CN117303993A - Nickel-catalyzed olefin asymmetric hydroarylation method and application - Google Patents

Nickel-catalyzed olefin asymmetric hydroarylation method and application Download PDF

Info

Publication number
CN117303993A
CN117303993A CN202311234947.4A CN202311234947A CN117303993A CN 117303993 A CN117303993 A CN 117303993A CN 202311234947 A CN202311234947 A CN 202311234947A CN 117303993 A CN117303993 A CN 117303993A
Authority
CN
China
Prior art keywords
migration
ligand
reaction
nickel
equiv
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.)
Pending
Application number
CN202311234947.4A
Other languages
Chinese (zh)
Inventor
朱少林
周钧岍
何玉立
王优
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.)
Nanjing University
Original Assignee
Nanjing University
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 Nanjing University filed Critical Nanjing University
Priority to CN202311234947.4A priority Critical patent/CN117303993A/en
Publication of CN117303993A publication Critical patent/CN117303993A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
    • 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
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
    • B01J31/1805—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms the ligands containing nitrogen
    • B01J31/181—Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine
    • B01J31/1815—Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine with more than one complexing nitrogen atom, e.g. bipyridyl, 2-aminopyridine
    • B01J31/182—Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine with more than one complexing nitrogen atom, e.g. bipyridyl, 2-aminopyridine comprising aliphatic or saturated rings
    • 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
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
    • B01J31/1805—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms the ligands containing nitrogen
    • B01J31/181—Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine
    • B01J31/1825—Ligands comprising condensed ring systems, e.g. acridine, carbazole
    • B01J31/183—Ligands comprising condensed ring systems, e.g. acridine, carbazole with more than one complexing nitrogen atom, e.g. phenanthroline
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
    • C07C303/30—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reactions not involving the formation of esterified sulfo groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C315/00—Preparation of sulfones; Preparation of sulfoxides
    • C07C315/04—Preparation of sulfones; Preparation of sulfoxides by reactions not involving the formation of sulfone or sulfoxide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
    • C07C319/20—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by reactions not involving the formation of sulfide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/80—Complexes comprising metals of Group VIII as the central metal
    • B01J2531/84—Metals of the iron group
    • B01J2531/847—Nickel
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Inorganic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Materials Engineering (AREA)
  • Catalysts (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention discloses a nickel-catalyzed olefin asymmetric hydroarylation method and application, a method for realizing migration asymmetric hydroarylation of nitrogen-containing olefin by combining nickel with two ligand relay combination catalysis and application in preparing Nicotine (S) -Nicotine and a small molecule inhibitor, belonging to the fields of organic chemistry and pharmaceutical chemistry. Under the action of a metal nickel source, chiral ligand, alkali, hydrogen source, additive and the like, the invention enables the nitrogen-containing olefin to react with the aryl bromide compound in an organic solvent, and the chiral alpha- (hetero) aryl substituted amine compound is obtained with excellent regioselectivity and enantioselectivity. The invention uses simple and easily available olefin and commercially available aryl bromide as raw materials, and high-yield metallic nickel as a catalyst, and through the migration ligand with simple combined structure and function and asymmetric coupling, the design and screening of the single chiral ligand with complex structure are avoided, and the dual functions of migration and asymmetric coupling are realized; the reaction condition is mild, the compatibility of functional groups is good, and the operation is simple.

Description

Nickel-catalyzed olefin asymmetric hydroarylation method and application
Technical Field
The method of the invention belongs to the fields of organic chemistry and pharmaceutical chemistry, and uses nickel and double ligand combination catalysis to realize the migration asymmetric hydroarylation reaction of olefin, thus obtaining important chiral alpha- (hetero) aryl substituted amine compounds with wide application range.
Background
Inexpensive metal hydrogen catalysis such as FeH, coH and CuH has begun to be of interest to synthetic chemists over the last two decades. Nickel is cheap and easy to obtain, has various oxidation states, has unique and wide application in the coupling chemistry field, and corresponding NiH catalysis can realize the conversion of various and high added value of the easily obtained olefin, so as to obtain a series of products with high added value.
Chiral α - (hetero) aryl substituted amines and their derivatives are widely found in various natural products, drugs and catalysts. In recent years, asymmetric hydroamination and hydroarylation catalyzed by metal hydrogen, especially CuH or NiH, are two methods for efficiently synthesizing such materials, starting from activated olefin feedstocks.
The reported asymmetric hydroamination catalyzed by metal hydrogen is mainly characterized by the following:
in 2013, buchwald group (S.Zhu, N.Niljianskul, S.L.Buchwald, J.Am.Chem.Soc.2013,135,15746) and Miura group (Y.Miki, K.Hirano, T.Satoh, M.Miura, angew.Chem.Int.Ed.2013,52,10830) achieved copper-hydrogen catalyzed asymmetric hydroalkylamidination of aryl substituted olefins to chiral alkylamines using copper salt/chiral phosphine ligand combinations, respectively.
a.
b.
In 2021, zhu Shaolin the subject group uses N, N-Biox ligands which are simple in structure and easy to synthesize to realize asymmetric hydroaromatic amination, hydroalkylamine and hydroamidation of olefin respectively, and the substrate application range is wide. (L.Meng, J.Yang, M.Duan, Y.Wang, S.Zhu, angew.Chem.Int.Ed.2021,60,23584.)
c.
The reported metal hydrogen catalyzed asymmetric hydroarylation has mainly the following:
2021, zhu Shaolin group (Y.He, H.Song, S.Zhu, nat.Commun.2021,12,638.) and Nevado group (s.cuesta-Galisteo, J).X.Wei, E.Merino, C.Nevado, angew.Chem.Int.Ed.2021,60,1605.) a mild, simple to operate NiH catalyzed highly regio-and enantioselective reductive hydroarylation of N-acyl enamines to obtain structurally diverse chiral benzylamines.
a.
2023, huo Haohua teaches that the subject group employs a halogen radical mediated hydrogen atom transfer strategy to achieve enantioselective asymmetric reductive coupling of alpha-amino acid derivatives with aryl bromides.
While the above strategy can achieve specific chiral α - (hetero) aryl substituted amines, a disadvantage is the need to prepare activated functionalized olefins. It is further desirable if the reaction feed is a commercially available or more readily prepared olefin.
The Zhu Shaolin subject group of Nanjing university is long-term focused on nickel-hydrogen catalytic chemistry, realizes (migration) asymmetric hydrogen functionalization of series olefins, selectively introduces functional groups such as aryl, alkyl and the like, and can regulate the enantioselectivity of the reaction through chiral ligands. The ligand relay strategy-assisted nickel-hydrogen catalyzed asymmetric hydrogen arylation method developed by the invention provides a brand new and high-efficiency method for synthesizing chiral amine, and is successfully applied to the synthesis of Nicotine (S) -Nicotine and a small molecule inhibitor MSC 2530818.
Disclosure of Invention
The invention aims to provide a nickel-catalyzed olefin asymmetric hydrogen arylation method and application thereof, which are novel synthesis methods of chiral amine compounds, wherein the method has the advantages of cheap and easily obtained raw materials, simple and convenient operation, wide substrate range, good functional group compatibility, good yield, excellent region and enantioselectivity, and can be applied to synthesis of Nicotine (S) -Nicotine and a small molecule inhibitor MSC 2530818. The invention uses simple and easily available olefin and commercially available aryl bromide as raw materials, and high-yield metallic nickel as a catalyst, and through the migration ligand with simple combined structure and function and asymmetric coupling, the design and screening of the single chiral ligand with complex structure are avoided, and the dual functions of migration and asymmetric coupling are realized; the reaction condition is mild, the compatibility of functional groups is good, and the operation is simple.
One of the above purposes of the present invention is achieved by the following technical scheme: a nickel-catalyzed asymmetric migration arylation process for olefins comprising the steps of: under the protection of inert gas, metallic nickel catalyst, migration ligand L, chiral ligand L, alkali, hydrogen source and additive are dissolved in organic solvent, then olefine is added(hetero) aryl compound (Het) Ar-Br to obtain a reaction mixture, and performing post-treatment and purification to obtain a target enantiomerically enriched alpha-aryl substituted chiral amine product;
wherein the migration ligand L isOne of the following;
chiral ligand L isOne of the following;
R 1 the substituent in the substrate is nitrogen-containing chain olefin, and is any one of alkyl and aryl;
R 2 is any one of hydrogen atom and alkyl;
when Ar is aryl, the substituent on the aryl is any one of chlorine atom, (hetero) aryl, (fluorine-containing) alkyl, (sulfur) ether, ketone, aldehyde, ester, amide and cyano; ar is any one of pyridine and pyrimidine when heteroaryl, and substituent groups on the heteroaryl are any one of chlorine atoms, fluorine atoms, (fluorine-containing) alkyl and alkoxy;
the solvent is one or more of toluene, N-methylpyrrolidone, N-dimethylformamide, N-dimethylacetamide, ethylene glycol dimethyl ether and diethyl ether;
Wherein preparation scheme 1:
or (b)
Preparation route 2:
or (b)
Preferably, the method comprises the steps of,
preparation route 1:
or (b)
Preparation of R in scheme 1 1 Is substituent groups in the nitrogenous chain olefin substrate, is any one of alkyl and aryl,
R 2 is any one of a hydrogen atom and an alkyl group,
the nickel catalyst is nickel (II) nitrate hexahydrate Ni (NO) 3 ) 2 ·6H 2 O, migration ligand L isChiral ligand L1>ent-L1 is>The hydrogen source is dimethoxy methyl silane (MeO) 2 MeSiH, sodium carbonate Na as base 2 CO 3 The additive is sodium iodide NaI, and the solvent is toluene and N-methylpyrrolidone;
preparation route 2:
or (b)
The nickel-based catalyst in preparation scheme 2 is nickel (II) nitrate hexahydrate Ni (NO 3 ) 2 ·6H 2 O, migration ligand L isChiral ligand L2>ent-L2 is>The hydrogen source is dimethoxy methyl silane (MeO) 2 MeSiH or diethoxymethylsilane (EtO) 2 One of MeSiH, the alkali is sodium carbonate K 2 CO 3 The additive is sodium iodide NaI, and the solvent is multiple of N, N-dimethylformamide, N-dimethylacetamide, ethylene glycol dimethyl ether and diethyl ether.
Preferably, the asymmetric migration arylation method for preparing the nickel-catalyzed olefin in the route 1 comprises the steps of reacting the olefin and aryl bromide for 1-24 hours at 25 ℃ in a solvent in the presence of a metallic nickel catalyst, chiral ligand L, migration ligand L, hydrogen source, additive and alkali; the molar ratio of the metallic nickel catalyst, the migration ligand L, the chiral ligand L1 or ent-L1 to the hydrogen source, the additive, the alkali, the olefin and the aryl bromine is (0-0.01): (0-0.012): (0-0.001): (0.2-0.6): (0-0.1): (0.2-0.4): (0.2-0.3): (0.2-0.3); the reaction time was measured until the reaction was complete.
Preferably, the asymmetric migration arylation method for preparing the nickel-catalyzed olefin in the scheme 2 comprises the steps of reacting the olefin and aryl bromide for 1-24 hours at 25 ℃ in a solvent in the presence of a metallic nickel catalyst, chiral ligand L, migration ligand L, hydrogen source, additive and alkali; the molar ratio of the metallic nickel catalyst, the migration ligand L, the chiral ligand L, the hydrogen source, the additive, the alkali, the olefin and the aryl bromide is (0-0.02): (0-0.024): (0-0.002): (0.2-0.6): (0-0.4): (0.2-0.4): (0.2-0.3): (0.2-0.3); the reaction time was measured until the reaction was complete.
Preferably, the metallic nickel catalyst is a metallic nickel salt, the hydrogen source is silicon hydrogen or boron hydrogen pinacol, and the additive is an inorganic salt of iodine.
The invention realizes the application of the nickel catalytic olefin asymmetric migration arylation method in preparing Nicotine (S) -Nicotine according to the following another technical scheme, wherein the specific preparation method has the following reaction formula:
firstly, adding nickel (II) nitrate hexahydrate and chiral ligand ent-L2 in a reaction tube under nitrogen atmosphere, and then adding dry N, N-dimethylformamide and diethyl ether solution containing migration ligand L; stirring at 25 ℃ for 5 minutes, adding the olefin, the heteroaryl bromide and the diethoxymethylsilane, covering a cover of a reaction tube, and reacting at 25 ℃ for 24 hours; after the reaction is finished, concentrating under reduced pressure to remove a reaction solvent, and separating and purifying by column chromatography to obtain a pyrrolidine derivative;
Secondly, dissolving lithium aluminum hydride in tetrahydrofuran under the nitrogen atmosphere, and then adding pyrrolidine derivatives into the solution at 0 ℃; reflux-reacting for six hours, and then quenching with water at 0 ℃; the mixture was filtered through celite, washed with dichloromethane, and rotary distilled to give crude material; subsequently, the crude material is dissolved in methanol, and palladium carbon and sodium hydroxide are added; after the air was vented, hydrogen was filled into the flask via a balloon; the reaction is stirred for 4 hours at normal temperature; after the reaction was completed, the mixture was filtered through celite and concentrated; the crude product is purified by column chromatography to obtain the target product of Nicotine (S) -Nicotine.
The invention realizes the application of the asymmetric migration arylation method of the nickel catalytic olefin in preparing the inhibitor MSC2530818 by adopting the following another technical scheme, wherein the specific preparation method has the following reaction formula:
in the first step, nickel (II) nitrate hexahydrate and chiral ligand ent-L2 are added into a reaction tube under the nitrogen atmosphere * Carbonic acid, carbonic acidPotassium, sodium iodide, then dried N, N-dimethylacetamide, ethylene glycol dimethyl ether solution containing migration ligand L; stirring at 25 ℃ for 5 minutes, adding the olefin, the aryl bromide and the diethoxymethylsilane, covering a cover of a reaction tube, and reacting at 25 ℃ for 24 hours; after the reaction is finished, concentrating under reduced pressure to remove a reaction solvent, and separating and purifying by column chromatography to obtain a pyrrolidine derivative;
In a second step, the pyrrolidine derivative is added to dry dichloromethane under nitrogen atmosphere, placed in an ice-water bath, BBr is carefully added at 0 ℃ 3 The method comprises the steps of carrying out a first treatment on the surface of the The reaction was stirred at room temperature for 5h; excess BBr 3 Quenching with methanol; subsequently concentrating the reaction mixture to give a crude product; purifying the crude product by column chromatography to obtain a target compound; next, the resulting product was dissolved in N, N-dimethylformamide, followed by addition of 3-methyl-1H-pyrazolo [3,4-B ]]Pyridine-5-carboxylic acid, N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole; after stirring for a few minutes, N-methylmorpholine was added at room temperature and the reaction mixture was stirred at room temperature overnight; after the reaction was completed, the reaction solution was diluted with ethyl acetate, washed with water and brine and dried over anhydrous sodium sulfate; removing the solvent under reduced pressure to obtain a crude product; purifying the crude product by column chromatography to obtain the target product.
Preferably, the metal nickel salt is any one of nickel iodide, nickel iodide hydrate, nickel chloride hexahydrate, nickel chloride ethylene glycol dimethyl ether complex, nickel bromide trihydrate, nickel bromide diethylene glycol dimethyl ether complex, nickel bromide ethylene glycol dimethyl ether complex, bis- (1, 5-cyclooctadiene) nickel complex, nickel nitrate hexahydrate, nickel perchlorate hexahydrate, and nickel tetrafluoroborate hexahydrate;
The hydrogen source is any one of Polymethylhydrosiloxane (PMHS), trimethoxysilane, triethoxysilane, dimethoxymethylsilane (DMMS), diethoxymethylsilane (DEMS), phenylsilane, diphenylsilane, triphenylsilane, triethylsilane, borane dimethyl sulfide and pinacol borane;
the additive is one or more of lithium chloride, sodium chloride, lithium bromide, potassium bromide, magnesium bromide hydrate, lithium iodide, sodium iodide, zinc iodide, magnesium iodide, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, sodium acetate, potassium acetate, methanol, isopropanol, tertiary butanol, hexafluoroisopropanol, benzyl alcohol and acetonitrile;
the solvent is one or more of tetrahydrofuran, 1, 4-dioxane, diethyl ether, ethylene glycol dimethyl ether, diethylene glycol diethyl ether, toluene, xylene, trimethylbenzene, benzotrifluoride, 1, 2-dichloroethane, chloroform, acetonitrile, N-dimethylformamide, N-dimethylacetamide, N-dimethylpropenyl urea, N-methylpyrrolidone, dimethyl sulfoxide, methanol, ethanol and water.
The cation of the alkali is Li + 、Na + 、K + 、Cs + And Mg (magnesium) 2+ Any one of anions is [ CO ] 3 ] 2- 、[HCO 3 ] - 、[PO 4 ] 3- 、[HPO 4 ] 2- 、[H 2 PO 4 ] - 、F - 、[OH] - 、[CH 3 COO] - 、[OMe] - And [ O ] t Bu] - Any one of them.
The beneficial effects are that:
1. the reaction temperature is 25 ℃, the reaction condition is mild, the reaction effect is good, and the product can be obtained with good yield, excellent regioselectivity and enantioselectivity.
2. The olefin is low in price, commercially available, or simple in synthetic route.
3. The application of the dual ligand relay strategy nickel catalytic olefin asymmetric hydroarylation method in preparing Nicotine (S) -Nicotine and inhibitor MSC2530818 is simple and convenient in synthesis steps, and the precursor of the Nicotine (S) -Nicotine and inhibitor MSC2530818 is obtained in good yield, excellent area and enantioselectivity by using a cheap and easily available metal nickel catalyst.
4. The chiral ligand and the migration ligand function: ideally, the migration ligand controls chain walking, the chiral ligand controls asymmetric coupling, and asymmetric migration arylation of the unactivated distal olefin is achieved through a ligand relay strategy, thereby obtaining chiral alpha- (hetero) aryl substituted amine.
5. Comparative example 1 it can be seen that in the reaction of example 1, the ligand was migratedInstead ofThe results show that: the regioselectivity is improved but the yield and enantioselectivity are significantly reduced.
6. Comparative example 2 it can be seen that in the reaction of example 1, the results without additive NaI show: enantioselectivity is improved, but regioselectivity and yield are significantly reduced.
7. Comparative example 3 it can be seen that in the reaction of example 1, the aryl iodide substituted for the aryl bromide results showed that: the enantioselectivity remains substantially unchanged, but the regioselectivity is reduced and the yield is significantly reduced.
8. Comparative example 4 it can be seen that in the reaction of example 1, the potassium carbonate instead of sodium carbonate results show: the regioselectivity and yield remained essentially unchanged, but the enantioselectivity was significantly reduced.
Drawings
The invention is further described below with reference to the accompanying drawings.
FIG. 1 is an H spectrum of the product of example 1;
FIG. 2 is a C spectrum of the product of example 1;
FIG. 3 is an H spectrum of the product of example 4;
FIG. 4 is a C spectrum of the product of example 4;
FIG. 5 is an H spectrum of the product of example 7;
FIG. 6 is a C spectrum of the product of example 7;
FIG. 7 is an H spectrum of the product of example 15;
FIG. 8 is a C spectrum of the product of example 15;
FIG. 9 is an H spectrum of the product of example 16;
FIG. 10 is a C spectrum of the product of example 16;
FIG. 11 is an H spectrum of the product of example 22;
FIG. 12 is a C spectrum of the product of example 22;
FIG. 13 is an H spectrum of the product of example 24;
FIG. 14 is a C spectrum of the product of example 24;
FIG. 15 is an H spectrum of the product of example 29;
FIG. 16 is a C spectrum of the product of example 29;
FIG. 17 is an H spectrum of the product of example 30;
FIG. 18 is a C-spectrum of the product of example 30.
Detailed Description
A further understanding of the nature and advantages of the present invention may be realized by the following detailed description. The examples provided are merely illustrative of the methods of the present invention and are not intended to limit the remainder of the disclosure in any way whatsoever.
In the following examples, ni (NO 3 ) 2 ·6H 2 O refers to nickel (II) nitrate hexahydrate, (MeO) 2 MeSiH refers to Dimethoxymethylsilane (DMMS), (EtO) 2 MeSiH refers to Diethoxymethylsilane (DEMS), tol refers to toluene, NMP refers to N-methylpyrrolidone, DMA refers to N, N-dimethylacetamide, DMF refers to N, N-dimethylformamide, DME refers to ethylene glycol dimethyl ether, et 2 O means diethyl ether, equiv means equivalent number, migration ligand L meansChiral ligand L * Is that One of them.
Example 1
Nickel (II) nitrate hexahydrate (2.9 mg,5.0 mol%) and chiral ligand L1 were added to a reaction tube under a nitrogen atmosphere * (5.8 mg,6.0 mol%), sodium carbonate (42.4 mg,2.0 equiv), sodium iodide (15.0 mg,0.5 equiv), and then dried 0.25mL of N-methylpyrrolidone, 0.75mL of toluene solution containing migration ligand L (toluene solution preparation method of migration ligand L: 11.8mg of migration ligand L was dissolved in 30mL of toluene) were added. After stirring at 25℃for 5 minutes, the above-mentioned olefin (35.0 mg,0.20mmol,1.0 equiv), aryl bromide (64.5 mg,0.30mmol,1.5 equiv) and dimethoxymethylsilane (74. Mu.L, 0.60mmol,3.0 equiv) were added, the lid of the reaction tube was closed, and the reaction was carried out at 25℃for 24 hours. After the completion of the reaction, the reaction solvent was removed by concentration under reduced pressure, and the desired product (44.1 mg, white solid, yield: 72%) was obtained by separation and purification by column chromatography, and the desired product was measured for rr (97:3) and ee (92%). 1 H NMR(500MHz,CDCl 3 )δ8.01(d,J＝8.3Hz,2H),7.81–7.70(m,2H),7.58–7.46(m,1H),7.48–7.37(m,4H),6.39(d,J＝7.6Hz,1H),5.21(q,J＝7.6Hz,1H),3.90(s,3H),2.03–1.73(m,2H),1.55–1.31(m,2H),0.96(t,J＝7.3Hz,3H)； 13 C NMR(126MHz,CDCl 3 )δ167.0,147.9,134.5,131.8,130.2,129.4,128.8,127.0,126.7,53.7,52.2,38.5,19.6,14.0；HRMS(ESI)calcd.for C 19 H 21 NO 3 Na[M+Na] + m/z 334.1413,found 334.1414；IR(neat,cm -1 )3356,2920,1632,1282,709；m.p.131.1–132.4℃；[α] D 17 ＝+2.0(c＝0.51,CHCl 3 )；HPLC analysisAD-H column,20％ i PrOH in hexane,0.8mL/min,254nm UV detector,t R (major)＝11.2min,t R (minor)＝16.9min.
Example 2
Nickel (II) nitrate hexahydrate (2.9 mg,5.0 mol%) and chiral ligand L1 were added to a reaction tube under a nitrogen atmosphere * (5.8 mg,6.0 mol%), sodium carbonate (42.4 mg,2.0 equiv), sodium iodide (15.0 mg,0.5 equiv), followed by the addition of dried 0.25mL of N-methylpyrrolidone0.75mL of a toluene solution containing migration ligand L (toluene solution preparation method of migration ligand L: 11.8mg of migration ligand L is dissolved in 30mL of toluene). After stirring at 25℃for 5 minutes, the above-mentioned olefin (35.0 mg,0.20mmol,1.0 equiv), aryl bromide (67.5 mg,0.30mmol,1.5 equiv) and dimethoxymethylsilane (74. Mu.L, 0.60mmol,3.0 equiv) were added, the lid of the reaction tube was closed, and the reaction was carried out at 25℃for 24 hours. After the completion of the reaction, the reaction solvent was removed by concentration under reduced pressure, and the desired product (42.8 mg, white solid, yield 67%) was obtained by column chromatography separation and purification, and the desired product was measured for rr (95:5) and ee (90%). 1 H NMR(500MHz,CDCl 3 )δ7.77(d,J＝7.5Hz,2H),7.63–7.54(m,2H),7.52–7.38(m,5H),6.56(d,J＝7.6Hz,1H),5.19(q,J＝7.5Hz,1H),1.93–1.73(m,2H),1.51–1.25(m,2H),0.95(t,J＝7.4Hz,3H)； 13 C NMR(126MHz,CDCl 3 )δ167.1,146.8,134.4,131.8,129.6(q,J＝32.7Hz),128.7,127.1,127.0,125.7(q,J＝3.7Hz),124.2(q,J＝272.2Hz),53.6,38.5,19.6,13.9； 19 F NMR(471MHz,CDCl 3 )δ–62.5；；HRMS(ESI)calcd.for C 18 H 18 F 3 NONa[M+Na] + m/z 344.1232,found 344.1236；IR(neat,cm -1 )3322,1633,1330,1121,760；m.p.148.9–150.1℃；[α] D 17 ＝–3.5(c＝1.44,CHCl 3 )；HPLC analysisAD-H column,20％ i PrOH in hexane,0.8mL/min,220nm UV detector,t R (major)＝6.0min,t R (minor)＝7.6min.
Example 3
Nickel (II) nitrate hexahydrate (2.9 mg,5.0 mol%) and chiral ligand L1 were added to a reaction tube under a nitrogen atmosphere * (5.8 mg,6.0 mol%), sodium carbonate (42.4 mg,2.0 equiv), sodium iodide (15.0 mg,0.5 equiv), then dried 0.25mL of N-methylpyrrolidone, 0.75mL of toluene solution containing migration ligand L (toluene solution of migration ligand L) The liquid preparation method comprises the following steps: 11.8mg of migration ligand L was dissolved in 30mL of toluene). After stirring at 25℃for 5 minutes, the above-mentioned olefin (35.0 mg,0.20mmol,1.0 equiv), aryl bromide (87.9 mg,0.30mmol,1.5 equiv) and dimethoxymethylsilane (74. Mu.L, 0.60mmol,3.0 equiv) were added, the lid of the reaction tube was closed, and the reaction was carried out at 25℃for 24 hours. After the reaction, the reaction solvent is removed by decompression concentration, the target product (41.2 mg, white solid, yield 53%) is obtained by column chromatography separation and purification, and the rr value of the target product is measured>99:1) and ee (94%). 1 H NMR(500MHz,CDCl 3 )δ7.82–7.70(m,5H),7.61–7.48(m,1H),7.46–7.38(m,2H),6.63(d,J＝7.5Hz,1H),5.23(q,J＝7.5Hz,1H),1.97–1.76(m,2H),1.57–1.29(m,2H),0.97(t,J＝7.4Hz,3H)； 13 C NMR(126MHz,CDCl 3 )δ167.2,145.7,134.0,132.1,132.0(q,J＝34.0Hz),128.9,127.1,126.9(d,J＝2.5Hz),123.4(q,J＝273.4Hz),121.5(p,J＝3.8Hz),53.5,38.5,19.7,13.9； 19 F NMR(471MHz,CDCl 3 )δ–62.8；HRMS(ESI)calcd.for C 19 H 17 F 6 NONa[M+Na] + m/z 412.1106,found 412.1108；IR(neat,cm -1 )3323,1264,904,724；m.p.135.9–136.0℃；[α] D 17 ＝–19.0(c＝1.16,CHCl 3 )；HPLC analysisAD-H column,5％ i PrOH in hexane,0.8mL/min,220nm UV detector,t R (major)＝7.8min,t R (minor)＝8.7min.
Example 4
Nickel (II) nitrate hexahydrate (2.9 mg,5.0 mol%) and chiral ligand L1 were added to a reaction tube under a nitrogen atmosphere * (5.8 mg,6.0 mol%), sodium carbonate (42.4 mg,2.0 equiv), sodium iodide (15.0 mg,0.5 equiv), and then dried 0.25mL of N-methylpyrrolidone, 0.75mL of toluene solution containing migration ligand L (toluene solution preparation method of migration ligand L: 11.8mg of migration ligand L was dissolved in 30mL of toluene) were added. 25After stirring at a temperature of 5 minutes, the above-mentioned olefin (35.0 mg,0.20mmol,1.0 equiv), aryl bromide (54.3 mg,0.30mmol,1.5 equiv) and dimethoxymethylsilane (74. Mu.L, 0.60mmol,3.0 equiv) were added, the lid of the reaction tube was closed, and the reaction was carried out at 25℃for 24 hours. After the completion of the reaction, the reaction solvent was removed by concentration under reduced pressure, and the desired product (29.1 mg, white solid, yield 52%) was obtained by column chromatography separation and purification, and the desired product was measured for rr (95:5) and ee (95%). 1 H NMR(500MHz,CDCl 3 )δ7.79–7.74(m,2H),7.63–7.63(m,2H),7.55–7.48(m,1H),7.48–7.39(m,4H),6.45(d,J＝7.6Hz,1H),5.16(q,J＝7.5Hz,1H),1.93–1.78(m,2H),1.50–1.31(m,2H),0.96(t,J＝7.3Hz,3H)； 13 C NMR(126MHz,CDCl 3 )δ167.1,148.3,134.2,132.6,131.9,128.8,127.4,127.1,118.9,111.3,53.7,38.3,19.6,13.9；HRMS(ESI)calcd.for C 18 H 18 N 2 ONa[M+Na] + m/z 301.1311,found 301.1309；IR(neat,cm -1 )3019,2229,1214,744；m.p.148.0–149.2℃；[α] D 17 ＝–16.2(c＝0.58,CHCl 3 )；HPLC analysis AD-H column,20％ i PrOH in hexane,0.8mL/min,220nm UV detector,t R (major)＝10.7min,t R (minor)＝14.9min.
Example 5
Nickel (II) nitrate hexahydrate (2.9 mg,5.0 mol%) and chiral ligand L1 were added to a reaction tube under a nitrogen atmosphere * (5.8 mg,6.0 mol%), sodium carbonate (42.4 mg,2.0 equiv), sodium iodide (15.0 mg,0.5 equiv), and then dried 0.25mL of N-methylpyrrolidone, 0.75mL of toluene solution containing migration ligand L (toluene solution preparation method of migration ligand L: 11.8mg of migration ligand L was dissolved in 30mL of toluene) were added. After stirring at 25℃for 5 minutes, the above-mentioned olefin (35.0 mg,0.20mmol,1.0 equiv), aryl bromide (54.3 mg,0.30mmol,1.5 equiv) and dimethoxymethylsilane (74. Mu.L, 0.60mmol,3.0 e) were addedquiv), the reaction tube was capped and reacted at 25℃for 24 hours. After the completion of the reaction, the reaction solvent was removed by concentration under reduced pressure, and the desired product (31.9 mg, white solid, yield: 57%) was obtained by column chromatography separation and purification, and the desired product was measured for rr (96:4) and ee (90%). 1 H NMR(500MHz,CDCl 3 )δ7.79–7.75(m,2H),7.64(s,1H),7.60(d,J＝8.1Hz,1H),7.56–7.49(m,2H),7.48–7.41(m,3H),6.46(d,J＝7.7Hz,1H),5.15(q,J＝7.5Hz,1H),1.95–1.80(m,2H),1.51–1.30(m,2H),0.97(t,J＝7.3Hz,3H)； 13 C NMR(126MHz,CDCl 3 )δ167.1,144.5,134.1,132.0,131.6,131.1,130.1,129.6,128.8,127.1,119.0,112.9,53.4,38.4,19.6,13.9；HRMS(ESI)calcd.for C 18 H 18 N 2 ONa[M+Na] + m/z 301.1311,found 301.1310；IR(neat,cm -1 )3019,1634,1214,745；m.p.120.6–121.7℃；[α] D 17 ＝–10.0(c＝0.34,CHCl 3 )；HPLC analysisAD-H column,20％ i PrOH in hexane,0.8mL/min,220nm UV detector,t R (major)＝7.2min,t R (minor)＝9.8min.
Example 6
Nickel (II) nitrate hexahydrate (2.9 mg,5.0 mol%) and chiral ligand L1 were added to a reaction tube under a nitrogen atmosphere * (5.8 mg,6.0 mol%), sodium carbonate (42.4 mg,2.0 equiv), sodium iodide (15.0 mg,0.5 equiv), and then dried 0.25mL of N-methylpyrrolidone, 0.75mL of toluene solution containing migration ligand L (toluene solution preparation method of migration ligand L: 11.8mg of migration ligand L was dissolved in 30mL of toluene) were added. After stirring at 25℃for 5 minutes, the above-mentioned olefin (35.0 mg,0.20mmol,1.0 equiv), aryl bromide (70.2 mg,0.30mmol,1.5 equiv) and dimethoxymethylsilane (74. Mu.L, 0.60mmol,3.0 equiv) were added, the lid of the reaction tube was closed, and the reaction was carried out at 25℃for 24 hours. After the reaction, the reaction solvent is removed by decompression concentration, and the column chromatography is separated Purification gave the desired product (32.5 mg, white solid, yield 50%) which was measured for rr (97:3) and ee (93%). 1 H NMR(500MHz,CDCl 3 )δ7.97–7.91(m,1H),7.87–7.75(m,3H),7.70–7.63(m,1H),7.57–7.46(m,2H),7.45–7.38(m,2H),6.65(d,J＝7.7Hz,1H),5.22(q,J＝7.6Hz,1H),3.03(s,3H),1.96–1.78(m,2H),1.59–1.29(m,2H),0.94(t,J＝7.3Hz,3H)； 13 C NMR(126MHz,CDCl 3 )δ167.1,145.1,141.0,134.2,132.6,131.9,129.8,128.8,127.1,126.3,125.0,53.6,44.6,38.6,19.7,13.9；HRMS(ESI)calcd.for C 18 H 21 NO 3 SNa[M+Na] + m/z 354.1134,found 354.1132；IR(neat,cm -1 )3329,1650,1214,743；m.p.179.1–180.6℃；[α] D 17 ＝–7.6(c＝0.55,CHCl 3 )；HPLC analysisAD-H column,20％ i PrOH in hexane,0.8mL/min,220nm UV detector,t R (major)＝9.4min,t R (minor)＝13.0min.
Example 7
Nickel (II) nitrate hexahydrate (2.9 mg,5.0 mol%) and chiral ligand L1 were added to a reaction tube under a nitrogen atmosphere * (5.8 mg,6.0 mol%), sodium carbonate (42.4 mg,2.0 equiv), sodium iodide (15.0 mg,0.5 equiv), and then dried 0.25mL of N-methylpyrrolidone, 0.75mL of toluene solution containing migration ligand L (toluene solution preparation method of migration ligand L: 11.8mg of migration ligand L was dissolved in 30mL of toluene) were added. After stirring at 25℃for 5 minutes, the above-mentioned olefin (35.0 mg,0.20mmol,1.0 equiv), aryl bromide (59.4 mg,0.30mmol,1.5 equiv) and dimethoxymethylsilane (74. Mu.L, 0.60mmol,3.0 equiv) were added, the lid of the reaction tube was closed, and the reaction was carried out at 25℃for 24 hours. After the completion of the reaction, the reaction solvent was removed by concentration under reduced pressure, and the desired product (34.4 mg, white solid, yield 58%) was obtained by column chromatography separation and purification, and the desired product was measured for rr value (94:6) and ee value (92%). 1 H NMR(500MHz,CDCl 3 )δ7.98–7.89(m,2H),7.82–7.73(m,2H),7.52–7.45(m,1H),7.45–7.36(m,4H),6.55(d,J＝7.6Hz,1H),5.19(q,J＝7.6Hz,1H),2.57(s,3H),1.96–1.80(m,2H),1.52–1.29(m,2H),0.95(t,J＝7.4Hz,3H)； 13 C NMR(126MHz,CDCl 3 )δ197.8,167.0,148.2,136.4,134.5,131.8,129.0,128.8,127.1,126.9,53.7,38.5,26.8,19.6,13.9；HRMS(ESI)calcd.for C 19 H 21 NO 2 Na[M+Na] + m/z 318.1464,found 318.1466；IR(neat,cm -1 )3019,1633,1214,745；m.p.157.2–158.6℃；[α] D 17 ＝+5.5(c＝0.62,CHCl 3 )；HPLC analysisAD-H column,20％ i PrOH in hexane,0.8mL/min,220nm UV detector,t R (major)＝10.5min,t R (minor)＝18.2min.
Example 8
Nickel (II) nitrate hexahydrate (2.9 mg,5.0 mol%) and chiral ligand L1 were added to a reaction tube under a nitrogen atmosphere * (5.8 mg,6.0 mol%), sodium carbonate (42.4 mg,2.0 equiv), sodium iodide (15.0 mg,0.5 equiv), and then dried 0.25mL of N-methylpyrrolidone, 0.75mL of toluene solution containing migration ligand L (toluene solution preparation method of migration ligand L: 11.8mg of migration ligand L was dissolved in 30mL of toluene) were added. After stirring at 25℃for 5 minutes, the above-mentioned olefin (35.0 mg,0.20mmol,1.0 equiv), aryl bromide (67.5 mg,0.30mmol,1.5 equiv) and dimethoxymethylsilane (74. Mu.L, 0.60mmol,3.0 equiv) were added, the lid of the reaction tube was closed, and the reaction was carried out at 25℃for 24 hours. After the completion of the reaction, the reaction solvent was removed by concentration under reduced pressure, and the desired product (32.2 mg, white solid, yield 50%) was obtained by column chromatography separation and purification, and the desired product was measured for rr (95:5) and ee (92%). 1 H NMR(500MHz,CDCl 3 )δ8.00(d,J＝8.4Hz,2H),7.84–7.70(m,2H),7.52–7.38(m,5H),6.35(d,J＝7.8Hz,1H),5.22(q,J＝7.5Hz,1H),2.74–2.61(m,1H),2.02–1.81(m,2H),1.53–1.32(m,2H),1.25–1.13(m,2H),1.09–1.00(m,2H),0.97(t,J＝7.4Hz,3H)； 13 C NMR(126MHz,CDCl 3 )δ200.3,166.9,147.6,137.3,131.8,128.8,128.7,127.0,126.8,53.7,38.5,19.7,17.3,14.0,11.7；HRMS(ESI)calcd.for C 21 H 23 NO 2 Na[M+Na] + m/z 344.1621,found 344.1626；IR(neat,cm -1 )3018,1633,1215,747；m.p.183.3–184.7℃；[α] D 17 ＝+4.9(c＝0.57,CHCl 3 )；HPLC analysisAD-H column,20％ i PrOH in hexane,0.8mL/min,254nm UV detector,t R (major)＝13.9min,t R (minor)＝24.2min.
Example 9
Nickel (II) nitrate hexahydrate (2.9 mg,5.0 mol%) and chiral ligand L1 were added to a reaction tube under a nitrogen atmosphere * (5.8 mg,6.0 mol%), sodium carbonate (42.4 mg,2.0 equiv), sodium iodide (15.0 mg,0.5 equiv), and then dried 0.25mL of N-methylpyrrolidone, 0.75mL of toluene solution containing migration ligand L (toluene solution preparation method of migration ligand L: 11.8mg of migration ligand L was dissolved in 30mL of toluene) were added. After stirring at 25℃for 5 minutes, the above-mentioned olefin (35.0 mg,0.20mmol,1.0 equiv), aryl bromide (55.5 mg,0.30mmol,1.5 equiv) and dimethoxymethylsilane (74. Mu.L, 0.60mmol,3.0 equiv) were added, the lid of the reaction tube was closed, and the reaction was carried out at 25℃for 24 hours. After the completion of the reaction, the reaction solvent was removed by concentration under reduced pressure, and the desired product (37.4 mg, white solid, yield 66%) was obtained by column chromatography separation and purification, and the desired product was measured for rr value (97:3) and ee value (89%). 1 H NMR(500MHz,CDCl 3 )δ9.99(s,1H),7.86(d,J＝8.3Hz,2H),7.81–7.74(m,2H),7.55–7.48(m,3H),7.48–7.40(m,2H),6.39(d,J＝7.7Hz,1H),5.22(q,J＝7.6Hz,1H),2.00–1.80(m,2H),1.51–1.33(m,2H),0.97(t,J＝7.3Hz,3H)； 13 C NMR(126MHz,CDCl 3 )δ192.0,167.0,149.8,135.7,134.4,131.9,130.4,128.8,127.3,127.1,53.8,38.5,19.7,14.0；HRMS(ESI)calcd.for C 18 H 19 NO 2 Na[M+Na] + m/z 304.1308,found 304.1305；IR(neat,cm -1 )3355,2921,1635,1264,729；[α] D 17 ＝–1.6(c＝0.37,CHCl 3 )；89％ee；
m.p.125.3–126.1℃；HPLC analysisAD-H column,20％ i PrOH in hexane,0.8mL/min,220nm UV detector,t R (major)＝10.6min,t R (minor)＝16.3min.
Example 10
Nickel (II) nitrate hexahydrate (2.9 mg,5.0 mol%) and chiral ligand L1 were added to a reaction tube under a nitrogen atmosphere * (5.8 mg,6.0 mol%), sodium carbonate (42.4 mg,2.0 equiv), sodium iodide (15.0 mg,0.5 equiv), and then dried 0.25mL of N-methylpyrrolidone, 0.75mL of toluene solution containing migration ligand L (toluene solution preparation method of migration ligand L: 11.8mg of migration ligand L was dissolved in 30mL of toluene) were added. After stirring at 25℃for 5 minutes, the above-mentioned olefin (35.0 mg,0.20mmol,1.0 equiv), aryl bromide (57.0 mg,0.30mmol,1.5 equiv) and dimethoxymethylsilane (74. Mu.L, 0.60mmol,3.0 equiv) were added, the lid of the reaction tube was closed, and the reaction was carried out at 25℃for 24 hours. After the reaction, the reaction solvent is removed by decompression concentration, the target product (41.1 mg, white solid, yield 72%) is obtained by column chromatography separation and purification, and the rr value of the target product is measured >99:1) and ee (89%). 1 H NMR(500MHz,CDCl 3 )δ7.80–7.72(m,2H),7.56–7.46(m,1H),7.46–7.39(m,2H),7.34–7.26(m,4H),6.29(d,J＝7.7Hz,1H),5.14(q,J＝7.6Hz,1H),2.01–1.77(m,2H),1.50–1.29(m,2H),0.96(t,J＝7.3Hz,3H)； 13 C NMR(126MHz,CDCl 3 )δ166.9,141.2,134.6,133.2,131.7,129.0,128.8,128.1,127.0,53.3,38.5,19.7,14.0；HRMS(ESI)calcd.for C 17 H 18 ClNONa[M+Na] + m/z 310.0969,found 310.0967；IR(neat,cm -1 )3326,2926,1632,1214,744；m.p.141.5–142.6℃；[α] D 17 ＝+1.6(c＝0.37,CHCl 3 )；89％ee；HPLC analysis AD-H column,20％ i PrOH in hexane,0.8mL/min,220nm UV detector,t R (major)＝7.1min,t R (minor)＝9.5min.
Example 11
Nickel (II) nitrate hexahydrate (2.9 mg,5.0 mol%) and chiral ligand L1 were added to a reaction tube under a nitrogen atmosphere * (5.8 mg,6.0 mol%), sodium carbonate (42.4 mg,2.0 equiv), sodium iodide (15.0 mg,0.5 equiv), and then dried 0.25mL of N-methylpyrrolidone, 0.75mL of toluene solution containing migration ligand L (toluene solution preparation method of migration ligand L: 11.8mg of migration ligand L was dissolved in 30mL of toluene) were added. After stirring at 25℃for 5 minutes, the above-mentioned olefin (35.0 mg,0.20mmol,1.0 equiv), aryl bromide (91.5 mg,0.30mmol,1.5 equiv) and dimethoxymethylsilane (74. Mu.L, 0.60mmol,3.0 equiv) were added, the lid of the reaction tube was closed, and the reaction was carried out at 25℃for 24 hours. After the completion of the reaction, the reaction solvent was removed by concentration under reduced pressure, and the desired product (54.4 mg, white solid, yield 68%) was obtained by column chromatography separation and purification, and the desired product was measured for rr value (96:4) and ee value (88%). 1 H NMR(500MHz,CDCl 3 )δ7.76(d,J＝7.1Hz,2H),7.57–7.48(m,1H),7.46–7.38(m,4H),7.24–7.20(m,2H),6.49(d,J＝7.6Hz,1H),5.18(q,J＝7.6Hz,1H),1.93–1.77(m,2H),1.52–1.29(m,2H),0.95(t,J＝7.3Hz,3H)； 13 C NMR(126MHz,CDCl 3 )δ167.0,148.7,143.4,134.3,131.8,128.8,128.6,127.1,121.6,118.8(q,J＝321.3Hz),53.1,38.4,19.7,13.9； 19 F NMR(471MHz,CDCl 3 )δ-72.9；HRMS(ESI)calcd.for C 18 H 18 F 3 NO 4 SNa[M+Na] + m/z 424.0801,found 424.0801；IR(neat,cm -1 )3294,1634,1422,1209,1139,888；m.p.110.0–111.4℃；[α] D 17 ＝+1.6(c＝1.01,CHCl 3 )；HPLC analysisOD-H column,20％ i PrOH in hexane,0.8mL/min,254nm UV detector,t R (minor)＝6.6min,t R (major)＝7.7min.
Example 12
Nickel (II) nitrate hexahydrate (2.9 mg,5.0 mol%) and chiral ligand L1 were added to a reaction tube under a nitrogen atmosphere * (5.8 mg,6.0 mol%), sodium carbonate (42.4 mg,2.0 equiv), sodium iodide (15.0 mg,0.5 equiv), and then dried 0.25mL of N-methylpyrrolidone, 0.75mL of toluene solution containing migration ligand L (toluene solution preparation method of migration ligand L: 11.8mg of migration ligand L was dissolved in 30mL of toluene) were added. After stirring at 25℃for 5 minutes, the above-mentioned olefin (35.0 mg,0.20mmol,1.0 equiv), aryl bromide (98.2 mg,0.30mmol,1.5 equiv) and dimethoxymethylsilane (74. Mu.L, 0.60mmol,3.0 equiv) were added, the lid of the reaction tube was closed, and the reaction was carried out at 25℃for 24 hours. After the completion of the reaction, the reaction solvent was removed by concentration under reduced pressure, and the desired product (46.2 mg, white solid, yield: 55%) was obtained by column chromatography separation and purification, and the desired product was measured for rr (97:3) and ee (91%). 1 H NMR(500MHz,CDCl 3 )δ7.77–7.68(m,4H),7.54–7.40(m,3H),7.33–7.25(m,4H),6.99–6.93(m,2H),6.25(d,J＝7.8Hz,1H),5.15(q,J＝7.7Hz,1H),2.44(s,3H),1.92–1.76(m,2H),1.45–1.30(m,2H),0.95(t,J＝7.3Hz,3H)； 13 C NMR(126MHz,CDCl 3 )δ166.9,148.8,145.5,141.6,134.5,131.8,129.9,128.8,128.6,127.9,127.0,122.7,53.1,38.5,21.9,19.6,13.9；HRMS(ESI)calcd.for C 24 H 25 NO 4 SNa[M+Na] + m/z 446.1396,found 446.1393；IR(neat,cm -1 )3327,2928,1638,1306,1149,769；[α] D 17 ＝–11.2(c＝0.34,CHCl 3 )；HPLC analysis AD-H column,30％ i PrOH in hexane,0.8mL/min,254nm UV detector,t R (minor)＝11.6min,t R (major)＝14.5min.
Example 13
Nickel (II) nitrate hexahydrate (2.9 mg,5.0 mol%) and chiral ligand L1 were added to a reaction tube under a nitrogen atmosphere * (5.8 mg,6.0 mol%), sodium carbonate (42.4 mg,2.0 equiv), sodium iodide (15.0 mg,0.5 equiv), and then dried 0.25mL of N-methylpyrrolidone, 0.75mL of toluene solution containing migration ligand L (toluene solution preparation method of migration ligand L: 11.8mg of migration ligand L was dissolved in 30mL of toluene) were added. After stirring at 25℃for 5 minutes, the above-mentioned olefin (35.0 mg,0.20mmol,1.0 equiv), aryl bromide (70.2 mg,0.30mmol,1.5 equiv) and dimethoxymethylsilane (74. Mu.L, 0.60mmol,3.0 equiv) were added, the lid of the reaction tube was closed, and the reaction was carried out at 25℃for 24 hours. After the completion of the reaction, the reaction solvent was removed by concentration under reduced pressure, and the desired product (72.3 mg, white solid, yield 62%) was obtained by column chromatography separation and purification, and the desired product was measured for rr value (97:3) and ee value (86%). 1 H NMR(500MHz,CDCl 3 )δ7.76(d,J＝7.3Hz,2H),7.54–7.46(m,1H),7.45–7.33(m,4H),7.18(d,J＝8.2Hz,2H),6.40(d,J＝8.0Hz,1H),5.17(q,J＝7.6Hz,1H),2.34–1.64(m,2H),1.67–1.16(m,2H),0.96(t,J＝7.3Hz,3H)； 13 C NMR(126MHz,CDCl 3 )δ166.9,148.5,141.4,134.5,131.8,128.7,128.1,127.1,121.3,120.6(q,J＝258.3Hz),53.2,38.5,19.7,13.9； 19 F NMR(471MHz,CDCl 3 )δ–57.9；HRMS(ESI)calcd.for C 18 H 18 F 3 NO 2 Na[M+Na] + m/z 360.1182,found 360.1179；IR(neat,cm -1 )3314,2924,1638,1215,745；m.p.127.7–128.7℃；[α] D 17 ＝+2.8(c＝0.50,CHCl 3 )；HPLC analysisAD-H column,20％ i PrOH in hexane,0.8mL/min,220nm UV detector,t R (major)＝5.7min,t R (minor)＝6.9min.
Example 14
Nickel (II) nitrate hexahydrate (2.9 mg,5.0 mol%) and chiral ligand L1 were added to a reaction tube under a nitrogen atmosphere * (5.8 mg,6.0 mol%), sodium carbonate (42.4 mg,2.0 equiv), sodium iodide (15.0 mg,0.5 equiv), and then dried 0.25mL of N-methylpyrrolidone, 0.75mL of toluene solution containing migration ligand L (toluene solution preparation method of migration ligand L: 11.8mg of migration ligand L was dissolved in 30mL of toluene) were added. After stirring at 25℃for 5 minutes, the above-mentioned olefin (35.0 mg,0.20mmol,1.0 equiv), aryl bromide (60.9 mg,0.30mmol,1.5 equiv) and dimethoxymethylsilane (74. Mu.L, 0.60mmol,3.0 equiv) were added, the lid of the reaction tube was closed, and the reaction was carried out at 25℃for 24 hours. After the completion of the reaction, the reaction solvent was removed by concentration under reduced pressure, and the desired product (27.6 mg, white solid, yield 46%) was obtained by column chromatography separation and purification, and the desired product was measured for rr value (98:2) and ee value (92%). 1 H NMR(500MHz,CDCl 3 )δ7.83–7.71(m,2H),7.55–7.40(m,1H),7.44–7.37(m,2H),7.33–7.24(m,2H),7.26–7.20(m,2H),6.37(d,J＝8.1Hz,1H),5.13(q,J＝7.6Hz,1H),2.46(s,3H),1.95–1.78(m,2H),1.53–1.29(m,2H),0.94(t,J＝7.4Hz,3H)； 13 C NMR(126MHz,CDCl 3 )δ166.8,139.5,137.5,134.7,131.6,128.7,127.3,127.1,127.0,53.4,38.4,19.7,16.1,14.0；HRMS(ESI)calcd.for C 18 H 21 NOSNa[M+Na] + m/z 322.1236,found 322.1233；IR(neat,cm -1 )3321,1631,1214,744；m.p.177.3–179.3℃；[α] D 17 ＝+21.4(c＝0.72,CHCl 3 )；HPLC analysis AD-H column,20％ i PrOH in hexane,0.8mL/min,254nm UV detector,t R (major)＝8.8min,t R (minor)＝12.4min.
Example 15
Nickel (II) nitrate hexahydrate (2.9 mg,5.0 mol%) and chiral ligand L1 were added to a reaction tube under a nitrogen atmosphere * (5.8 mg,6.0 mol%), sodium carbonate (42.4 mg,2.0 equiv), sodium iodide (15.0 mg,0.5 equiv), and then dried 0.25mL of N-methylpyrrolidone, 0.75mL of toluene solution containing migration ligand L (toluene solution preparation method of migration ligand L: 11.8mg of migration ligand L was dissolved in 30mL of toluene) were added. After stirring at 25℃for 5 minutes, the above-mentioned olefin (35.0 mg,0.20mmol,1.0 equiv), aryl bromide (56.7 mg,0.30mmol,1.5 equiv) and dimethoxymethylsilane (74. Mu.L, 0.60mmol,3.0 equiv) were added, the lid of the reaction tube was closed, and the reaction was carried out at 25℃for 24 hours. After the reaction, the reaction solvent is removed by decompression concentration, the target product (36.2 mg, white solid, yield 64%) is obtained by column chromatography separation and purification, and the rr value of the target product is measured>99:1) and ee (94%). 1 H NMR(500MHz,CDCl 3 )δ8.50(s,2H),7.75–7.70(m,2H),7.51–7.44(m,1H),7.42–7.35(m,2H),6.67–6.62(m,1H),5.09(q,J＝7.6Hz,1H),3.97(s,3H),1.97–1.78(m,2H),1.50–1.29(m,2H),0.95(t,J＝7.3Hz,3H)； 13 C NMR(126MHz,CDCl 3 )δ167.2,165.1,158.1,134.1,131.9,129.2,128.7,127.1,55.1,49.4,37.6,19.6,13.8；HRMS(ESI)calcd.for C 16 H 20 N 3 O 2 [M+H] + m/z 286.1550,found 286.1541；IR(neat,cm -1 )3309,2957,1479,1311,1032,802,694；m.p.132.9–133.1℃；[α] D 25 ＝-4.7(c＝0.80,CHCl 3 )；HPLC analysis OD-H column,20％ i PrOH in hexane,0.8mL/min,254nm UV detector,t R (major)＝8.1min,t R (minor)＝10.4min.
Example 16
Nickel (II) nitrate hexahydrate (2.9 mg,5.0 mol%) and chiral ligand L1 were added to a reaction tube under a nitrogen atmosphere * (5.8 mg,6.0 mol%), sodium carbonate (42.4 mg,2.0 equiv), sodium iodide (15.0 mg,0.5 equiv), and then dried 0.25mL of N-methylpyrrolidone, 0.75mL of toluene solution containing migration ligand L (toluene solution preparation method of migration ligand L: 11.8mg of migration ligand L was dissolved in 30mL of toluene) were added. After stirring at 25℃for 5 minutes, the above-mentioned olefin (45.0 mg,0.20mmol,1.0 equiv), aryl bromide (64.5 mg,0.30mmol,1.5 equiv) and dimethoxymethylsilane (74. Mu.L, 0.60mmol,3.0 equiv) were added, the lid of the reaction tube was closed, and the reaction was carried out at 25℃for 24 hours. After the reaction, the reaction solvent is removed by decompression concentration, the target product (43.0 mg, white solid, yield 60%) is obtained by column chromatography separation and purification, and the rr value of the target product is measured >99:1) and ee (93%). 1 H NMR(500MHz,CDCl 3 )δ8.27(s,1H),8.04–8.00(m,2H),7.93–7.79(m,4H),7.64–7.49(m,2H),7.46(d,J＝8.4Hz,2H),6.61(d,J＝7.9Hz,1H),5.27(q,J＝7.6Hz,1H),3.90(s,3H),2.01–1.81(m,2H),1.51–1.34(m,2H),0.97(t,J＝7.3Hz,3H)； 13 C NMR(126MHz,CDCl 3 )δ167.1,167.0,147.9,134.9,132.7,131.7,130.2,129.4,129.0,128.7,127.9,127.8,127.5,127.0,126.8,123.7,53.8,52.2,38.5,19.7,14.0；HRMS(ESI)calcd.for C 23 H 23 NO 3 Na[M+Na] + m/z 384.1570,found 384.1563；IR(neat,cm -1 )3302,2956,1721,1279,906,731；m.p.148.5–150.2℃；[α] D 17 ＝–47.8(c＝1.0,CHCl 3 )；HPLC analysis AD-H column,30％ i PrOH in hexane,0.8mL/min,254nm UV detector,t R (major)＝8.8min,t R (minor)＝11.6min.
Example 17
Nickel (II) nitrate hexahydrate (2.9 mg,5.0 mol%) and chiral ligand L1 were added to a reaction tube under a nitrogen atmosphere * (5.8 mg,6.0 mol%), sodium carbonate (42.4 mg,2.0 equiv), sodium iodide (15.0 mg,0.5 equiv), and then dried 0.25mL of N-methylpyrrolidone, 0.75mL of toluene solution containing migration ligand L (toluene solution preparation method of migration ligand L: 11.8mg of migration ligand L was dissolved in 30mL of toluene) were added. After stirring at 25℃for 5 minutes, the above-mentioned olefin (41.0 mg,0.20mmol,1.0 equiv), aryl bromide (64.5 mg,0.30mmol,1.5 equiv) and dimethoxymethylsilane (74. Mu.L, 0.60mmol,3.0 equiv) were added, the lid of the reaction tube was closed, and the reaction was carried out at 25℃for 24 hours. After the reaction, the reaction solvent is removed by decompression concentration, the target product (39.9 mg, white solid, yield 59%) is obtained by column chromatography separation and purification, and the rr value of the target product is measured>99:1) and ee (93%). 1 H NMR(500MHz,CDCl 3 )δ7.98(d,J＝8.4Hz,2H),7.73(d,J＝8.8Hz,2H),7.40(d,J＝8.4Hz,2H),6.88(d,J＝8.9Hz,2H),6.52(d,J＝8.0Hz,1H),5.17(q,J＝7.6Hz,1H),3.89(s,3H),3.82(s,3H),1.95–1.75(m,2H),1.47–1.27(m,2H),0.93(t,J＝7.3Hz,3H)； 13 C NMR(126MHz,CDCl 3 )δ167.0,166.5,162.4,148.2,130.1,129.2,128.9,126.7,126.6,113.9,55.5,53.6,52.2,38.5,19.6,13.9；HRMS(ESI)calcd.for C 20 H 23 NO 4 Na[M+Na] + m/z 364.1519,found 364.1517；IR(neat,cm -1 )3310,3019,1214,744；m.p.193.0–194.3℃；[α] D 17 ＝–25.8(c＝1.07,CHCl 3 )；HPLC analysisAD-H column,30％ i PrOH in hexane,0.8mL/min,254nm UV detector,t R (major)＝10.8min,t R (minor)＝17.6min.
Example 18
Nickel (II) nitrate hexahydrate (2.9 mg,5.0 mol%) and chiral ligand L1 were added to a reaction tube under a nitrogen atmosphere * (5.8 mg,6.0 mol%), sodium carbonate (42.4 mg,2.0 equiv), sodium iodide (15.0 mg,0.5 equiv), and then dried 0.25mL of N-methylpyrrolidone, 0.75mL of toluene solution containing migration ligand L (toluene solution preparation method of migration ligand L: 11.8mg of migration ligand L was dissolved in 30mL of toluene) were added. After stirring at 25℃for 5 minutes, the above-mentioned olefin (46.6 mg,0.20mmol,1.0 equiv), aryl bromide (64.5 mg,0.30mmol,1.5 equiv) and dimethoxymethylsilane (74. Mu.L, 0.60mmol,3.0 equiv) were added, the lid of the reaction tube was closed, and the reaction was carried out at 25℃for 24 hours. After the reaction, the reaction solvent is removed by decompression concentration, the target product (41.6 mg, white solid, yield 56%) is obtained by column chromatography separation and purification, and the rr value of the target product is measured >99:1) and ee (87%). 1 H NMR(500MHz,CDCl 3 )δ8.04–8.01(m,2H),8.00–7.96(m,2H),7.81–7.78(m,2H),7.42–7.38(m,2H),6.73(d,J＝7.9Hz,1H),5.18(q,J＝7.6Hz,1H),3.92(s,3H),3.89(s,3H),2.05–1.77(m,2H),1.44–1.30(m,2H),0.94(t,J＝7.3Hz,3H)； 13 C NMR(126MHz,CDCl 3 )δ166.9,166.4,166.1,147.5,138.4,133.0,130.2,130.0,129.5,127.1,126.7,53.9,52.6,52.3,38.4,19.7,13.9；HRMS(ESI)calcd.for C 21 H 23 NO 5 Na[M+Na] + m/z 392.1468,found 392.1466；IR(neat,cm -1 )3019,1720,1214,744；m.p.178.3–179.9℃；[α] D 17 ＝–19.7(c＝1.22,CHCl 3 )；HPLC analysisOD-H column,20％ i PrOH in hexane,0.8mL/min,254nm UV detector,t R (minor)＝12.1min,t R (major)＝15.6min.
Example 19
Nitrogen gasNickel (II) nitrate hexahydrate (2.9 mg,5.0 mol%) and chiral ligand L1 were added to a reaction tube under an atmosphere * (5.8 mg,6.0 mol%), sodium carbonate (42.4 mg,2.0 equiv), sodium iodide (15.0 mg,0.5 equiv), and then dried 0.25mL of N-methylpyrrolidone, 0.75mL of toluene solution containing migration ligand L (toluene solution preparation method of migration ligand L: 11.8mg of migration ligand L was dissolved in 30mL of toluene) were added. After stirring at 25℃for 5 minutes, the above-mentioned olefin (25.4 mg,0.20mmol,1.0 equiv), aryl bromide (64.5 mg,0.30mmol,1.5 equiv) and dimethoxymethylsilane (74. Mu.L, 0.60mmol,3.0 equiv) were added, the lid of the reaction tube was closed, and the reaction was carried out at 25℃for 24 hours. After the reaction, the reaction solvent is removed by decompression concentration, the target product (26.5 mg, white solid, yield 50%) is obtained by column chromatography separation and purification, and the rr value of the target product is measured>99:1) and ee (92%). 1 H NMR(500MHz,CDCl 3 )δ8.02–7.97(m,2H),7.36–7.31(m,2H),5.76(d,J＝8.2Hz,1H),4.98(q,J＝7.6Hz,1H),3.90(s,3H),2.00(s,3H),1.80–1.71(m,2H),1.38–1.24(m,2H),1.24–1.09(m,2H),0.86(t,J＝7.1Hz,3H)； 13 C NMR(126MHz,CDCl 3 )δ169.4,167.0,147.9,130.1,129.3,126.7,53.5,52.2,36.0,28.4,23.6,22.6,14.0；HRMS(ESI)calcd.for C 15 H 21 NO 3 Na[M+Na] + m/z 286.1413,found 286.1409；IR(neat,cm -1 )3020,1722,1214,748；m.p.121.1–122.0℃；[α] D 25 ＝+96.6(c＝0.21,CHCl 3 )；HPLC analysisAD-H column,10％ i PrOH in hexane,0.8mL/min,254nm UV detector,t R (major)＝10.0min,t R (minor)＝12.1min.
Example 20
Nickel (II) nitrate hexahydrate (2.9 mg,5.0 mol%) and chiral ligand L1 were added to a reaction tube under a nitrogen atmosphere * (5.8 mg,6.0 mol%), sodium carbonate (42.4 mg,2.0 equiv), iodineSodium chloride (15.0 mg,0.5 equiv) was then added, followed by dried 0.25mL of N-methylpyrrolidone, 0.75mL of toluene solution containing migration ligand L (toluene solution preparation method for migration ligand L: 11.8mg of migration ligand L was dissolved in 30mL of toluene). After stirring at 25℃for 5 minutes, the above-mentioned olefin (40.6 mg,0.20mmol,1.0 equiv), aryl bromide (64.5 mg,0.30mmol,1.5 equiv) and dimethoxymethylsilane (74. Mu.L, 0.60mmol,3.0 equiv) were added, the lid of the reaction tube was closed, and the reaction was carried out at 25℃for 24 hours. After the reaction, the reaction solvent is removed by decompression concentration, the target product (34.8 mg, white solid, yield 51%) is obtained by column chromatography separation and purification, and the rr value of the target product is measured >99:1) and ee (91%). 1 H NMR(500MHz,CDCl 3 )δ8.00–7.96(m,2H),7.85–7.71(m,2H),7.55–7.43(m,1H),7.43–7.34(m,4H),6.64(d,J＝8.0Hz,1H),5.17(q,J＝7.6Hz,1H),3.89(s,3H),1.97–1.78(m,2H),1.39–1.22(m,6H),0.87–0.81(m,3H)； 13 C NMR(126MHz,CDCl 3 )δ167.0,166.9,147.9,134.5,131.8,130.2,129.3,128.8,127.1,126.7,53.9,52.2,36.3,31.6,26.0,22.6,14.1；HRMS(ESI)calcd.for C 21 H 25 NO 3 Na[M+Na] + m/z 362.1726,found 362.1723；IR(neat,cm -1 )3287,2929,1636,1214,748；m.p.131.1–132.1℃；[α] D 17 ＝+0.7(c＝0.81,CHCl 3 )；91％ee；HPLC analysisAD-H column,20％ i PrOH in hexane,0.8mL/min,254nm UV detector,t R (major)＝10.9min,t R (minor)＝16.1min.
Example 21
Nickel (II) nitrate hexahydrate (2.9 mg,5.0 mol%) and chiral ligand ent-L2 were added to a reaction tube under a nitrogen atmosphere * (7.2 mg,6.0 mol%), potassium carbonate (55.4 mg,2.0 equiv), sodium iodide (60.0 mg,2.0 equiv), followed by the addition of dried 0.1mL of N, N-dimethylacetamide, 0.9mL of ethylene glycol containing a migration ligand LAlcohol dimethyl ether solution (preparation method of ethylene glycol dimethyl ether solution of migration ligand L: 3.2mg of migration ligand L is dissolved in 10mL of ethylene glycol dimethyl ether). After stirring at 25℃for 5 minutes, the above-mentioned olefin (40.6 mg,0.20mmol,1.0 equiv), aryl bromide (64.5 mg,0.30mmol,1.5 equiv) and dimethoxymethylsilane (74. Mu.L, 0.60mmol,3.0 equiv) were added, the lid of the reaction tube was closed, and the reaction was carried out at 25℃for 24 hours. After the reaction, the reaction solvent is removed by decompression concentration, the target product (45.5 mg, yellow oily liquid, yield 67%) is obtained by column chromatography separation and purification, and the rr value of the target product is measured>99:1) and ee value (90%). 1 H NMR(500MHz,CDCl 3 )δ8.01–7.93(m,2H),7.44–7.10(m,6H),6.88(d,J＝7.3Hz,1H),5.20–4.87(m,3H),3.96–3.85(m,3H),3.77–3.59(m,2H),2.43–2.27(m,1H),1.97–1.77(m,3H)； 13 C NMR(126MHz,CDCl 3 )δ167.0,155.0,149.8&149.0,137.0&136.5,129.9,128.8,128.5&128.3,128.1&128.0,127.7&127.5,125.6,67.0&66.8,61.3&61.1,52.2&52.1,47.8&47.3,35.9&34.8,23.8&23.1；HRMS(ESI)calcd.for C 20 H 21 NO 4 Na[M+Na] + m/z 362.1363,found 362.1366；IR(neat,cm -1 )2951,1699,1408,1276,1105,770,699；[α] D 25 ＝–81.9(c＝1.04,CHCl 3 )；HPLC analysisOD-H column,20％ i PrOH in hexane,0.8mL/min,254nm UV detector,t R (major)＝10.2min,t R (minor)＝12.2min.
Example 22
Nickel (II) nitrate hexahydrate (2.9 mg,5.0 mol%) and chiral ligand ent-L2 were added to a reaction tube under a nitrogen atmosphere * (7.2 mg,6.0 mol%), potassium carbonate (55.4 mg,2.0 equiv), sodium iodide (60.0 mg,2.0 equiv), followed by addition of dried 0.1mL of N, N-dimethylacetamide, 0.9mL of an ethylene glycol dimethyl ether solution containing a migration ligand L (migration The preparation method of the ethylene glycol dimethyl ether solution of the transfer ligand L comprises the following steps: 3.2mg of migration ligand L was dissolved in 10mL of ethylene glycol dimethyl ether). After stirring at 25℃for 5 minutes, the above-mentioned olefin (40.6 mg,0.20mmol,1.0 equiv), aryl bromide (57.0 mg,0.30mmol,1.5 equiv) and diethoxymethylsilane (96. Mu.L, 0.60mmol,3.0 equiv) were added, the lid of the reaction tube was closed, and the reaction was carried out at 25℃for 24 hours. After the reaction, the reaction solvent is removed by decompression concentration, the target product (49.7 mg, yellow oily liquid, yield 79%) is obtained by column chromatography separation and purification, and the rr value of the target product is measured>99:1) and ee value (88%). 1 H NMR(500MHz,CDCl 3 )δ7.52–7.01(m,8H),6.91(d,J＝5.8Hz,1H),5.21–4.82(m,3H),3.74–3.56(m,2H),2.39–2.24(m,1H),1.99–1.76(m,3H)； 13 C NMR(126MHz,CDCl 3 )δ155.0,143.0&142.2,137.0&136.7,132.5,128.6,128.3&128.1,127.8,127.5,127.1,67.0&66.8,61.0&60.7,47.8&47.3,36.0&34.9,23.8&23.1；HRMS(ESI)calcd.for C 20 H 21 NO 4 Na[M+H] + m/z 316.1099,found 316.1092；IR(neat,cm -1 )2952,1697,1406,1089,820,696；[α] D 25 ＝–46.5(c＝1.44,CHCl 3 )；HPLC analysisOD-H column,20％ i PrOH in hexane,0.8mL/min,254nm UV detector,t R (major)＝7.6min,t R (minor)＝9.1min.
Example 23
Nickel (II) nitrate hexahydrate (5.8 mg,10.0 mol%) chiral ligand ent-L2 was added to a reaction tube under a nitrogen atmosphere * (14.4 mg,12.0 mol%), potassium carbonate (55.4 mg,2.0 equiv), sodium iodide (60.0 mg,2.0 equiv), and then dried 0.1mL of N, N-dimethylformamide were added, and 0.9mL of an ether solution containing the migration ligand L (preparation method of an ether solution of the migration ligand L: 6.5mg of the migration ligand L was dissolved in 10mL of ether). Stirring at 25deg.C for 5 min, adding the aboveOlefins (40.6 mg,0.20mmol,1.0 equiv), aryl bromides (67.8 mg,0.30mmol,1.5 equiv) and dimethoxymethylsilanes (74. Mu.L, 0.60mmol,3.0 equiv) were reacted at 25℃for 24 hours with the lid of the reaction tube covered. After the reaction, the reaction solvent is removed by decompression concentration, the target product (55.4 mg, yellow oily liquid, yield 79%) is obtained by column chromatography separation and purification, and the rr value of the target product is measured >99:1) and ee value (88%). 1 H NMR(500MHz,CDCl 3 )δ8.64–8.49(m,1H),7.71–7.49(m,2H),7.41–7.14(m,4H),6.91(d,J＝7.2Hz,1H),5.22–4.84(m,3H),3.76–3.66(m,2H),2.46–2.38(m,1H),2.01–1.81(m,3H)； 13 C NMR(126MHz,CDCl 3 )δ155.1&154.7,148.1,146.9(q,J＝34.8Hz),143.2&142.4,136.7&136.2,134.7&134.4,128.7&128.5,128.3&128.2,128.1&127.9,121.7(q,J＝273.9Hz),120.3,67.3&67.2,59.3&58.9,47.9&47.4,35.9&34.6,23.9&23.3； 19 F NMR(471MHz,CDCl 3 )δ–67.7,–67.8；HRMS(ESI)calcd.for C 18 H 18 F 3 N 2 O 2 [M+H] + m/z 351.1315,found 351.1310；IR(neat,cm -1 )2955,1698,1337,1131,1086,698；[α] D 25 ＝–44.6(c＝1.93,CHCl 3 )；HPLC analysisOD-H column,20％ i PrOH in hexane,0.8mL/min,254nm UV detector,t R (major)＝9.5min,t R (minor)＝12.6min.
Example 24
Nickel (II) nitrate hexahydrate (5.8 mg,10.0 mol%) chiral ligand ent-L2 was added to a reaction tube under a nitrogen atmosphere * (14.4 mg,12.0 mol%), potassium carbonate (55.4 mg,2.0 equiv), sodium iodide (60.0 mg,2.0 equiv), then dried 0.1mL of N, N-dimethylformamide was added, and 0.9mL of an ether solution containing migration ligand L was added (method for preparing an ether solution of migration ligand L: 6.5mg migration)The mobile ligand L was dissolved in 10mL diethyl ether). After stirring at 25℃for 5 minutes, the above-mentioned olefin (40.6 mg,0.20mmol,1.0 equiv), aryl bromide (57.7 mg,0.30mmol,1.5 equiv) and diethoxymethylsilane (96. Mu.L, 0.60mmol,3.0 equiv) were added, the lid of the reaction tube was closed, and the reaction was carried out at 25℃for 24 hours. After the reaction, the reaction solvent is removed by decompression concentration, the target product (47.3 mg, yellow oily liquid, yield 75%) is obtained by column chromatography separation and purification, and the rr value of the target product is measured>99:1) and ee (92%). 1 H NMR(500MHz,CDCl 3 )δ8.31–8.17(m,1H),7.52–7.11(m,6H),6.96(s,1H),5.20–4.82(m,3H),3.75–3.57(m,2H),2.43–2.29(m,1H),1.98–1.77(m,3H)； 13 C NMR(126MHz,CDCl 3 )δ155.0&154.8,149.9,147.6,138.8&138.0,136.7&136.4,136.2&136.1,128.6&128.4,128.1&128.0,127.8,124.1,67.1,58.8&58.5,47.7&47.2,35.8&34.6,23.9&23.2；HRMS(ESI)calcd.for C 17 H 17 ClN 2 O 2 Na[M+Na] + m/z 339.0871,found 339.0864；IR(neat,cm -1 )2954,2879,1700,1409,1104,698；[α] D 25 ＝–69.5(c＝1.09,CHCl 3 )；HPLC analysisOD-H column,20％ i PrOH in hexane,0.8mL/min,254nm UV detector,t R (major)＝11.9min,t R (minor)＝13.8min.
Example 25
Nickel (II) nitrate hexahydrate (5.8 mg,10.0 mol%) chiral ligand ent-L2 was added to a reaction tube under a nitrogen atmosphere * (14.4 mg,12.0 mol%), potassium carbonate (55.4 mg,2.0 equiv), sodium iodide (60.0 mg,2.0 equiv), and then 0.9mL of a dry 0.1mL N, N-dimethylformamide diethyl ether solution containing the migration ligand L (preparation method of the diethyl ether solution of the migration ligand L: 6.5mg of the migration ligand L in 10mL diethyl ether) were added. After stirring at 25℃for 5 minutes, the above-mentioned olefin (40.6 mg,0.20 mmol) was added 1.0 equiv), aryl bromide (58.2 mg,0.30mmol,1.5 equiv) and dimethoxymethylsilane (74 μl,0.60mmol,3.0 equiv), the reaction tube was capped and reacted at 25 ℃ for 24 hours. After the reaction, the reaction solvent is removed by decompression concentration, the target product (56.7 mg, yellow oily liquid, yield 89%) is obtained by column chromatography separation and purification, and the rr value of the target product is measured>99:1) and ee (91%). 1 H NMR(500MHz,CDCl 3 )δ7.90–7.74(m,1H),7.45–7.19(m,5H),7.01(d,J＝6.8Hz,1H),5.20–4.80(m,3H),3.75–3.57(m,2H),2.47–2.28(m,1H),2.05–1.79(m,3H)； 13 C NMR(126MHz,CDCl 3 )δ155.1&154.7,151.1(d,J＝236.9Hz),145.4(d,J＝260.8Hz),139.8,138.9,136.6&136.2,128.6&128.5,128.2,128.1&128.0,124.2(d,J＝41.6Hz),67.3,58.5&58.1,47.7&47.3,35.8&34.6,23.9&23.3； 19 F NMR(471MHz,CDCl 3 )δ–90.0,–90.1,–90.2,–90.3,–139.6,–139.7,–140.0,–140.1；HRMS(ESI)calcd.for C 17 H 17 F 2 N 2 O 2 [M+H] + m/z 313.1547,found 313.1548；IR(neat,cm -1 )2948,1698,1395,1103,1042,697；[α] D 25 ＝–66.1(c＝1.08,CHCl 3 )；HPLC analysisOD-H column,20％ i PrOH in hexane,0.8mL/min,254nm UV detector,t R (major)＝9.5min,t R (minor)＝11.1min.
Example 26
Nickel (II) nitrate hexahydrate (5.8 mg,10.0 mol%) chiral ligand ent-L2 was added to a reaction tube under a nitrogen atmosphere * (14.4 mg,12.0 mol%), potassium carbonate (55.4 mg,2.0 equiv), sodium iodide (60.0 mg,2.0 equiv), and then 0.9mL of a dry 0.1mL N, N-dimethylformamide diethyl ether solution containing the migration ligand L were added (preparation method of diethyl ether solution of the migration ligand L: 6.5mg of the migration ligand L was dissolved in 10 mL)Diethyl ether). After stirring at 25℃for 5 minutes, the above-mentioned olefin (40.6 mg,0.20mmol,1.0 equiv), aryl bromide (52.8 mg,0.30mmol,1.5 equiv) and diethoxymethylsilane (96. Mu.L, 0.60mmol,3.0 equiv) were added, the lid of the reaction tube was closed, and the reaction was carried out at 25℃for 24 hours. After the reaction, the reaction solvent is removed by decompression concentration, the target product (53.7 mg, yellow oily liquid, yield 89%) is obtained by column chromatography separation and purification, and the rr value of the target product is measured >99:1) and ee value (88%). 1 H NMR(500MHz,CDCl 3 )δ8.14–8.06(m,1H),7.47–7.14(m,4H),7.07–6.90(m,2H),6.70(d,J＝27.8Hz,1H),5.23–4.81(m,3H),3.87–3.50(m,2H),2.48–2.27(m,1H),2.02–1.73(m,3H)； 13 C NMR(126MHz,CDCl 3 )δ164.2(d,J＝239.3Hz),159.2(d,J＝98.5Hz),155.0&154.7,147.8&147.7,136.6&136.2,128.6&128.4,128.2&128.1,127.7,118.6(d,J＝21.5Hz),106.6&106.3,67.2&67.1,60.4&60.1,47.7&47.3,35.3&34.2,23.8&23.1； 19 F NMR(471MHz,CDCl 3 )δ–68.1,–68.3；HRMS(ESI)calcd.for C 17 H 17 FN 2 O 2 Na[M+Na] + m/z 323.1166,found 323.1166；IR(neat,cm -1 )2953,1700,1409,1107,772,735；[α] D 25 ＝–55.8(c＝1.06,CHCl 3 )；HPLC analysisOD-H column,30％ i PrOH in hexane,0.8mL/min,254nm UV detector,t R (major)＝8.5min,t R (minor)＝12.2min.
Example 27
Nickel (II) nitrate hexahydrate (5.8 mg,10.0 mol%) chiral ligand ent-L2 was added to a reaction tube under a nitrogen atmosphere * (14.4 mg,12.0 mol%), potassium carbonate (55.4 mg,2.0 equiv), sodium iodide (60.0 mg,2.0 equiv), followed by the addition of dried 0.1mL of N, N-dimethylformamide 0.9mL of an ether solution containing the migration ligand L (ethyl acetate of the migration ligand L)The preparation method of the ether solution comprises the following steps: 6.5mg of migration ligand L was dissolved in 10mL of diethyl ether). After stirring at 25℃for 5 minutes, the above-mentioned olefin (40.6 mg,0.20mmol,1.0 equiv), aryl bromide (56.4 mg,0.30mmol,1.5 equiv) and dimethoxymethylsilane (74. Mu.L, 0.60mmol,3.0 equiv) were added, the lid of the reaction tube was closed, and the reaction was carried out at 25℃for 24 hours. After the reaction, the reaction solvent is removed by decompression concentration, the target product (50.1 mg, yellow oily liquid, yield 80%) is obtained by column chromatography separation and purification, and the rr value of the target product is measured>99:1) and ee value (90%). 1 H NMR(500MHz,CDCl 3 )δ8.07(dd,J＝11.5,5.3Hz,1H),7.43–7.15(m,4H),7.01–6.94(m,1H),6.68(dd,J＝23.4,5.4Hz,1H),6.53(d,J＝21.9Hz,1H),5.23–4.78(m,3H),3.91(s,3H),3.71–3.54(m,2H),2.38–2.24(m,1H),1.94–1.78(m,3H)； 13 C NMR(126MHz,CDCl 3 )δ164.6,156.2&155.5,155.0&154.9,147.0,136.9&136.6,128.6&128.3,128.1&128.0,127.8&127.6,114.5&114.3,107.5,67.1&66.9,60.5&60.2,53.5,47.7&47.2,35.2&34.1,23.7&23.0；HRMS(ESI)calcd.for C 18 H 21 N 2 O 3 [M+H] + m/z 311.1754,found 311.1752；IR(neat,cm -1 )2952,1700,1409,1355,1110,698；[α] D 25 ＝–71.7(c＝1.72,CHCl 3 )；HPLC analysisOD-H column,20％ i PrOH in hexane,0.8mL/min,254nm UV detector,t R (major)＝8.7min,t R (minor)＝10.9min.
Example 28
Nickel (II) nitrate hexahydrate (5.8 mg,10.0 mol%) chiral ligand ent-L2 was added to a reaction tube under a nitrogen atmosphere * (14.4 mg,12.0 mol%), potassium carbonate (55.4 mg,2.0 equiv), sodium iodide (60.0 mg,2.0 equiv), followed by the addition of dried 0.1mL of N, N-dimethylformamide 0.9mL of an ether solution containing the migration ligand L (migration ligand L) The preparation method of the diethyl ether solution comprises the following steps: 6.5mg of migration ligand L was dissolved in 10mL of diethyl ether). After stirring at 25℃for 5 minutes, the above-mentioned olefin (40.6 mg,0.20mmol,1.0 equiv), aryl bromide (55.8 mg,0.30mmol,1.5 equiv) and diethoxymethylsilane (96. Mu.L, 0.60mmol,3.0 equiv) were added, the lid of the reaction tube was closed, and the reaction was carried out at 25℃for 24 hours. After the reaction, the reaction solvent is removed by decompression concentration, the target product (50.0 mg, yellow oily liquid, yield 81%) is obtained by column chromatography separation and purification, and the rr value of the target product is measured>99:1) and ee (89%). 1 H NMR(500MHz,CDCl 3 )δ:7.31–7.25(m,4H),7.24–7.19(m,2H),7.15–7.08(m,3H),6.93–6.88(m,2H),6.59–6.53(m,2H),4.22(t,J＝6.8Hz,1H),3.82(s,3H),1.94–1.77(m,2H),0.97(t,J＝7.4Hz,3H)； 13 C NMR(126MHz,CH 2 Cl 2 )δ:159.1,148.6,140.5,136.4,135.8,129.1,127.9,127.4,125.5,118.5,114.3,114.2,59.3,55.6,32.0,11.0；HRMS(ESI)calcd.for C 22 H 23 NNaOS[M+Na] + m/z 372.1393,found 372.1390；IR(neat,cm -1 )2961,2923,1258,1082,1010,789；[α] D 26 ＝–45.4(c＝1.0,CHCl 3 )；HPLC analysis CHIRALCEL AD-H column,10％ i PrOH in n-hexane,0.8mL/min,254nm UV detector,t R (minor)＝11.0min,t R (major)＝13.3min。
Example 29
Lithium aluminum hydride (200 mg,5.0 equiv) was dissolved in tetrahydrofuran under nitrogen atmosphere, and then pyrrolidine derivative (6 d) was added to the solution at 0 ℃. The reaction was refluxed for six hours, and then quenched with water at 0 ℃. The mixture was filtered through celite, washed with dichloromethane and evaporated in vacuo to give the starting material. Into a flask containing the starting material was added 5mL of methanol followed by Pd/C [ palladium 10% wt carbon (soaked with about 55% water), 10.6mg,10mol ]]And sodium hydroxide (160.0 mg,4.0 equiv). After the air was vented, hydrogen was filled into the flask via a balloon. The reaction was stirred at room temperature for 4 hours. The mixture is then passed through silicon The algae soil is filtered and concentrated. The crude product was purified by column chromatography (dimethyl methane/methanol=10:1) to give the product (110.2 mg, yellow oil, yield 68%) and the desired product was measured for ee (92%). 1 H NMR(500MHz,CDCl 3 )δ8.57–8.43(m,2H),7.76–7.62(m,1H),7.29–7.22(m,1H),3.29–3.21(m,1H),3.09(t,J＝8.3Hz,1H),2.32(q,J＝9.0Hz,1H),2.24–2.18(m,1H),2.17(s,3H),2.02–1.91(m,1H),1.88–1.79(m,1H),1.77–1.68(m,1H).； 13 C NMR(126MHz,CDCl 3 )δ149.8,148.8,135.0,123.7,69.1,57.2,40.5,35.3,22.8；HRMS(ESI)calcd.for C 10 H 15 N 2 [M+H] + m/z 163.1230,found 163.1237；IR(neat,cm -1 )2927,1706,1414,1264,731；[α] D 25 ＝–12.0(c＝1.00,CHCl 3 )；HPLC analysisOD-H column,3％ i PrOH in hexane,0.8mL/min,254nm UV detector,t R (major)＝10.4min,t R (minor)＝12.8min.
Example 30
Pyrrolidine derivative 6b (315.0 mg,1.0 mmol) was added to dry 40mL of methylene chloride under nitrogen, placed in an ice-water bath and BBr was carefully added at 0deg.C 3 (6 mL,1M solution CH) 2 Cl 2 6.0mmol,6 equiv). The reaction was stirred at room temperature for 5h. Excess BBr 3 Quenched with methanol. The reaction mixture was then concentrated to give the crude product. The crude product was purified by column chromatography (EtOAc/MeOH/triethylamine=9:1:0.1) to give the title compound. Next, the obtained product was dissolved in 5mL of N, N-dimethylformamide, followed by addition of 3-methyl-1H-pyrazolo [3,4-B]Pyridine-5-carboxylic acid (212.4 mg,1.2mmol,1.2 equiv), N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (383.4 mg,2.0mmol,2.0 equiv), 1-hydroxybenzotriazole (135.1 mg,1.0mmol,1.0 equiv). Stirring for several minutes, and adding N-methylmorpholine at room temperature303.3mg,3.0mmol,3.0 equiv) and the reaction mixture was stirred at room temperature overnight. After the completion of the reaction, the reaction solution was diluted with ethyl acetate, washed with water and brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give a crude product. The crude product was purified by column chromatography (EtOAc/MeOH/triethylamine=9:1:1.0.1) to give the desired product (221.1 mg, white solid, 65% yield). 1 H NMR(500MHz,DMSO-d 6 )δ13.50–13.22(m,1H),8.90–6.88(m,6H),5.27–4.92(m,1H),4.00–3.52(m,2H),2.57–2.53(m,2H),2.44–2.28(m,2H),1.94–1.69(m,3H)； 13 C NMR(126MHz,DMSO-d 6 )δ167.3,152.4,148.2,147.0,143.1,142.2,130.9,129.2,128.2,127.7,124.9,112.9,60.41,50.71,34.82,24.94,12.25；HRMS(ESI)calcd.for C 10 H 15 N 2 [M+H] + m/z 341.1164,found 341.1158；m.p.104.0–105.7℃；[α] D 25 ＝–102.4(c＝0.92,CHCl 3 )；HPLC analysisOJ-H column,30％ i PrOH in hexane,0.8mL/min,254nm UV detector,t R (major)＝8.4min,t R (minor)＝12.4min.
Comparative example 1
Nickel (II) nitrate hexahydrate (2.9 mg,5.0 mol%) and chiral ligand L1 were added to a reaction tube under a nitrogen atmosphere * (5.8 mg,6.0 mol%), sodium carbonate (42.4 mg,2.0 equiv), sodium iodide (15.0 mg,0.5 equiv), and then dried 0.25mL of N-methylpyrrolidone, 0.75mL of a toluene solution containing the migration ligand L1 (toluene solution preparation method of the migration ligand L1: 7.4mg of the migration ligand L is dissolved in 30mL of toluene) were added. After stirring at 25℃for 5 minutes, the above-mentioned olefin (35.0 mg,0.20mmol,1.0 equiv), aryl bromide (64.5 mg,0.30mmol,1.5 equiv) and dimethoxymethylsilane (74. Mu.L, 0.60mmol,3.0 equiv) were added, the lid of the reaction tube was closed, and the reaction was carried out at 25℃for 24 hours. After the reaction, the reaction solvent is removed by decompression concentration, and column chromatography is carried outSeparating and purifying to obtain target product (white solid, yield 12%), measuring rr value of target product>99:1) and ee (89%).
Conclusion: migration ligandsReplace->The results show that: the regioselectivity is improved but the yield and enantioselectivity are significantly reduced.
Comparative example 2:
nickel (II) nitrate hexahydrate (2.9 mg,5.0 mol%) and chiral ligand L1 were added to a reaction tube under a nitrogen atmosphere * (5.8 mg,6.0 mol%) sodium carbonate (42.4 mg,2.0 equiv) was added followed by dried 0.25mL of N-methylpyrrolidone, 0.75mL of toluene solution containing migration ligand L (toluene solution preparation method of migration ligand L: 11.8mg of migration ligand L was dissolved in 30mL of toluene). After stirring at 25℃for 5 minutes, the above-mentioned olefin (35.0 mg,0.20mmol,1.0 equiv), aryl bromide (64.5 mg,0.30mmol,1.5 equiv) and dimethoxymethylsilane (74. Mu.L, 0.60mmol,3.0 equiv) were added, the lid of the reaction tube was closed, and the reaction was carried out at 25℃for 24 hours. After the reaction, the reaction solvent was removed by concentration under reduced pressure, and the target product (white solid, yield 14%) was obtained by column chromatography separation and purification, and the rr value (60:40) and ee value (95%) of the target product were measured.
Conclusion: the results without additive NaI showed that: enantioselectivity is improved, but regioselectivity and yield are significantly reduced.
Comparative example 3:
nickel (II) nitrate hexahydrate (2.9 mg,5.0 mol%) and chiral ligand L1 were added to a reaction tube under a nitrogen atmosphere * (5.8 mg,6.0 mol%), sodium carbonate (42.4 mg,2.0 equiv), sodium iodide (15.0 mg,0.5 equiv), and then dried 0.25mL of N-methylpyrrolidone, 0.75mL of toluene solution containing migration ligand L (toluene solution preparation method of migration ligand L: 11.8mg of migration ligand L was dissolved in 30mL of toluene) were added. After stirring at 25℃for 5 minutes, the above-mentioned olefin (35.0 mg,0.20mmol,1.0 equiv), aryl iodide (78.6 mg,0.30mmol,1.5 equiv) and dimethoxymethylsilane (74. Mu.L, 0.60mmol,3.0 equiv) were added, the lid of the reaction tube was closed, and the reaction was carried out at 25℃for 24 hours. After the completion of the reaction, the reaction solvent was removed by concentration under reduced pressure, and the target product (white solid, yield 59%) was obtained by separation and purification by column chromatography, and the target product was measured for rr value (94:6) and ee value (92%).
Conclusion: the aryl iodide instead of aryl bromide results showed that: the enantioselectivity remains substantially unchanged, but the regioselectivity is reduced and the yield is significantly reduced.
Comparative example 4:
nickel (II) nitrate hexahydrate (2.9 mg,5.0 mol%) and chiral ligand L1 were added to a reaction tube under a nitrogen atmosphere * (5.8 mg,6.0 mol%), potassium carbonate (55.3 mg,2.0 equiv), sodium iodide (15.0 mg,0.5 equiv), and then dried 0.25mL of N-methylpyrrolidone, 0.75mL of a toluene solution containing a migration ligand L (toluene solution preparation method of migration ligand L: 11.8mg of migration ligand L is dissolved in 30mL of toluene) were added. After stirring at 25℃for 5 minutes, the above-mentioned olefin (35.0 mg,0.20mmol,1.0 equiv), aryl bromide (64.5 mg,0.30mmol,1.5 equiv) and dimethoxymethylsilane (74. Mu.L, 0.60mmol,3.0 equiv) were added, the lid of the reaction tube was closed, and the reaction was carried out at 25℃for 24 hours. After the reaction, the reaction solvent is removed by decompression concentration, the target product (white solid, yield 70%) is obtained by column chromatography separation and purification, and the rr value of the target product is measured>99:1) and ee value (60%).
Conclusion: the results of potassium carbonate instead of sodium carbonate show that: the regioselectivity and yield remained essentially unchanged, but the enantioselectivity was significantly reduced.

Claims (7)

1. A process for the asymmetric migration of arylates of nickel-catalyzed olefins, comprising the steps of: under the protection of inert gas, metallic nickel catalyst, migration ligand L, chiral ligand L, alkali, hydrogen source and additive are dissolved in organic solvent, then olefine is added (hetero) aryl compound (Het) Ar-Br to obtain a reaction mixture, and performing post-treatment and purification to obtain a target enantiomerically enriched alpha-aryl substituted chiral amine product;
Wherein the migration ligand L isOne of the following;
chiral ligand LOne of the following;
R 1 the substituent in the substrate is nitrogen-containing chain olefin, and is any one of alkyl and aryl;
R 2 is any one of hydrogen atom and alkyl;
when Ar is aryl, the substituent on the aryl is any one of chlorine atom, (hetero) aryl, (fluorine-containing) alkyl, (sulfur) ether, ketone, aldehyde, ester, amide and cyano; ar is any one of pyridine and pyrimidine when heteroaryl, and substituent groups on the heteroaryl are any one of chlorine atoms, fluorine atoms, (fluorine-containing) alkyl and alkoxy;
the solvent is one or more of toluene, N-methylpyrrolidone, N-dimethylformamide, N-dimethylacetamide, ethylene glycol dimethyl ether and diethyl ether;
wherein preparation scheme 1:
preparation route 2:
2. the method for the asymmetric migration and arylation of nickel-catalyzed olefins according to claim 1, wherein,
preparation route 1:
preparation of R in scheme 1 1 Is substituent groups in the nitrogenous chain olefin substrate, is any one of alkyl and aryl,
R 2 is any one of a hydrogen atom and an alkyl group,
the nickel catalyst is nickel (II) nitrate hexahydrate Ni (NO) 3 ) 2 ·6H 2 O, migration ligand L isChiral ligand L1- >ent-L1 is->The hydrogen source is dimethoxy methyl silane (MeO) 2 MeSiH, sodium carbonate Na as base 2 CO 3 The additive is sodium iodide NaI, and the solvent is toluene and N-methyl pyridineA pyrrolidone;
preparation route 2:
the nickel-based catalyst in preparation scheme 2 is nickel (II) nitrate hexahydrate Ni (NO 3 ) 2 ·6H 2 O, migration ligand L isChiral ligand L2 ＊ ent-L2 ＊ Is->The hydrogen source is dimethoxy methyl silane (MeO) 2 MeSiH or diethoxymethylsilane (EtO) 2 One of MeSiH, the alkali is sodium carbonate K 2 CO 3 The additive is sodium iodide NaI, and the solvent is multiple of N, N-dimethylformamide, N-dimethylacetamide, ethylene glycol dimethyl ether and diethyl ether.
3. The method for the asymmetric migration and arylation of nickel-catalyzed olefins according to claim 1, wherein: the asymmetric migration arylation method for preparing the nickel-catalyzed olefin in the route 1 comprises the steps of reacting olefin and aryl bromide for 1 to 24 hours in the presence of a metallic nickel catalyst, chiral ligand L, migration ligand L, hydrogen source, additive and alkali at the temperature of 25 ℃ and in a solvent; the molar ratio of the metallic nickel catalyst, the migration ligand L, the chiral ligand L1 or ent-L1, the hydrogen source, the additive, the alkali, the olefin and the aryl bromine is (0-0.01): (0-0.012): (0-0.001): (0.2-0.6): (0-0.1): (0.2-0.4): (0.2-0.3): (0.2-0.3); the reaction time was measured until the reaction was complete.
4. The method for the asymmetric migration and arylation of nickel-catalyzed olefins according to claim 1, wherein: the asymmetric migration arylation method for preparing the nickel-catalyzed olefin in the route 2 comprises the steps of reacting olefin and aryl bromide for 1-24 hours in the presence of a metallic nickel catalyst, chiral ligand L, migration ligand L, hydrogen source, additive and alkali at the temperature of 25 ℃ and in a solvent; the molar ratio of the metallic nickel catalyst, the migration ligand L, the chiral ligand L, the hydrogen source, the additive, the alkali, the olefin and the aryl bromine is (0-0.02): (0-0.024): (0-0.002): (0.2-0.6): (0-0.4): (0.2-0.4): (0.2-0.3): (0.2-0.3); the reaction time was measured until the reaction was complete.
5. The method for the asymmetric migration and arylation of nickel-catalyzed olefins according to claim 1, wherein: the metal nickel catalyst is metal nickel salt, the hydrogen source is silicon hydrogen or boron hydrogen pinacol, and the additive is inorganic salt of iodine.
6. Use of the nickel-catalyzed asymmetric migration arylation process of olefins according to claim 1, characterized in that: application in preparing Nicotine (S) -Nicotine, the specific preparation method has the following reaction formula:
in the first step, nickel (II) nitrate hexahydrate and chiral ligand ent-L2 are added into a reaction tube under the nitrogen atmosphere * Potassium carbonate, followed by addition of dry N, N-dimethylformamide, an ether solution containing the migration ligand L; stirring at 25 ℃ for 5 minutes, adding the olefin, the heteroaryl bromide and the diethoxymethylsilane, covering a cover of a reaction tube, and reacting at 25 ℃ for 24 hours; after the reaction is finished, concentrating under reduced pressure to remove a reaction solvent, and separating and purifying by column chromatography to obtain a pyrrolidine derivative;
secondly, dissolving lithium aluminum hydride in tetrahydrofuran under the nitrogen atmosphere, and then adding pyrrolidine derivatives into the solution at 0 ℃; reflux-reacting for six hours, and then quenching with water at 0 ℃; the mixture was filtered through celite, washed with dichloromethane, and rotary distilled to give crude material; subsequently, the crude material is dissolved in methanol, and palladium carbon and sodium hydroxide are added; after the air was vented, hydrogen was filled into the flask via a balloon; the reaction is stirred for 4 hours at normal temperature; after the reaction was completed, the mixture was filtered through celite and concentrated; the crude product is purified by column chromatography to obtain the target product of Nicotine (S) -Nicotine.
7. Use of the nickel-catalyzed asymmetric migration arylation process of olefins according to claim 1, characterized in that: application in preparing inhibitor MSC2530818, the specific preparation method is as follows:
In the first step, nickel (II) nitrate hexahydrate and chiral ligand ent-L2 are added into a reaction tube under the nitrogen atmosphere ＊ Potassium carbonate, sodium iodide, then dried N, N-dimethylacetamide, ethylene glycol dimethyl ether solution containing migration ligand L; stirring at 25 ℃ for 5 minutes, adding the olefin, the aryl bromide and the diethoxymethylsilane, covering a cover of a reaction tube, and reacting at 25 ℃ for 24 hours; after the reaction is finished, concentrating under reduced pressure to remove a reaction solvent, and separating and purifying by column chromatography to obtain a pyrrolidine derivative;
in a second step, the pyrrolidine derivative is added to dry dichloromethane under nitrogen atmosphere, placed in an ice-water bath, BBr is carefully added at 0 ℃ 3 The method comprises the steps of carrying out a first treatment on the surface of the The reaction was stirred at room temperature for 5h; excess BBr 3 Quenching with methanol; subsequently concentrating the reaction mixture to give a crude product; purifying the crude product by column chromatography to obtain a target compound; next, the resulting product was dissolved in N, N-dimethylformamide, followed by addition of 3-methyl-1H-pyrazolo [3,4-B ]]Pyridine-5-carboxylic acid, N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole; after stirring for a few minutes, N-methylmorpholine was added at room temperature and the reaction mixture was stirred at room temperature overnight; after the reaction, the reaction mixture was used as the second catalyst Dilute with ethyl acetate, wash with water and brine and dry over anhydrous sodium sulfate; removing the solvent under reduced pressure to obtain a crude product; purifying the crude product by column chromatography to obtain the target product.
CN202311234947.4A 2023-09-22 2023-09-22 Nickel-catalyzed olefin asymmetric hydroarylation method and application Pending CN117303993A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202311234947.4A CN117303993A (en) 2023-09-22 2023-09-22 Nickel-catalyzed olefin asymmetric hydroarylation method and application

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202311234947.4A CN117303993A (en) 2023-09-22 2023-09-22 Nickel-catalyzed olefin asymmetric hydroarylation method and application

Publications (1)

Publication Number Publication Date
CN117303993A true CN117303993A (en) 2023-12-29

Family

ID=89259605

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202311234947.4A Pending CN117303993A (en) 2023-09-22 2023-09-22 Nickel-catalyzed olefin asymmetric hydroarylation method and application

Country Status (1)

Country Link
CN (1) CN117303993A (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114716466A (en) * 2022-05-16 2022-07-08 南京大学 Method for preparing chiral alpha-amino boric acid/boric acid ester through nickel-catalyzed asymmetric hydroamidation

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114716466A (en) * 2022-05-16 2022-07-08 南京大学 Method for preparing chiral alpha-amino boric acid/boric acid ester through nickel-catalyzed asymmetric hydroamidation
CN114716466B (en) * 2022-05-16 2024-03-19 南京大学 Method for preparing chiral alpha-aminoboric acid/boric acid ester by nickel-catalyzed asymmetric hydrogen amidation

Similar Documents

Publication Publication Date Title
CN113754689B (en) Nickel-catalyzed asymmetric hydroamination method for olefin
Horniakova et al. Pyridine-derived palladium complexes immobilized on ordered mesoporous silica as catalysts for Heck-type reactions
Jin et al. Design of N-cinnamyl sulfinamides as new sulfur-containing olefin ligands for asymmetric catalysis: achieving structural simplicity with a categorical linear framework
CN117303993A (en) Nickel-catalyzed olefin asymmetric hydroarylation method and application
Laborde et al. Double [3+ 2]-dimerisation cascade synthesis of bis (triazolyl) bisphosphanes, a new scaffold for bidentate bisphosphanes
Chen et al. Chiral cyclopalladated complex promoted asymmetric synthesis of diester-substituted P, N-ligands via stepwise hydrophosphination and hydroamination reactions
CN112939750B (en) Method for transferring asymmetric functionalization by nickel-hydrogen catalysis olefin promoted by ligand relay strategy
CN110317221B (en) Polysubstituted alkynamidine compound and preparation method and application thereof
Wen et al. Unsymmetric salen ligands bearing a Lewis base: intramolecularly cooperative catalysis for cyanosilylation of aldehydes
WO2015102020A1 (en) Novel n-heterocyclic carbene compounds, their preparation and use
CN112679290B (en) Nickel-catalyzed asymmetric hydrogen alkynylation method for olefins and application of nickel-catalyzed asymmetric hydrogen alkynylation method in preparation of AMG837
CN104610256A (en) Method for preparing tetrahydro-1,5-naphthyridine compound and prepared chiral product thereof
CN109666049B (en) Chiral amino sulfonamide ligand metal complex and application thereof in catalytic reaction
CN102336698A (en) Method for synthesizing chiral indoline through palladium-catalyzed asymmetric hydrogenation
EP1650212B1 (en) Optically active quaternary ammonium salt, process for producing the same, and process for producing optically active alpha-amino acid derivative with the same
WO2015122502A1 (en) Method for producing optically active compound, and novel metal-diamine complex
CN111116450B (en) Axial chiral naphthylamine squaramide organic catalyst, and preparation method and application thereof
CN114716466A (en) Method for preparing chiral alpha-amino boric acid/boric acid ester through nickel-catalyzed asymmetric hydroamidation
CN114456203A (en) Method for preparing beta-boron-based ketone by catalyzing chitosan Schiff base copper functional material
CN111825508B (en) Preparation method of dihydro 9-phenanthrene amine compound and chiral product prepared by same
CN109748883B (en) Process for the preparation of chiral beta-amino derivatives
JP2015172024A (en) Chiral bicyclic diene ligand having hydrogen bond formation amide group
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
CN112876328B (en) Method for asymmetric catalytic synthesis of gamma-cyano amide compound and chiral drug using compound

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