA＝3:1).1H NMR(400MHz,CDCl3)δ8.03(d,J＝8.0Hz,1H),7.71(d,J＝7.2Hz,2H),7.62–7.51(m,2H),7.51–7.40(m,3H),7.30(d,J＝4.3Hz,4H),7.24–7.18(m,2H),6.51(d,J＝3.6Hz,1H),4.38(t,J＝8.0Hz,1H),3.68(m,2H),2.58(s,3H),1.65(s,9H).13C NMR(100MHz,CDCl3)δ149.7,141.9,137.5,135.9,132.5,130.8,129.0,128.6,128.2,127.3,126.7,126.3,124.5,120.3,115.2,107.3,83.7,54.9,49.8,35.4,28.1.HRMS:m/z(ESI)calculated[M+H]+:491.1999,measured:491.2000.IR νmax/cm-12962,1729,1469,1332,1258,1160,1083,1022,746,698,576,544.[α] D 29.01.55(c 1.02,CHCl3) HPLC (AD-H,0.46 × 25cm,5 μm, n-hexane/isopropanol 7/3, flow rate 0.7mL/min, detection range wavelength 214nm) retention time 10.00min (small amount) and 11.95min (large amount).
Compound P16
After 5.5 days of reaction, 37.1mg (43% yield, 91% ee), R, of a colorless viscous liquid are obtainedf＝0.5(PE/EA＝10:3).1H NMR(400MHz,CDCl3)δ8.09–8.05(m,1H),7.84–7.80(m,1H),7.77–7.68(m,3H),7.57–7.38(m,7H),7.27–7.18(m,2H),6.85–6.76(m,2H),5.06(t,J＝8.0Hz,1H),3.88(dd,J＝13.2,7.2Hz,1H),3.73(s,3H),3.52(dd,J＝13.2,8.0Hz,1H),2.59(s,3H).13C NMR(100MHz,CDCl3)δ158.3,137.3,136.9,134.0,133.6,132.5,131.6,129.4,129.0,128.9,127.5,127.3,126.2,125.4,125.3,124.8,123.3,114.0,55.1,54.9,44.1,35.6.HRMS:m/z(ESI)calculated[M+H]+:432.1628,measured:432.1632.IR νmax/cm-12961,2917,2850,1512,1443,1334,1252,1157,1086,1025,934,799,746,693,578,549.[α] D 28.730.89(c0.70,CHCl3) HPLC (AD-H,0.46 × 25cm,5 μm, n-hexane/isopropanol 8/2, flow rate 0.7mL/min, detection range wavelength 214nm) retention time 15.37min (bulk) and 20.47min (small).
Compound P17
After 5.5 days of reaction, 54.5mg (65% yield, 92% ee), R, of a yellow, viscous liquid are obtainedf＝0.4(PE/EA＝5:1).1H NMR(400MHz,CDCl3)δ8.04–8.02(m,1H),7.88–7.81(m,1H),7.79–7.69(m,3H),7.57–7.39(m,7H),7.35–7.25(m,2H),7.01–6.91(m,2H),5.17–5.06(m,1H),3.82(dd,J＝13.6,7.2Hz,1H),3.59(dd,J＝13.6,8.8Hz,1H),2.60(s,3H).13C NMR(100MHz,CDCl3)δ161.6(d,J＝243.6Hz),137.2(d,J＝3.0Hz),137.2,136.5,134.1,132.6,131.5,129.9(d,J＝8.4Hz),129.1,129.0,127.7,127.3,126.3,125.6,125.3,124.8,123.1,115.5(d,J＝21.3Hz),54.9,44.2,35.7.19F NMR(375MHz,CDCl3)δ-115.83(m).HRMS:m/z(ESI)calculated[M+H]+:420.1428,measured:420.1432.IR νmax/cm-12962,1507,1259,1013,790,758,691,577.[α] D 28.644.05(c 0.96,CHCl3) HPLC (AD-H,0.46 × 25cm,5 μm, n-hexane/isopropanol 7/3, flow rate 0.7mL/min, detection range wavelength 214nm) retention time 9.41min (bulk) and 10.47min (small).
Compound P18
After 7.5 days of reaction, 44.4mg (52% yield, 91% ee), R, of a yellow solid are obtainedf＝0.6(PE/EA＝4:1).1H NMR(400MHz,CDCl3)δ8.20–8.07(m,2H),7.79–7.69(m,2H),7.60–7.43(m,6H),7.18–7.10(m,2H),6.99–6.90(m,2H),5.35(t,J＝8.0Hz,1H),3.84(dd,J＝13.6,7.6Hz,1H),3.65(dd,J＝13.6,8.4Hz,1H),2.60(s,3H).13C NMR(100MHz,CDCl3)δ158.1(d,J＝241.2Hz),145.1,137.3,132.8(d,J＝4.6Hz),132.7,132.6,129.1,127.4,127.3,126.9,126.0(d,J＝2.0Hz),125.5,124.8(d,J＝9.1Hz),124.4,124.1(d,J＝15.9Hz),123.1(d,J＝2.9Hz),121.3(d,J＝6.0Hz),108.9(d,J＝19.7Hz),55.8,40.7,36.2.19F NMR(376MHz,CDCl3)δ-123.47(m).HRMS:m/z(ESI)calculated[M+H]+:426.0992,measured:426.0999.IR νmax/cm-12960,2924,1604,1446,1336,1258,1162,739,691,575,541.[α] D 28.439.15(c 0.92,CHCl3) HPLC (AD-H,0.46 × 25cm,5 μm, n-hexane/isopropanol 7/3, flow rate 0.7mL/min, detection range wavelength 214nm) retention time 8.80min (bulk) and 9.75min (small).
Compound P19
After 7.5 days of reaction, 68.4mg (72% yield, 90% ee), R, of a brownish red viscous liquid are obtainedf＝0.6(PE/EA＝4:1).1H NMR(400MHz,CDCl3)δ8.16-8.14(m,2H),7.78–7.62(m,4H),7.59–7.48(m,4H),7.48–7.40(m,2H),7.36–7.10(m,4H),5.40(t,J＝7.6Hz,1H),3.88(dd,J＝13.6,7.6Hz,1H),3.76(dd,J＝13.6,8.4Hz,1H),2.65(s,3H).13C NMR(100MHz,CDCl3)δ158.3(d,J＝251.3Hz),146.0,139.6,139.3,137.1,132.8(d,J＝4.5Hz),132.7,132.0(d,J＝4.6Hz),129.1,127.5,127.3,126.1(d,J＝2.2Hz),124.9(d,J＝8.3Hz),124.3,124.2(d,J＝15.9Hz),124.0,123.3,123.1(d,J＝3.0Hz),122.2,122.1,121.4(d,J＝6.0Hz),108.9(d,J＝19.8Hz),55.4,41.4,36.2.19F NMR(376MHz,CDCl3)δ-123.01(dd,J＝9.5,4.9Hz).HRMS:m/z(ESI)calculated[M+H]+:476.1149,measured:476.1147.IR νmax/cm-12961,1458,1396,1334,1159,1015,798,739,689,575.[α] D 28.4-11.50(c 1.08,CHCl3).HPLC(AD-H,0.46 × 25cm,5 μm, n-hexane/isopropanol 7/3, flow rate 0.7mL/min, detection range wavelength 214nm) retention time 11.37min (bulk) and 15.18min (bulk).
Compound P20
After 7 days of reaction, 34.5mg (48% yield, 86% ee), R, of a yellow viscous liquid are obtainedf＝0.5(PE/EA＝2:1).1H NMR(400MHz,CDCl3)δ7.72(d,J＝7.2Hz,2H),7.60–7.45(m,3H),7.36–7.13(m,5H),6.83(m,3H),4.23(t,J＝8.0Hz,1H),3.86(s,3H),3.85(s,3H),3.69(dd,J＝13.6,8.8Hz,1H),3.51(dd,J＝13.6,7.6Hz,1H),2.59(s,3H).13C NMR(100MHz,CDCl3)δ148.9,147.8,141.8,137.4,133.7,132.5,129.0,128.6,128.0,127.3,126.8,120.1,111.6,111.1,55.9,55.8,54.6,49.4,35.2.HRMS:m/z(ESI)calculated[M+H]+:412.1577,measured:412.1577.[α] D 25.416.62(c 0.39,CHCl3) HPLC (IC,0.46 × 25cm,5 μm, n-hexane/isopropanol 5/5, flow rate 0.7mL/min, detection range wavelength 214nm) retention time 27.05min (bulk) and 29.36min (small).
Example 4
Optically active 2, 2-arylethylamine (17.3Mg,0.042mmol,1.0equiv), Mg powder (48.0Mg,2.0mmol,47equiv), and methanol (1.0mL) were added to a 10mL sealed tube under an argon atmosphere, and the reaction mixture became a gel after reacting for 40min under sonication. TLC keeps the substrate reaction complete, after the reaction solvent is drained, the reaction solvent is filtered by diatomite and rinsed by ethyl acetate/methanol (10: 1). Concentrating the filtrate, and separating by flash column chromatography (PE/EA/MeOH/NEt)310:10:1:1) to yield 9.5mg (83% yield, 88% ee), R, as a pale yellow liquidf＝0.4(PE/EA/MeOH/TEA＝10:10:1:1).1HNMR(400MHz,CDCl3)δ7.33–7.17(m,5H),6.79(m,3H),4.19(t,J＝7.6Hz,1H),3.85(s,3H),3.84(s,3H),3.20(d,J＝7.6Hz,2H),2.45(s,3H),2.33(br,1H).13C NMR(100MHz,CDCl3)δ148.9,147.7,142.8,135.1,128.6,127.8,126.6,119.6,111.5,111.2,56.5,55.8,55.8,50.3,36.2.HRMS:m/z(ESI)calculated[M+H]+:272.1645,measured:272.1644.IR νmax/cm-12930,2835,2792,1591,1513,1447,1417,1260,1236,1186,1146,1025,753,700,583,540.[α] D 25.82.93(c 0.37,CHCl3) HPLC (IC,0.46 × 25cm,5 μm, n-hexane/isopropanol/diethylamine 90/10/1, flow rate 0.7mL/min, detection range wavelength 214nm) retention time 35.03min (bulk) and 44.90min (small).
Example 5
The reaction behavior of the various substituted nitrogen fluorine amination reagents is shown in Table 1, with the same reaction conditions and procedure as in example 2, except that different fluorine nitrogen type amination reagents were used and the reaction was carried out at room temperature for 18 hours for monitoring. The structure and experimental results of the aminating reagent of the fluorine-nitrogen type are shown in Table 1.
TABLE 1

Claims (16)

1. The application of a fluorine nitrogen type amination reagent shown as a formula I in preparing 2, 2-diaryl ethylamine compound intermediates is characterized by comprising the following steps: under the protection of gas, under the action of a copper catalyst, a dinitrogen ligand and alkali, carrying out the following reaction on a fluorine nitrogen type amination reagent shown as a formula I, a compound shown as a formula II and a compound shown as a formula III in an organic solvent to prepare a compound shown as a formula IV;
wherein,
R1is substituted or unsubstituted C6-C30An aryl group; said substituted C6-C30The substituents in the aryl group are selected from halogen, C1-C10Alkyl, halogen substituted C1-C10Alkyl radical, C1-C10Alkoxy andone or more of R1’Is C1-C10An alkyl group; when the number of the substituents is plural, the substituents may be the same or different; said substituted or unsubstituted C6-C30Aryl is substituted or unsubstituted phenyl;
R2is C1-C10Straight chain alkyl orWherein R is1aDefinition of (A) and R1The same;
R3and R4Independently is substituted or unsubstituted C6-C30Aryl, or, substituted or unsubstituted C2-C30A heteroaryl group; said C2-C30The heteroatom in heteroaryl is selected from one or more of N, O and S; when there are a plurality of heteroatoms, the heteroatoms may be the same or different; said substituted C6-C30Aryl and said substituted C2-C30The substituents in the heteroaryl group are independently selected from nitro and C2-C6Heteroaryl of (A), C1-C10Alkyl, halogen substituted C1-C10Alkyl radical, C6-C14Aryl, halogen,And cyano groups; wherein, said C2-C6Is a heteroatom selected from N, O and S, heteroC having 1 to 4 atomic numbers2-C6The heteroaryl group of (a); r5Is C1-C10Alkyl, halogen substituted C1-C10Alkyl orR6And R7Independently is C1-C10Alkyl orWhen the substituent is plural, the substituents may be the same or different.
2. The use according to claim 1,
in the fluorine nitrogen type amination reagent shown as the formula I, R1In (b), said substituted C6-C30The substituents in the aryl group are selected from the group consisting of F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, n-pentyl or its isomer, n-hexyl or its isomer, trifluoromethyl, pentafluoroethyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and mixtures thereof,One or more of; when the number of the substituents is plural, the substituents may be the same or different;
and/or, in the fluorine nitrogen type amination reagent shown as the formula I, R2In (b), the C1-C10Straight chain alkyl is C1-C6A linear alkyl group.
3. The use according to claim 2,
R1in (b), said substituted C6-C30Aryl is
And/or, R2In (b), the C1-C6The straight chain alkyl group is methyl, ethyl, n-propyl, n-butyl, n-pentyl or n-hexyl.
4. The use according to any one of claims 1 to 3,
R3and R4In (b), said substituted C6-C30Aryl and said substituted C2-C30The substituents in the heteroaryl group are independently selected from nitro, or nitro,Methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, n-pentyl or its isomer, n-hexyl or its isomer, chloromethyl, trifluoromethyl, phenyl, naphthyl, anthryl, phenanthryl, F, Cl, Br, I,And cyano groups; wherein R is5Is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, n-pentyl or an isomer thereof, n-hexyl or an isomer thereof,Trifluoromethyl orR7Independently methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, n-pentyl or an isomer thereof, n-hexyl or an isomer thereof orWhen the number of the substituents is plural, the substituents may be the same or different;
and/or, R3And R4Wherein said substituted or unsubstituted C6-C30Aryl being substituted or unsubstituted C6-C14An aryl group;
and/or, R3And R4Wherein said substituted or unsubstituted C2-C30C in heteroaryl2-C30Heteroaryl is C2-C12The heteroaryl group of (a); said substituted or unsubstituted C2-C30In heteroaryl, when the heteroatom is N and the N atom is sp3 hybridized, the N may be attached with a substituent which is C1-C10Alkyl radical, C6-C14Aryl, halogen,
5. The use of claim 4, wherein R is3And R4Wherein said substituted or unsubstituted C6-C14Aryl is substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted anthryl, or substituted or unsubstituted phenanthryl;
and/or, R3And R4Wherein said substituted or unsubstituted C2-C30C in heteroaryl2-C30Heteroaryl is C4-C12The heteroaryl group of (a); said substituted or unsubstituted C2-C30In the heteroaryl, when the heteroatom is N and the N atom is sp3 hybridized, a substituent can be connected to the N, and the substituent is tert-butyloxycarbonyl or acetyl; said substituted or unsubstituted C2-C30Heteroaryl is the following substituted or unsubstituted group:wherein X is N, O, S, NBoc or NAc.
6. The use of claim 5, wherein R is3And R4Wherein said substituted or unsubstituted C6-C14Aryl is
And/or, R3And R4Wherein said substituted or unsubstituted C2-C30Heteroaryl is the following substituted or unsubstituted group:
7. the use according to any one of claims 1 to 3,
in the preparation method of the compound shown in the formula IV, the gas in the gas protection is nitrogen or argon;
and/or in the preparation method of the compound shown in the formula IV, the organic solvent is one or more of a nitrile solvent, an aromatic hydrocarbon solvent, a halogenated alkane solvent, a ketone solvent and an amide solvent;
and/or in the preparation method of the compound shown in the formula IV, the copper catalyst is copper powder, cuprous iodide, cuprous chloride, cuprous bromide, cupric chloride, cupric bromide, cupric acetate, cuprous acetate, copper tetraacetonitrile hexafluorophosphate, copper tetraacetonitrile tetrafluoroborate, copper tetraacetonitrile trifluoromethanesulfonate, copper trifluoromethanesulfonate or cuprous thiophenecarboxylate;
and/or in the preparation method of the compound shown in the formula IV, the double-nitrogen ligand is a chiral double-nitrogen ligand;
and/or in the preparation method of the compound shown in the formula IV, the alkali is alkali metal salt of alcohol or sodium phenolate;
and/or in the preparation method of the compound shown as the formula IV, the reaction temperature is-40-0 ℃.
8. The use according to claim 7,
in the preparation method of the compound shown in the formula IV, the nitrile solvent is acetonitrile;
and/or in the preparation method of the compound shown in the formula IV, the aromatic hydrocarbon solvent is toluene;
and/or in the preparation method of the compound shown in the formula IV, the halogenated aromatic hydrocarbon solvent is one or more of chlorobenzene, fluorobenzene and trifluorotoluene;
and/or in the preparation method of the compound shown in the formula IV, the halogenated alkane solvent is dichloromethane and/or dichloroethane;
and/or in the preparation method of the compound shown in the formula IV, the ketone solvent is acetone;
and/or in the preparation method of the compound shown in the formula IV, the amide solvent is N, N-dimethylformamide and/or N, N-dimethylacetamide;
and/or in the preparation method of the compound shown in the formula IV, the copper catalyst is copper tetraethyl cyanide hexafluorophosphate, copper tetraethyl cyanide tetrafluoroborate, copper tetraethyl cyanide trifluoromethanesulfonate or copper trifluoromethanesulfonate;
and/or in the preparation method of the compound shown as the formula IV, the chiral double nitrogen ligand is chiral double oxazoline ligand Wherein R is3a、R3b、R3cAnd R3dIndependently is C1-C10Alkyl or C6-C30Aryl substituted C1-C10An alkyl group;R4a、R5a、R4band R5bIndependently of one another is hydrogen, C1-C10Alkyl radical, C6-C30Aryl, or R4aAnd R5a、R4bAnd R5bTogether with the carbon atom to which they are attached form C3-C10A cycloalkyl group; r6a、R6bAnd R6cIndependently of one another is hydrogen, C1-C10Alkyl, halogen,Cyano, trifluoromethyl or C6-C30An aryl group; r8Is C1-C10An alkyl group; n is 1, 2, 3 or 4; when n is 2, 3 or 4, R6aAnd R6bThe same or different;
and/or in the preparation method of the compound shown as the formula IV, the alkali is Ra-ONa、Rb-OK、Rc-OLi andwherein R isa、RbAnd RcIndependently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl; ra1、Ra2、Ra3、Ra4And Ra5Independently of one another hydrogen, halogen, C1-C10Alkyl orR9Is C1-C10An alkyl group;
and/or in the preparation method of the compound shown as the formula IV, the reaction temperature is-10-0 ℃.
9. The use according to claim 8, wherein in the process for the preparation of the compound of formula IV, the copper catalyst is copper tetraacetonitrile hexafluorophosphate;
and/or, said is of the formulaIV, the bis-nitrogen ligand, R3a、R3b、R3c、R3d、R4a、R5a、R4b、R5b、R6a、R6b、R6cAnd R8In (b), the C1-C10Alkyl is C1-C6An alkyl group; said C6-C30Aryl substituted C1-C10Alkyl is C6-C14Aryl substituted C1-C6An alkyl group; when R is4aAnd R5a、R4bAnd R5bTogether with the carbon atom to which they are attached form C3-C10When there is a cycloalkyl group, said C3-C10Cycloalkyl being C3-C7A cycloalkyl group; r6a、R6bAnd R6cWherein the halogen is F, Cl, Br or I;
and/or in the preparation method of the compound shown in the formula IV, the alkali R in the preparation method of the compound shown in the formula IVa1、Ra2、Ra3、Ra4And Ra5Wherein the halogen is F, Cl, Br or I; ra1、Ra2、Ra3、Ra4、Ra5And R9In (b), the C1-C10Alkyl is C1-C6An alkyl group.
10. The use of claim 9, wherein the compound of formula IV is prepared by a process wherein the bis-nitrogen ligand is a chiral bis-nitrogen ligand, R3a、R3b、R3c、R3d、R4a、R5a、R4b、R5b、R6a、R6b、R6cAnd R8In (b), the C1-C6The alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, n-pentyl, n-hexyl and various isomers thereof; said C6-C14Aryl substituted C1-C6Alkyl radicalIs benzyl; said C3-C7Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl;
and/or, in the preparation method of the compound shown as the formula IV, the alkali Ra1、Ra2、Ra3、Ra4、Ra5And R9In (b), the C1-C6The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, n-pentyl, n-hexyl or various isomers thereof.
11. The use according to any one of claims 1 to 3, wherein in the preparation method of the compound represented by the formula IV, the molar ratio of the copper catalyst to the dinitrogen ligand is 2:1 to 1: 3;
and/or the dosage of the catalyst is 1-100% of the molar equivalent of the compound shown in the formula II;
and/or the dosage of the dinitrogen ligand is 1-100% of the molar equivalent of the compound shown in the formula II;
and/or the molar ratio of the compound shown in the formula II to the compound shown in the formula III is 1:1-1: 3;
and/or the dosage of the fluorine nitrogen type amination reagent shown in the formula I is 100-400% of the molar equivalent of the compound shown in the formula II;
and/or the dosage of the alkali is 20-200% of the molar equivalent of the compound shown in the formula II.
12. Use according to any one of claims 1 to 3, wherein the compound of formula IV is prepared by a process comprising the steps of: under the protection of gas, mixing the mixture of the copper catalyst, the dinitrogen ligand and the organic solvent with a fluorine nitrogen type amination reagent shown in a formula I, a compound shown in a formula II, a compound shown in a formula III and the alkali, and carrying out the reaction to obtain the compound shown in a formula IV.
13. The application of the fluorine nitrogen type amination reagent shown in the formula I in any one of claims 1 to 10 in the preparation of 2, 2-diarylethylamine compounds, which is characterized by comprising the following steps:
(1) under the protection of gas, under the action of the copper catalyst, the dinitrogen ligand and the alkali, carrying out the reaction shown in the specification on a fluorine nitrogen type amination reagent shown in the formula I, a compound shown in the formula II and a compound shown in the formula III in the organic solvent to obtain a compound shown in the formula IV;
(2) under the protection of gas, in an organic solvent, under the action of a reducing agent, carrying out a reaction of removing a sulfonyl protecting group on the compound shown as the formula IV to prepare a 2, 2-diaryl ethylamine compound shown as the formula V;
wherein R is1、R2、R3And R4As defined in claim 1; r2’Is C1-C10Straight chain alkyl or R1a；R1aDefinition of (A) and R1The same is true.
14. The use according to claim 13,
in the process for the preparation of 2, 2-diarylethylamine compounds represented by formula V, the reaction conditions in step (1) are as defined in any one of claims 1 to 12;
and/or in the preparation method of the 2, 2-diaryl ethyl amine compound shown in the formula V, in the step (2), the organic solvent is an alcohol solvent;
and/or in the preparation method of the 2, 2-diaryl ethyl amine compound shown in the formula V, in the step (2), the reducing agent is magnesium powder;
and/or in the preparation method of the 2, 2-diaryl ethyl amine compound shown in the formula V, in the step (2), the reaction temperature is room temperature;
and/or in the preparation method of the 2, 2-diaryl ethyl amine compound shown in the formula V, in the step (2), the molar ratio of the reducing agent to the compound shown in the formula IV is 2:1-100: 1.
15. The use according to claim 14, wherein in the process for the preparation of 2, 2-diarylethylamine compounds represented by formula V, in step (2), the alcoholic solvent is methanol;
and/or the molar ratio of the reducing agent to the compound shown as the formula IV is 5:1-50: 1.
16. A fluorine-nitrogen type amination reagent shown as formula I is
CN201710283728.3A 2017-04-26 2017-04-26 A kind of fluorine nitrogen type amination reagent, preparation method and application Active CN107011218B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201710283728.3A CN107011218B (en) 2017-04-26 2017-04-26 A kind of fluorine nitrogen type amination reagent, preparation method and application

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201710283728.3A CN107011218B (en) 2017-04-26 2017-04-26 A kind of fluorine nitrogen type amination reagent, preparation method and application

Publications (2)

Publication Number Publication Date
CN107011218A CN107011218A (en) 2017-08-04
CN107011218B true CN107011218B (en) 2018-12-18

Family

ID=59446923

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201710283728.3A Active CN107011218B (en) 2017-04-26 2017-04-26 A kind of fluorine nitrogen type amination reagent, preparation method and application

Country Status (1)

Country Link
CN (1) CN107011218B (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112390735B (en) * 2019-08-16 2021-12-14 中国科学院上海有机化学研究所 Preparation method of allyl nitrile compound

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3623184A1 (en) * 1986-07-10 1988-01-14 Kali Chemie Ag METHOD FOR PRODUCING N-FLUORSULFONAMIDES
CN105152988B (en) * 2015-08-13 2017-06-30 湖北卓熙氟化股份有限公司 One-step method prepares the new technology of N fluoro-diphenyl sulfimides

Also Published As

Publication number Publication date
CN107011218A (en) 2017-08-04

Similar Documents

Publication Publication Date Title
JP5419444B2 (en) Method of binding carboxylic acid and carbon electrophile by CC bond while decarboxylating (decarboxylation)
EP1064243B1 (en) Coupling reactions with palladium catalysts
CN110668913B (en) Preparation method of trifluoroethyl compound
CN108017479B (en) Method for producing aromatic compound
CN105294536B (en) A kind of method for preparing 3- iminoisoindolinone class compounds
US8022255B2 (en) Process for preparing ketones from alpha-oxo carboxylates and aryl bromides
CN110117237B (en) Preparation method of aromatic nitrile or alkenyl nitrile compound
CN110551115B (en) Oxazoline ligand, preparation method and application thereof
CN107011218B (en) A kind of fluorine nitrogen type amination reagent, preparation method and application
CN111440205B (en) Biboric acid diol ester, preparation method thereof, intermediate thereof and application thereof
CN114957103B (en) Axial chiral halogenated biaryl compound and preparation method thereof
WO2016057771A1 (en) Method for coupling a first compound to a second compound
US20180237459A1 (en) Method for coupling an aromatic or vinylic compound to a boron-containing compound
JP2003183187A (en) N-heterocyclic carbene complex and its use
CN102190581A (en) Process for preparing 4'-halogenalkyl-biphenyl-2-carboxylic acids
CN107778182B (en) Method for synthesizing N-alkyl arylamine
JP5685570B2 (en) Asymmetric catalyst used for allylation of N-acylhydrazone
CN107667093A (en) Benzo [h] quinoline part and its complex compound
CN111217841B (en) Nitrogen-phosphine ligand coordination type trifluoromethoxy reagent and preparation method and application thereof
CN114409714B (en) Method for synthesizing 1, 3-disubstituted plane chiral metallocene compound
JP6689750B2 (en) Solid-phase supported ruthenium-diamine complex and method for producing optically active compound
CN107253928A (en) Chiral vicinal diamine derivative and catalytic asymmetric synthesis method thereof
CN111440091B (en) Synthesis method of (E) -2, 2-dimethyl-4-aryl-but-3-enenitrile compound
CN107690436A (en) Method
US20180237363A1 (en) Method for coupling an aromatic compound to an alkyne

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant