CN113292444A - Multi-substituent-containing bia-dilute amide compound and preparation method thereof - Google Patents
Multi-substituent-containing bia-dilute amide compound and preparation method thereof Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 45
- -1 amide compound Chemical class 0.000 title claims abstract description 35
- 150000001408 amides Chemical class 0.000 claims abstract description 64
- UEXCJVNBTNXOEH-UHFFFAOYSA-N Ethynylbenzene Chemical group C#CC1=CC=CC=C1 UEXCJVNBTNXOEH-UHFFFAOYSA-N 0.000 claims abstract description 38
- 150000001879 copper Chemical class 0.000 claims abstract description 21
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical compound N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 claims abstract description 14
- 150000007529 inorganic bases Chemical class 0.000 claims abstract description 12
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims abstract description 4
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims abstract description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 57
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 41
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 39
- 239000000758 substrate Substances 0.000 claims description 26
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 24
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 23
- 150000003950 cyclic amides Chemical class 0.000 claims description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 21
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 18
- 239000000243 solution Substances 0.000 claims description 17
- 239000007810 chemical reaction solvent Substances 0.000 claims description 15
- 238000003756 stirring Methods 0.000 claims description 14
- 239000003960 organic solvent Substances 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 10
- 239000007864 aqueous solution Substances 0.000 claims description 10
- 238000005406 washing Methods 0.000 claims description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 8
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 8
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 8
- 238000001704 evaporation Methods 0.000 claims description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 8
- 239000012299 nitrogen atmosphere Substances 0.000 claims description 8
- 239000000741 silica gel Substances 0.000 claims description 8
- 229910002027 silica gel Inorganic materials 0.000 claims description 8
- 239000007787 solid Substances 0.000 claims description 8
- BTEJSUVVNDDTPL-UHFFFAOYSA-N n-fluoro-n-phenylbenzenesulfonamide Chemical compound C=1C=CC=CC=1S(=O)(=O)N(F)C1=CC=CC=C1 BTEJSUVVNDDTPL-UHFFFAOYSA-N 0.000 claims description 7
- LFZJRTMTKGYJRS-UHFFFAOYSA-N 1-chloro-4-ethynylbenzene Chemical group ClC1=CC=C(C#C)C=C1 LFZJRTMTKGYJRS-UHFFFAOYSA-N 0.000 claims description 6
- KSZVOXHGCKKOLL-UHFFFAOYSA-N 4-Ethynyltoluene Chemical group CC1=CC=C(C#C)C=C1 KSZVOXHGCKKOLL-UHFFFAOYSA-N 0.000 claims description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 6
- 239000012044 organic layer Substances 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 6
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 4
- 238000004587 chromatography analysis Methods 0.000 claims description 4
- 239000011259 mixed solution Substances 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 3
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 3
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 3
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 3
- 229960001701 chloroform Drugs 0.000 claims description 3
- RFKZUAOAYVHBOY-UHFFFAOYSA-M copper(1+);acetate Chemical compound [Cu+].CC([O-])=O RFKZUAOAYVHBOY-UHFFFAOYSA-M 0.000 claims description 3
- PDZKZMQQDCHTNF-UHFFFAOYSA-M copper(1+);thiocyanate Chemical compound [Cu+].[S-]C#N PDZKZMQQDCHTNF-UHFFFAOYSA-M 0.000 claims description 3
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 3
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 3
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 3
- 229940045803 cuprous chloride Drugs 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 3
- QERYCTSHXKAMIS-UHFFFAOYSA-N thiophene-2-carboxylic acid Chemical compound OC(=O)C1=CC=CS1 QERYCTSHXKAMIS-UHFFFAOYSA-N 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 2
- RLKHFSNWQCZBDC-UHFFFAOYSA-N n-(benzenesulfonyl)-n-fluorobenzenesulfonamide Chemical compound C=1C=CC=CC=1S(=O)(=O)N(F)S(=O)(=O)C1=CC=CC=C1 RLKHFSNWQCZBDC-UHFFFAOYSA-N 0.000 claims description 2
- 238000010791 quenching Methods 0.000 claims description 2
- 230000000171 quenching effect Effects 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 10
- 238000003786 synthesis reaction Methods 0.000 abstract description 10
- 239000003054 catalyst Substances 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 4
- 239000011368 organic material Substances 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 38
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- 238000005481 NMR spectroscopy Methods 0.000 description 24
- 150000001875 compounds Chemical class 0.000 description 17
- 239000003480 eluent Substances 0.000 description 10
- 239000003208 petroleum Substances 0.000 description 10
- 238000010898 silica gel chromatography Methods 0.000 description 10
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- 238000001514 detection method Methods 0.000 description 6
- 238000002390 rotary evaporation Methods 0.000 description 6
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 5
- ZIUHHBKFKCYYJD-UHFFFAOYSA-N n,n'-methylenebisacrylamide Chemical class C=CC(=O)NCNC(=O)C=C ZIUHHBKFKCYYJD-UHFFFAOYSA-N 0.000 description 5
- 239000000463 material Substances 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 238000004293 19F NMR spectroscopy Methods 0.000 description 3
- 150000001361 allenes Chemical class 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229930014626 natural product Natural products 0.000 description 2
- 229910000510 noble metal Inorganic materials 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 125000003046 allene group Chemical group 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
Images
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
- C07C233/11—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
-
- 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
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/22—Separation; Purification; Stabilisation; Use of additives
- C07C231/24—Separation; Purification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C239/00—Compounds containing nitrogen-to-halogen bonds; Hydroxylamino compounds or ethers or esters thereof
- C07C239/02—Compounds containing nitrogen-to-halogen bonds
- C07C239/06—N-halogenated carboxamides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/18—Systems containing only non-condensed rings with a ring being at least seven-membered
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyridine Compounds (AREA)
Abstract
The invention belongs to the technical field of organic material synthesis, and relates to a multisubstituent-group-containing diluted amide compound and a preparation method thereof, wherein the multisubstituent-group-containing diluted amide compound has a structural formula shown in a formula I:
wherein: n is 0, 1 or 2; ar is any one of phenyl, p-methylphenyl and p-chlorophenyl. The preparation method is that under the action of copper salt, inorganic base and 2, 2' -dipyridine as catalysts, alpha, beta unsaturated amide derivatives react with phenylacetylene compounds to generate multi-substituent bi-dilute amide compounds. The invention has the advantages of easily obtained raw materials and low cost; combination of Chinese herbsMild condition, high synthesis yield and great industrialization potential.
Description
Technical Field
The invention belongs to the technical field of organic material synthesis, and relates to a multi-substituent-containing biannuine amide compound and a preparation method thereof.
Background
The allene is an important organic intermediate containing an allene functional group, and can be widely applied to synthesis of a plurality of natural compounds and drug molecules due to a plurality of allene reaction sites. The synthesis of polysubstituted allenes has been a very important research direction in the field of organic chemistry. Although the methods for constructing the allene compounds are various at present, most of the allene compounds are aryl or heteroatom substitution type allene compounds, and the synthesis of the allene compounds has problems and defects; the preparation of the multi-substituted dilute compound by using the noble metal catalyst is relatively high in cost, high in noble metal residue and not friendly to the environment.
The polysubstituted dienamide compound has very high atom economy and step economy due to the structural characteristics, and the synthesized polysubstituted dienamide compound can be used in the fields of medicines and materials, but the literature for constructing the polysubstituted dienamide compound is not reported so far.
Disclosure of Invention
Aiming at the problems, the invention provides a bidilute amide compound containing polysubstituent groups and a preparation method thereof, and the compound has the advantages of easily obtained raw materials and low cost; the synthesis condition is mild, the synthesis yield is high, and the method has great industrialization potential.
In order to achieve the purpose, the invention adopts the technical scheme that:
the structural formula of the bis-dilute amide compound containing polysubstituent is shown as the formula I:
wherein: n is 0, 1 or 2; ar is any one of phenyl, p-methylphenyl and p-chlorophenyl.
The preparation process of bidilute amide compound containing polysubstituent includes the following steps:
1) preparing alpha, beta unsaturated amide derivatives for later use; the structural formula of the alpha, beta unsaturated amide derivative is shown as a formula II:
wherein: n is 0, 1 or 2;
2) sequentially adding a phenylacetylene compound, copper salt, inorganic base and 2, 2' -bipyridyl into the alpha, beta unsaturated amide derivative prepared in the step 1), mixing, adding a reaction solvent in a nitrogen atmosphere, and reacting at the temperature of 20-60 ℃ for 10-24 hours;
3) and after the reaction is finished, adding silica gel, evaporating, concentrating and carrying out chromatography to obtain a white solid, namely the bidilute amide compound shown in the formula I.
Further, in the step 2), the molar ratio of the alpha, beta unsaturated amide derivative to the phenylacetylene compound is 1: 1-3; the molar ratio of the copper salt to the alpha, beta unsaturated amide derivative is 1: 10-20; the molar ratio of the alpha, beta unsaturated amide derivative to the inorganic base is 1: 1-3; the molar ratio of the copper salt to the 2, 2' -bipyridine is 1: 1-2; (ii) a The molar volume ratio of the alpha, beta unsaturated amide derivative to the reaction solvent is 1 mmol: 2-3 mL.
Further, the phenylacetylene compound is phenylacetylene, p-methylphenylacetylene or p-chlorophenylacetylene; the reaction solvent is tetrahydrofuran, diethyl ether, toluene, n-hexane or dichloromethane.
Further, the copper salt is any one of cuprous iodide, cuprous bromide, cuprous chloride, cuprous acetate, cuprous thiophene-2-formate CuTc and cuprous thiocyanate.
Further, the inorganic base is any one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium ethoxide, sodium methoxide, sodium tert-butoxide and potassium tert-butoxide.
Further, in the step 1), the α, β unsaturated amide derivative is prepared by:
1.1) taking an alpha, beta-unsaturated cyclic amide substrate, exchanging air with nitrogen for multiple times, continuously adding an organic solvent into the alpha, beta-unsaturated cyclic amide substrate, and stirring the mixture in an ice bath for 15min to obtain a reaction system A;
1.2) slowly dropwise adding n-butyllithium into the reaction system A, and continuously stirring for 1.5 hours under the ice bath condition to obtain a reaction system B;
1.3) dissolving N-fluoro-diphenyl sulfonamide NFSI in an organic solution to obtain a mixed solution, dropwise adding the mixed solution into the reaction system B obtained in the step 2), and stirring for 10 hours after the room temperature is restored in an ice bath to obtain a reaction system C;
1.4) quenching the reaction system C by using a hydrochloric acid aqueous solution, extracting by using dichloromethane, and sequentially washing, drying, filtering, evaporating, concentrating, carrying out chromatography and purifying on the obtained organic layer to obtain yellow oily liquid, namely the alpha, beta unsaturated amide derivative.
Further, in the step 1.1), the mass-to-volume ratio of the α, β -unsaturated cyclic amide substrate to the organic solvent is 1 g: 15-50 mL; the structural formula of the alpha, beta-unsaturated cyclic amide substrate is shown in the specification
The organic solvent is any one of dichloromethane, trichloromethane, anhydrous tetrahydrofuran, 1, 2-dichloroethane, acetonitrile, toluene and 1, 4-dioxane.
Further, in the step 1.2), the volume-to-mass ratio of the n-butyllithium to the α, β -unsaturated cyclic amide substrate is 2.0 to 3.0 mL: 1g of the total weight of the composition.
Further, in the step 1.3), the mass ratio of the N-fluoro-diphenyl sulfonamide to the alpha, beta-unsaturated cyclic amide substrate is 1.5-5: 1; the mass-volume ratio of the N-fluorobisbenzenesulfonamide to the organic solution is 1 g: 15-30 mL; the organic solution is tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether or methyl tert-butyl ether.
The invention has the beneficial effects that:
1. the invention takes copper salt, inorganic base and 2, 2' -bipyridyl as catalysts, takes alpha, beta unsaturated amide derivatives with different structures and phenylacetylene compounds as raw materials, synthesizes the polysubstituted biarylamide derivatives with high yield, has high synthesis yield, and simultaneously synthesizes the synthesized biarylamide derivatives which are the core skeletons of a plurality of natural products and drug molecules.
2. The preparation method provided by the invention has the advantages of easily available raw materials, low catalyst price, mild reaction conditions, wide substrate application range, good yield, no metal residue in synthesis and environmental friendliness; has great industrialization potential.
Drawings
FIG. 1 is II-a1H nuclear magnetic resonance spectrogram;
FIG. 2 is II-a13C nuclear magnetic resonance spectrogram;
FIG. 3 is II-a19F nuclear magnetic resonance spectrogram;
FIG. 4 is II-b1H nuclear magnetic resonance spectrogram;
FIG. 5 is II-b13C nuclear magnetic resonance spectrogram;
FIG. 6 is II-b19F nuclear magnetic resonance spectrogram;
FIG. 7 is II-c1H nuclear magnetic resonance spectrogram;
FIG. 8 is II-c13C nuclear magnetic resonance spectrogram;
FIG. 9 is II-c19F nuclear magnetic resonance spectrogram;
FIG. 10 is I-a1H nuclear magnetic resonance spectrogram;
FIG. 11 is I-a13C nucleusA magnetic resonance spectrogram;
FIG. 12 is I-b1H nuclear magnetic resonance spectrogram;
FIG. 13 is I-b13C nuclear magnetic resonance spectrogram;
FIG. 14 is the 1H NMR spectrum of I-c;
FIG. 15 is I-c13C nuclear magnetic resonance spectrogram;
FIG. 16 is I-d1H nuclear magnetic resonance spectrogram;
FIG. 17 is I-d13C nuclear magnetic resonance spectrogram;
FIG. 18 is I-e1H nuclear magnetic resonance spectrogram;
FIG. 19 is I-e13C nuclear magnetic resonance spectrogram;
Detailed Description
The present invention will now be described in detail with reference to the accompanying drawings and examples.
According to the invention, copper salt, inorganic base and bipyridyl are used as catalysts to realize an ethynylation reaction of alpha, beta unsaturated amide derivatives (structural formula is shown in formula II) and phenylacetylene compounds, so that polysubstituted bisacrylamide derivatives (structural formula is shown in formula I) are generated through isomerization.
In the present invention, in formula I and formula II, n is any one of 0, 1, and 2; in the formula I, Ar is any one of phenyl, p-methylphenyl and p-chlorophenyl.
The structure of formula II in the invention includes II-a, II-b or II-c, and the specific structural formulas are respectively as follows:
in the present invention, formula II is prepared from an α, β -unsaturated cyclic amide substrate. The structure of the alpha, beta-unsaturated cyclic amide substrate is 1a, 1b or 1c, and II-a, II-b or II-c is respectively prepared.
The preparation method of the polysubstituted bisacrylamide derivative comprises the following steps:
1) preparing alpha, beta unsaturated amide derivatives by adopting different alpha, beta-unsaturated cyclic amide substrates for later use; the preparation method comprises the following specific steps:
1.1) adding an alpha, beta-unsaturated cyclic amide substrate into a three-necked bottle, exchanging air with nitrogen for 3 times, adding an organic solvent, and stirring in an ice bath for 15 minutes to obtain a reaction system A;
1.2) slowly reducing the valence of n-butyllithium into the reaction system A, and continuously stirring for 1.5 hours under the ice bath condition to obtain a reaction system B;
1.3) dissolving N-fluoro-diphenyl sulfonamide in an organic solution, and dropwise adding the solution into the reaction system B to obtain a reaction system C;
1.4) reaction C was then placed in an ice bath and stirred for 10 hours at room temperature, the reaction was quenched with 1M aqueous hydrochloric acid and transferred to a separating funnel, extracted three times with dichloromethane and the organic layer was then saturated with NaHCO3Washing the aqueous solution with saturated brine, and then washing the aqueous solution with MgSO 44Drying, filtering, rotary evaporating, concentrating, purifying by silica gel column chromatography (eluent is petroleum ether: ethyl acetate 20/1, v/v) to obtain yellow oily liquid, namely alpha, beta unsaturated amide derivatives;
in the invention, the mass-volume ratio of the alpha, beta-unsaturated cyclic amide substrate to the organic solvent is 1 g: 15-50 mL; the volume mass ratio of n-butyl lithium to the alpha, beta-unsaturated cyclic amide substrate is 2.0-3.0 mL: 1g of a compound; the mass-volume ratio of the N-fluoro-diphenyl sulfonamide to the organic solution is 1 g: 15-30 mL; the mass ratio of the N-fluoro-diphenyl sulfonamide to the alpha, beta-unsaturated cyclic amide substrate is 1.5-5: 1;
2) then preparing the alpha, beta unsaturated amide derivatives and phenylacetylene compounds to obtain the polysubstituted dienamide derivatives.
Adding alpha, beta unsaturated amide derivatives, phenylacetylene, copper salt, inorganic base and 2, 2' -bipyridine into a reaction tube in sequence, exchanging air for 3 times by using nitrogen, adding a reaction solvent under the nitrogen atmosphere, and reacting for 24 hours at room temperature;
in the invention, the mol ratio of the alpha, beta unsaturated amide derivative to the phenylacetylene compound is 1: 1-3; the molar ratio of the copper salt to the alpha, beta unsaturated amide derivative is 1: 10-20; the molar ratio of the alpha, beta unsaturated amide derivative to the inorganic base is 1: 1-3; the molar ratio of the copper salt to the 2, 2' -bipyridine is 1: 1-2; (ii) a The molar volume ratio of the alpha, beta unsaturated amide derivative to the reaction solvent is 1 mmol: 2-3 mL;
3) after the TCL detection reaction is finished, silica gel is directly added, and after rotary evaporation and concentration, silica gel column chromatography is performed (eluent is petroleum ether: ethyl acetate 20/1, v/v) gave a white solid, i.e. a polysubstituted bisacrylamide compound.
In the invention, the phenylacetylene compound is phenylacetylene, p-methylphenylacetylene or p-chlorophenylacetylene.
In the invention, the reaction solvent is tetrahydrofuran, diethyl ether, toluene, n-hexane or dichloromethane.
In the invention, the copper salt is any one of cuprous iodide, cuprous bromide, cuprous chloride, cuprous acetate, thiophene-2-formic acid, CuTc and cuprous thiocyanate.
In the invention, the inorganic base is any one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium ethoxide, sodium methoxide, sodium tert-butoxide and potassium tert-butoxide.
In the invention, the organic solvent is any one of dichloromethane, trichloromethane, anhydrous tetrahydrofuran, 1, 2-dichloroethane, acetonitrile, toluene and 1, 4-dioxane.
In the invention, the organic solution is tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether or methyl tert-butyl ether.
According to the preparation method, the alpha, beta unsaturated amide derivatives, the reaction solvent, the copper salt, the organic solvent and the organic solution are selected differently, and the ratio of the materials is different, so that the preparation of the target product can have various implementation routes. Some examples are shown in table 1.
Table 1 shows 9 preparation test examples according to the present invention
The preparation method of the polysubstituted bisacrylamide derivative provided by the invention is explained in detail by 1-5 groups.
Example 1
In the embodiment, the alpha, beta unsaturated amide derivatives with the structure of II-a and phenylacetylene are selected to synthesize the polysubstituted dienamide compound I-a.
The preparation process of the polysubstituted bisacrylamide compound I-a provided in this example is:
1) preparation of alpha, beta-unsaturated amide derivatives of formula II-a
In this example, an α, β -unsaturated amide derivative with a structure of II-a is prepared from an α, β -unsaturated cyclic amide substrate 1a, and the preparation route of formula II-a is as follows:
the preparation steps provided in this example are:
1.1) adding 1.95g of amide substrate 1a into a 100mL three-necked flask, exchanging air with nitrogen for 3 times, adding 30mL of an organic solvent (anhydrous tetrahydrofuran), and stirring in an ice bath for 15 minutes to obtain a reaction system A;
1.2) then slowly adding 4.6mL of n-butyllithium into the reaction system A at a low price, and continuously stirring for 1.5 hours under the ice bath condition to obtain a reaction system B;
1.3) dissolving 3.87g of N-fluoro-bis-benzenesulfonamide in 20mL of organic solution (tetrahydrofuran), and dropwise adding the solution into the reaction system B to obtain a reaction system C;
1.4) reaction C was then placed in an ice bath and stirred for 10 hours at room temperature, the reaction was quenched with 1M aqueous hydrochloric acid and transferred to a separating funnel, extracted three times with dichloromethane and the organic layer was then saturated with NaHCO3Washing the aqueous solution with saturated brine, and then washing the aqueous solution with MgSO 44Drying, filtering, rotary evaporating for concentrating, purifying by silica gel column chromatography (eluent is petroleum ether: ethyl acetate 20/1, v/v) to obtain yellow oily liquid, which is the alpha, beta unsaturated amide derivatives with structural formula as II-a, the yield is 65%;
the α, β unsaturated amide derivatives with structural formula II-a prepared in this example were subjected to nmr test, and the results are shown in fig. 1 to 3:
1H NMR(400MHz,CDCl3):δ5.96(dt,J＝7.2,1.2Hz,1H),2.78-2.62(m,2H),2.28-2.14(m,2H),1.72-1.54(m,6H),1.45(d,J＝2.0Hz,9H)；13C NMR(100MHz,CDCl3):δ173.3(d,J＝4.1Hz),162.5(d,J＝4.7Hz),113.2(d,J＝7.5Hz),64.0(d,J＝10.0Hz),38.3,30.3,28.7,27.9,27.2(d,J＝6.5Hz),26.3；19F NMR(376MHz,CDCl3):δ-72.18；
2) alpha, beta unsaturated amide derivatives with structural formula II-a and phenylacetylene synthesized polysubstituted dienamide compounds I-a
In the embodiment, the preparation technical route of I-a is as follows:
in this example, the preparation process of I-a includes:
0.2mmol of α, β -unsaturated amide-based derivative II-a (mass: 42.6mg), 0.4mmol of phenylacetylene (mass: 40.8mg), 0.02mmol of copper salt (copper iodide), 0.2mmol of cesium carbonate (mass: 65.2mg) and 0.02mmol of 2, 2' -bipyridine (mass: 3.12g) were sequentially added to a 25mL reaction tube, air was exchanged with nitrogen for 3 times, and 0.5mL of a reaction solvent (tetrahydrofuran) was added under a nitrogen atmosphere, and reacted at 20 ℃ for 24 hours;
3) after the TCL detection reaction is finished, silica gel is directly added, and after rotary evaporation and concentration, silica gel column chromatography is performed (eluent is petroleum ether: ethyl acetate 20/1, v/v) to obtain white solid, namely the polysubstituted bisacrylamide compound, namely I-a, the structural formula of which is shown in the specification
The yield was 74%.
The poly-substituted bisacrylamide compound I-a prepared in this example was subjected to nmr measurement, and the results are shown in fig. 10 and fig. 11.
As can be seen from fig. 10 and 11:1H NMR(400MHz,CDCl3):δ7.37-7.29(m,4H),7.28-7.22(m,1H),6.57(s,1H),6.22-6.16(m,1H),5.71(s,1H),2.23-1.96(m,4H),1.71-1.60(m,4H),1.35(s,9H)；13CNMR(100MHz,CDCl3):δ206.0,164.6,133.3,129.2,128.9,128.4,127.7,127.0,112.9,99.6,51.6,28.7,27.2,26.0,22.7,22.0。
example 2
In the embodiment, the alpha, beta unsaturated amide derivatives with the structure of II-a and p-methylphenylacetylene are used for synthesizing the polysubstituted dienamide compounds I-b.
The preparation process provided in this example includes the following steps:
1) preparation of alpha, beta-unsaturated amide derivatives of formula II-a
In this embodiment, the preparation of the α, β unsaturated amide derivatives of II-a is the same as that of example 1; the specific material and dosage selection is shown in group 2 in table 1;
2) alpha, beta unsaturated amide derivatives with structural formula II-a and p-methyl phenylacetylene for synthesizing polysubstituted dienamide compounds I-b
In the implementation, the preparation technical route of I-b is as follows:
in this embodiment, the preparation of I-b comprises:
2.1) adding 0.25mmol of the α, β unsaturated amide derivative II-a, 0.25mmol of p-tolylacetylene, 0.017mmol of copper salt (copper iodide), 0.5mmol of cesium carbonate (163 mg in mass) and 0.034mmol of 2, 2' -bipyridine in this order to a 25mL reaction tube, exchanging air with nitrogen for 3 times, adding 0.75mL of a reaction solvent (optionally diethyl ether) under nitrogen atmosphere, and reacting at 45 ℃ for 16 hours;
3) after the TCL detection reaction is finished, silica gel is directly added, and after rotary evaporation and concentration, silica gel column chromatography is performed (eluent is petroleum ether: ethyl acetate 20/1, v/v) gave a white solid; namely a polysubstituted dienamide compound, is marked as I-b, and has a structural formula
The yield was 70%.
The poly-substituted bisacrylamide compound I-b prepared in this example was subjected to nmr measurement, and the results are shown in fig. 12 and 13.
From fig. 12 and 13:1H NMR(400MHz,CDCl3):δ7.38-7.32(d,m,2H),7.13(s,1H),7.09-7.00(m,2H),6.72(s,1H),5.93(s,1H),2.35(s,3H),2.30-1.95(m,4H),1.74-1.56(m,4H),1.32(s,9H)；13C NMR(100MHz,CDCl3):δ206.0,164.7,133.3,129.2,129.0,128.8,127.9,127.0,112.9,99.7,51.6,28.6,27.3,26.0,25.3,22.7,22.0。
example 3
In the embodiment, the alpha, beta unsaturated amide derivatives with the structure of II-a and p-chlorophenyl acetylene are used to synthesize the polysubstituted dienamide compounds I-b, and the specific preparation method comprises the following steps:
1) preparation of alpha, beta-unsaturated amide derivatives of formula II-a
In the present embodiment, the preparation of the α, β unsaturated amide derivatives of II-a is the same as the preparation method of example 1, and the specific material and dosage are selected and shown in group 3 in table 1;
2) alpha, beta unsaturated amide derivatives with structural formula II-a and p-chlorophenyl acetylene synthesized polysubstituted dienamide compounds I-c
In the embodiment, the preparation technical route of I-c is as follows:
in this example, the preparation process of I-c includes:
0.12mmol of α, β -unsaturated amide derivative II-a, 0.36mmol of p-chlorophenylacetylene, 0.006mmol of copper salt (copper iodide), 0.36mmol of cesium carbonate (117.3 mg by mass), and 0.009mmol of 2, 2' -bipyridine were sequentially charged into a 25mL reaction tube, air was exchanged with nitrogen gas for 3 times, and 0.9mL of a reaction solvent (toluene) was added under a nitrogen atmosphere, and reacted at 60 ℃ for 10 hours;
3) after the TCL detection reaction is finished, silica gel is directly added, and after rotary evaporation and concentration, silica gel column chromatography is performed (eluent is petroleum ether: ethyl acetate 20/1, v/v) to obtain a white solid, namely the polysubstituted bisacrylamide compound, which is marked as I-c and has the structural formula
The yield was 58%.
The poly-substituted bisacrylamide compound I-c prepared in this example was subjected to nmr measurement, and the results are shown in fig. 14 and fig. 15.
As can be seen from fig. 14 and 15:1HNMR(400MHz,CDCl3):δ7.60(d,J＝7.6Hz,2H),7.40-7.30(m,2H),7.07(s,1H),6.42-6.30(m,1H),5.94(s,1H),2.38-1.99(m,4H),1.76-1.60(m,4H),1.37(s,9H)；13CNMR(100MHz,CDCl3):δ207.0,165.6,134.3,130.2,129.9,129.4,128.8,128.0,113.9,100.6,52.6,29.7,27.0,26.3,23.0,22.2。
example 4
In the embodiment, the alpha, beta unsaturated amide derivatives with the structure of II-b and phenylacetylene are selected to synthesize the polysubstituted dienamide compounds I-d, and the preparation process comprises the following steps:
1) preparation of alpha, beta-unsaturated amide derivatives of formula II-b
This example prepares α, β unsaturated amide derivatives of structural formula II-b from α, β -unsaturated cyclic amide substrate 1b
In this example, the route of the preparation technique of II-b is as follows:
in this example, the preparation process of II-b is:
1.1) adding 1.81g of amide substrate 1b into a 100mL three-necked flask, exchanging air with nitrogen for 3 times, adding 30mL of organic solvent (1, 2-dichloroethane), and stirring in an ice bath for 15 minutes to obtain a reaction system A;
1.2) then slowly adding 4.6mL of n-butyllithium into the reaction system A at a low price, and continuously stirring for 1.5 hours under the ice bath condition to obtain a reaction system B;
1.3) dissolving 3.87g of N-fluoro-bis-benzenesulfonamide in 20mL of organic solution (methyl tert-butyl ether), and dropwise adding the solution into the reaction system B to obtain a reaction system C;
1.4) reaction C was then placed in an ice bath and stirred for 10 hours at room temperature, the reaction was quenched with 1M aqueous hydrochloric acid and transferred to a separating funnel, extracted three times with dichloromethane and the organic layer was then saturated with NaHCO3Washing the aqueous solution with saturated brine, and then washing the aqueous solution with MgSO 44Drying, filtering, rotary evaporating, concentrating, purifying by silica gel column chromatography (eluent is petroleum ether: ethyl acetate 20/1, v/v) to obtain yellow oily liquid, i.e. the alpha, beta unsaturated amide derivatives with the structure of II-b, with the yield of 62%.
The alpha, beta unsaturated amide derivatives with the structural formula II-b prepared in this example were subjected to NMR tests, and the results are shown in FIGS. 4-6.
From FIGS. 4-6, it can be seen that:1H NMR(400MHz,CDCl3):δ5.93(dt,J＝7.2,1.2Hz,1H),2.72-2.60(m,2H),2.30-2.14(m,2H),1.70-1.54(m,4H),1.43(d,J＝2.0Hz,9H)；13C NMR(100MHz,CDCl3):δ173.4(d,J＝4.1Hz),162.5(d,J＝4.8Hz),113.2(d,J＝7.2Hz),63.9(d,J＝10.0Hz),38.2,30.3,28.7,27.9,27.2(d,J＝6.6Hz)；19F NMR(376MHz,CDCl3):δ-72.30；
2) alpha, beta unsaturated amide derivatives with structural formula II-b and phenylacetylene to synthesize polysubstituted dienamide compounds I-d
In the embodiment, the preparation technical route of I-d is as follows:
in this example, the preparation process of I-d is:
0.2mmol of α, β unsaturated amide-based derivative II-b (mass: 39.8mg), 0.4mmol of phenylacetylene (mass: 40.8mg), 0.02mmol of copper salt (copper iodide), 0.2mmol of cesium carbonate (mass: 65.2mg) and 0.02mmol of 2, 2' -bipyridine (mass: 3.12g) were sequentially added to a 25mL reaction tube, air was exchanged with nitrogen for 3 times, and 0.5mL of a reaction solvent (n-hexane was selected) was added under a nitrogen atmosphere, and reacted at 20 ℃ for 24 hours;
3) after the TCL detection reaction is finished, silica gel is directly added, and after rotary evaporation and concentration, silica gel column chromatography is performed (eluent is petroleum ether: ethyl acetate 20/1, v/v) to obtain a white solid, namely the polysubstituted bisacrylamide compound, which is marked as I-d and has the structural formula
The yield was 65%.
The poly-substituted bisacrylamide compounds I-d prepared in this example were subjected to a nuclear magnetic resonance test, and the results are shown in FIGS. 16 and 17.
As can be seen from fig. 16 and 17:1H NMR(400MHz,CDCl3):δ7.35-7.26(m,4H),7.30-7.20(m,1H),6.59(s,1H),6.22-6.13(m,1H),5.76(s,1H),2.29-1.97(m,4H),1.73-1.60(m,4H),1.34(s,9H)；13CNMR(100MHz,CDCl3):δ205.8,164.8,133.5,129.2,129.0,128.3,127.8,127.0,112.8,99.7,51.6,28.8,27.3,22.6,21.9。
example 5
In the embodiment, the alpha, beta unsaturated amide derivatives with the structure of II-c and phenylacetylene are selected to synthesize the polysubstituted dienamide compounds I-e, and the preparation process comprises the following steps:
1) preparation of alpha, beta unsaturated amide derivatives of structural formula II-c
This example prepares α, β unsaturated amide derivatives of structural formula II-c from α, β -unsaturated cyclic amide substrate 1c
In this example, the preparation route of II-c is as follows:
in this example, II-c was prepared by the following steps:
1.1) adding 2.0g of amide substrate 1c into a 100mL three-necked flask, exchanging air with nitrogen for 3 times, adding 30mL of organic solvent (acetonitrile), and stirring in an ice bath for 15 minutes to obtain a reaction system A;
1.2) then slowly adding 4.6mL of n-butyllithium into the reaction system A at a low price, and continuously stirring for 1.5 hours under the ice bath condition to obtain a reaction system B;
1.3) dissolving 3.87g of N-fluoro-bis-benzenesulfonamide in 20mL of organic solution (methyl tert-butyl ether), and dropwise adding the solution into the reaction system B to obtain a reaction system C;
1.4) reaction C was then placed in an ice bath and stirred for 10 hours at room temperature, the reaction was quenched with 1M aqueous hydrochloric acid and transferred to a separating funnel, extracted three times with dichloromethane and the organic layer was then saturated with NaHCO3Washing the aqueous solution with saturated brine, and then washing the aqueous solution with MgSO 44Drying, filtering, rotary evaporating for concentrating, and purifying by silica gel column chromatography (eluent is petroleum ether: ethyl acetate 20/1, v/v) to obtain yellow oily liquid, i.e. the alpha, beta unsaturated amide derivatives with structural formula II-c, with a yield of 57%.
The α, β unsaturated amide derivatives of formula II-c prepared in this example were subjected to NMR tests and the results are shown in FIGS. 7-9.
As can be seen from fig. 7-9:1H NMR(400MHz,CDCl3):δ5.98(dt,J＝7.2,1.2Hz,1H),2.78-2.62(m,2H),2.40-2.24(m,2H),1.79-1.54(m,8H),1.45(d,J＝2.0Hz,9H)；13C NMR(100MHz,CDCl3):δ173.7(d,J＝4.1Hz),162.8(d,J＝4.8Hz),113.4(d,J＝7.6Hz),63.9(d,J＝10.0Hz),38.2,30.3,28.7,27.9,27.2(d,J＝6.6Hz),26.4,26.3；19F NMR(376MHz,CDCl3):δ-73.02；
2) alpha, beta unsaturated amide derivatives with structural formula II-c and phenylacetylene to synthesize polysubstituted dienamide compounds I-e
In the embodiment, the preparation technical route of I-e is as follows:
in this example, the preparation process of I-e is:
0.2mmol of α, β unsaturated amide-based derivative II-c (45.4 mg in mass), 0.4mmol of phenylacetylene (40.8 mg in mass), 0.02mmol of copper salt (copper iodide), 0.2mmol of cesium carbonate (65.2 mg in mass), and 0.02mmol of 2, 2' -bipyridine (3.12 g in mass) were sequentially added to a 25mL reaction tube, air was exchanged with nitrogen 3 times, and 0.5mL of a reaction solvent (dichloromethane) was added under a nitrogen atmosphere, and reacted at 60 ℃ for 12 hours;
3) after the TCL detection reaction is finished, silica gel is directly added, and after rotary evaporation and concentration, silica gel column chromatography is performed (eluent is petroleum ether: ethyl acetate 20/1, v/v) to obtain a white solid, namely the polysubstituted bisacrylamide compound, which is marked as I-e and has the structural formula
The yield was 59%.
The poly-substituted bisacrylamide compounds I-e prepared in this example were subjected to a nuclear magnetic resonance test, and the results are shown in FIGS. 18 and 19.
As can be seen from fig. 18 and 19:1H NMR(400MHz,CDCl3):δ7.35-7.26(m,4H),7.27-7.25(m,1H),6.60(s,1H),6.27-6.20(m,1H),5.76(s,1H),2.25-1.99(m,4H),1.75-1.63(m,4H),1.39(s,9H)；13CNMR(100MHz,CDCl3):δ206.2,164.7,133.4,129.3,128.9,128.5,127.8,127.2,113.0,99.7,51.7,28.8,27.2,26.4,26.0,22.8,22.2。
Claims (10)
1. a bis-dilute amide compound containing polysubstituent, which is characterized in that: the structural formula of the bidilute amide compound is shown as the formula I:
wherein: n is 0, 1 or 2; ar is any one of phenyl, p-methylphenyl and p-chlorophenyl.
2. A method for preparing the multisubstituent-containing bis-dilute-amide compound of claim 1, which comprises the following steps: the preparation method comprises the following steps:
1) preparing alpha, beta unsaturated amide derivatives for later use; the structural formula of the alpha, beta unsaturated amide derivative is shown as a formula II:
wherein: n is 0, 1 or 2;
2) sequentially adding a phenylacetylene compound, copper salt, inorganic base and 2, 2' -bipyridyl into the alpha, beta unsaturated amide derivative prepared in the step 1), mixing, adding a reaction solvent in a nitrogen atmosphere, and reacting at the temperature of 20-60 ℃ for 10-24 hours;
3) and after the reaction is finished, adding silica gel, evaporating, concentrating and carrying out chromatography to obtain a white solid, namely the bidilute amide compound shown in the formula I.
3. The method of claim 2, wherein: in the step 2), the molar ratio of the alpha, beta unsaturated amide derivative to the phenylacetylene compound is 1: 1-3; the molar ratio of the copper salt to the alpha, beta unsaturated amide derivative is 1: 10-20; the molar ratio of the alpha, beta unsaturated amide derivative to the inorganic base is 1: 1-3; the molar ratio of the copper salt to the 2, 2' -bipyridine is 1: 1-2; (ii) a The molar volume ratio of the alpha, beta unsaturated amide derivative to the reaction solvent is 1 mmol: 2-3 mL.
4. The production method according to claim 3, characterized in that: the phenylacetylene compound is phenylacetylene, p-methylphenylacetylene or p-chlorophenylacetylene; the reaction solvent is tetrahydrofuran, diethyl ether, toluene, n-hexane or dichloromethane.
5. The production method according to claim 3, characterized in that: the copper salt is any one of cuprous iodide, cuprous bromide, cuprous chloride, cuprous acetate, thiophene-2-formic acid CuTc and cuprous thiocyanate.
6. The production method according to claim 3, characterized in that: the inorganic base is any one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium ethoxide, sodium methoxide, sodium tert-butoxide and potassium tert-butoxide.
7. The method of claim 2, wherein: in the step 1), the preparation process of the alpha, beta unsaturated amide derivative comprises the following steps:
1.1) taking an alpha, beta-unsaturated cyclic amide substrate, exchanging air with nitrogen for multiple times, continuously adding an organic solvent into the alpha, beta-unsaturated cyclic amide substrate, and stirring the mixture in an ice bath for 15min to obtain a reaction system A;
1.2) slowly dropwise adding n-butyllithium into the reaction system A, and continuously stirring for 1.5 hours under the ice bath condition to obtain a reaction system B;
1.3) dissolving N-fluoro-diphenyl sulfonamide NFSI in an organic solution to obtain a mixed solution, dropwise adding the mixed solution into the reaction system B obtained in the step 2), and stirring for 10 hours after the room temperature is restored in an ice bath to obtain a reaction system C;
1.4) quenching the reaction system C by using a hydrochloric acid aqueous solution, extracting by using dichloromethane, and sequentially washing, drying, filtering, evaporating, concentrating, carrying out chromatography and purifying on the obtained organic layer to obtain yellow oily liquid, namely the alpha, beta unsaturated amide derivative.
8. The method of claim 7, wherein: in the step 1.1), the mass-to-volume ratio of the alpha, beta-unsaturated cyclic amide substrate to the organic solvent is 1 g: 15-50 mL; the structural formula of the alpha, beta-unsaturated cyclic amide substrate is shown in the specification
The organic solvent is any one of dichloromethane, trichloromethane, anhydrous tetrahydrofuran, 1, 2-dichloroethane, acetonitrile, toluene and 1, 4-dioxane.
9. The method of claim 7, wherein: in the step 1.2), the volume mass ratio of the n-butyllithium to the alpha, beta-unsaturated cyclic amide substrate is 2.0-3.0 mL: 1g of the total weight of the composition.
10. The method of claim 7, wherein: in the step 1.3), the mass ratio of the N-fluoro-diphenyl sulfonamide to the alpha, beta-unsaturated cyclic amide substrate is 1.5-5: 1; the mass-volume ratio of the N-fluorobisbenzenesulfonamide to the organic solution is 1 g: 15-30 mL; the organic solution is tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether or methyl tert-butyl ether.
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| MINGYU LIU等: "Atom-Economical Cross-Coupling of Internal and Terminal Alkynes to Access 1,3-Enynes", 《J. AM. CHEM. SOC.》 * |
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