WO2022206010A1 - Simple preparation method for isoxazolines - Google Patents
Simple preparation method for isoxazolines Download PDFInfo
- Publication number
- WO2022206010A1 WO2022206010A1 PCT/CN2021/136208 CN2021136208W WO2022206010A1 WO 2022206010 A1 WO2022206010 A1 WO 2022206010A1 CN 2021136208 W CN2021136208 W CN 2021136208W WO 2022206010 A1 WO2022206010 A1 WO 2022206010A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- isoxazoline
- nmr
- mhz
- cdcl
- olefin
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 150000002547 isoxazolines Chemical class 0.000 title abstract description 7
- 150000001336 alkenes Chemical class 0.000 claims abstract description 36
- 238000006243 chemical reaction Methods 0.000 claims abstract description 32
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 claims abstract description 27
- 239000003054 catalyst Substances 0.000 claims abstract description 21
- ICGLPKIVTVWCFT-UHFFFAOYSA-N 4-methylbenzenesulfonohydrazide Chemical compound CC1=CC=C(S(=O)(=O)NN)C=C1 ICGLPKIVTVWCFT-UHFFFAOYSA-N 0.000 claims abstract description 19
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 13
- 239000003513 alkali Substances 0.000 claims abstract description 8
- 239000000758 substrate Substances 0.000 claims abstract description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 36
- WEQPBCSPRXFQQS-UHFFFAOYSA-N 4,5-dihydro-1,2-oxazole Chemical compound C1CC=NO1 WEQPBCSPRXFQQS-UHFFFAOYSA-N 0.000 claims description 35
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 18
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 claims description 17
- 239000000126 substance Substances 0.000 claims description 17
- 239000002904 solvent Substances 0.000 claims description 15
- -1 aldehyde compound Chemical class 0.000 claims description 13
- 229910052802 copper Inorganic materials 0.000 claims description 13
- 239000010949 copper Substances 0.000 claims description 13
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 125000003118 aryl group Chemical group 0.000 claims description 9
- 239000002585 base Substances 0.000 claims description 9
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzenecarboxaldehyde Natural products O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims description 9
- 150000001299 aldehydes Chemical class 0.000 claims description 8
- 150000001408 amides Chemical class 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 150000002148 esters Chemical class 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 150000002431 hydrogen Chemical class 0.000 claims description 7
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims description 7
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 5
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 239000011737 fluorine Substances 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 4
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000000304 alkynyl group Chemical group 0.000 claims description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 4
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 229910052710 silicon Inorganic materials 0.000 claims description 4
- 239000010703 silicon Substances 0.000 claims description 4
- 125000003107 substituted aryl group Chemical group 0.000 claims description 4
- 150000003568 thioethers Chemical class 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 3
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 3
- 229960003280 cupric chloride Drugs 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims description 2
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 2
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 2
- 229940045803 cuprous chloride Drugs 0.000 claims description 2
- 125000001072 heteroaryl group Chemical group 0.000 claims description 2
- 229910052751 metal Inorganic materials 0.000 claims description 2
- 239000002184 metal Substances 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 claims description 2
- 125000001174 sulfone group Chemical group 0.000 claims description 2
- 150000003457 sulfones Chemical class 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims 3
- IVYRHDODWUZMTQ-UHFFFAOYSA-N 4,5-dihydro-1,2-oxazole 4,5-dihydro-1,3-oxazole Chemical compound O1N=CCC1.O1C=NCC1 IVYRHDODWUZMTQ-UHFFFAOYSA-N 0.000 claims 2
- 229910019142 PO4 Inorganic materials 0.000 claims 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims 1
- 239000010452 phosphate Substances 0.000 claims 1
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 abstract description 9
- 239000002994 raw material Substances 0.000 abstract description 8
- 239000003814 drug Substances 0.000 abstract description 6
- 229940079593 drug Drugs 0.000 abstract description 5
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 239000012414 tert-butyl nitrite Substances 0.000 abstract description 4
- 230000009286 beneficial effect Effects 0.000 abstract description 3
- IOGXOCVLYRDXLW-UHFFFAOYSA-N tert-butyl nitrite Chemical compound CC(C)(C)ON=O IOGXOCVLYRDXLW-UHFFFAOYSA-N 0.000 abstract description 3
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 abstract 1
- 238000007306 functionalization reaction Methods 0.000 abstract 1
- 238000005580 one pot reaction Methods 0.000 abstract 1
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 20
- 238000012360 testing method Methods 0.000 description 8
- 229910021592 Copper(II) chloride Inorganic materials 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 239000012046 mixed solvent Substances 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000003208 petroleum Substances 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 4
- 229910052723 transition metal Inorganic materials 0.000 description 4
- ZRYZBQLXDKPBDU-UHFFFAOYSA-N 4-bromobenzaldehyde Chemical compound BrC1=CC=C(C=O)C=C1 ZRYZBQLXDKPBDU-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229940125904 compound 1 Drugs 0.000 description 3
- 238000003760 magnetic stirring Methods 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 150000003624 transition metals Chemical class 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- UHOVQNZJYSORNB-MZWXYZOWSA-N benzene-d6 Chemical compound [2H]C1=C([2H])C([2H])=C([2H])C([2H])=C1[2H] UHOVQNZJYSORNB-MZWXYZOWSA-N 0.000 description 2
- CQEYYJKEWSMYFG-UHFFFAOYSA-N butyl acrylate Chemical compound CCCCOC(=O)C=C CQEYYJKEWSMYFG-UHFFFAOYSA-N 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 239000012973 diazabicyclooctane Substances 0.000 description 2
- 150000001989 diazonium salts Chemical class 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 2
- JQJPBYFTQAANLE-UHFFFAOYSA-N Butyl nitrite Chemical group CCCCON=O JQJPBYFTQAANLE-UHFFFAOYSA-N 0.000 description 1
- UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical group CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- XTVVROIMIGLXTD-UHFFFAOYSA-N copper(II) nitrate Chemical compound [Cu+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O XTVVROIMIGLXTD-UHFFFAOYSA-N 0.000 description 1
- 238000006352 cycloaddition reaction Methods 0.000 description 1
- 239000012024 dehydrating agents Substances 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- SKRDXYBATCVEMS-UHFFFAOYSA-N isopropyl nitrite Chemical group CC(C)ON=O SKRDXYBATCVEMS-UHFFFAOYSA-N 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- 239000008204 material by function Substances 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 238000006452 multicomponent reaction Methods 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 125000002270 phosphoric acid ester group Chemical group 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/04—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0003—Androstane derivatives
- C07J1/0018—Androstane derivatives substituted in position 17 beta, not substituted in position 17 alfa
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
- C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
- C07J7/001—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group
- C07J7/0015—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa
- C07J7/002—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa not substituted in position 16
Definitions
- the invention relates to a method for preparing isoxazoline, belonging to the technical field of organic synthesis.
- Isoxazolines are the core skeletons that widely exist in natural products, drug molecules, bioactive molecules, pesticides and functional materials. In addition, it has also been used as a ligand for transition metal catalysis. Chemists have developed a series of methods for the preparation of isoxazolines, but they all have obvious shortcomings, such as: requiring a large excess of oxidant or dehydrating agent; expensive raw materials or complicated preparation; harsh reaction conditions; expensive and harmful transition metals, etc. .
- the purpose of the present invention is to provide a method for preparing isoxazoline, which has the advantages of abundant raw material sources, wide universality of reaction substrates, simple operation, mild reaction conditions and the like.
- the technical scheme adopted in the present invention is: a simple preparation method of isoxazoline, using aldehyde, p-toluenesulfonyl hydrazide, alkene and nitrite as reaction substrates, in the presence of alkali and copper catalyst. Under the following conditions, the isoxazoline is obtained by reaction in an organic solvent.
- the product that the present invention obtains is isoxazoline, and its chemical structural formula is: .
- the general formula of the chemical structure of the aldehyde is: ;
- the general chemical structure of the alkene is: ;
- the general formula of chemical structure of described nitrite is: .
- R 1 is selected from aryl, substituted aryl, heteroaryl, naphthyl or alkenyl, such as aryl or substituted aryl:
- R 2 and R 3 are independently selected from hydrogen, alkyl, fluorine, chlorine, bromine, carboxylic acid, amide, thioether, amino, alkoxy, trifluoromethyl, nitro, cyano, ester, hydroxyl or sulfone group;
- R 4 , R 5 are independently selected from hydrogen, alkyl, aryl, ester, ether, amide, carbonyl, silicon, hydroxyl, acetal, cyano, halogen, alkynyl, carboxyl, phosphoric acid Ester group;
- R 6 is selected from tert-butyl, n-butyl, isobutyl, isopropyl.
- the copper catalyst is cupric chloride, cuprous chloride, cuprous bromide or cuprous iodide; preferably, the copper catalyst is cupric chloride.
- the amount of the copper catalyst is 5-20% of the mole of the olefin; the preferred amount of the copper catalyst is 10% of the mole of the olefin.
- the invention also discloses a method for preparing isoxazoline without metal catalyst. After mixing benzaldehyde compound and p-toluenesulfonyl hydrazide in methanol solvent, olefin, nitrite, organic solvent and alkali are added to react to obtain Isoxazoline; wherein, the general formula of the chemical structure of the benzaldehyde compound is as follows: .
- R 1 is selected from hydrogen, alkyl, fluorine, chlorine, bromine, carboxylic acid, amide, thioether, amino, alkoxy, trifluoromethyl, nitro, cyano, ester, hydroxyl or sulfone ;
- R 2 is selected from alkyl, aryl, ester, carbonyl, ether, amide, silicon, hydroxyl, benzal compound, cyano, halogen, alkynyl, carboxyl or phosphate group;
- R 6 is selected from tertiary Butyl, n-butyl, isobutyl or isopropyl.
- R 1 is selected from hydrogen, alkyl, fluorine, chlorine, bromine;
- R 2 is selected from aryl, ester group, such as phenyl, -COOEt, substituted phenyl.
- the benzaldehyde compound and p-toluenesulfonyl hydrazide are stirred in an alcohol solvent at 60° C. for 30 minutes, the methanol solvent is removed, and olefin, nitrite, organic solvent and alkali are added to react to obtain isoxazole. morpholino.
- the reaction temperature of the reaction is 25-80°C; the reaction time is 12-24 hours; the preferred reaction temperature is 65°C; and the reaction time is 24 hours.
- the reaction is carried out in the presence of a base, and the bases used are TMEDA, DABCO, and sodium carbonate; and the organic solvent is ethyl acetate, tetrahydrofuran, acetonitrile, acetone, chloroform, N , N -dimethylmethane amide.
- the base is preferably an organic amine, such as TMEDA, and the organic solvent is tetrahydrofuran.
- the amount of the aldehyde compound is 1 to 1.5 times the mole of the olefin; the amount of p-toluenesulfonyl hydrazide is 1 to 1.5 times the mole of the olefin, and the amount of nitrite is 3 to 5 times the mole of the olefin;
- the dosage is 1 to 1.8 times the mole weight of olefin; preferably, the dosage of the aldehyde compound is 1.3 times the mole weight of olefin; the dosage of p-toluenesulfonyl hydrazide is 1.4 times the mole weight of olefin, and the dosage of nitrite is the mole weight of olefin 4 times the amount of the base, and the amount of the base is 1.5 times the molar amount of the olefin.
- the reaction of the present invention is carried out in air. After the reaction, it was quenched with saturated sodium chloride solution, extracted with ethyl acetate, the solvent was removed by rotary evaporator, adsorbed on silica gel, and finally the product was obtained by column chromatography with a mixed solvent of ethyl acetate and petroleum ether. Isoxazoline.
- the preparation method of the present invention is shown as follows: The invention also discloses the isoxazoline prepared according to the above method.
- the present invention has the following advantages compared with the prior art: the present invention uses CuCl 2 as a catalyst to realize the multi-component reaction of aldehyde, p-toluenesulfonyl hydrazide, olefin and tert-butyl nitrite to prepare Isoxazoline is more economical in reaction, more widely applicable to substrates, easy to obtain raw materials, and easier to functionalize later, compared with the prior art, which is difficult to prepare raw materials, large amount of raw materials and harsh conditions.
- the method disclosed by the invention has mild reaction conditions, cheap catalyst and less dosage, good gram-scale reaction, convenient post-processing, and is beneficial to the application in drug molecule synthesis and large-scale industrialization.
- the reactants, additives, bases, catalysts and other raw materials used in the invention are cheap and easy to obtain, the reaction composition is reasonable, no ligand is required, and the reaction steps are few, and the functionalized isoxazoline can be obtained by only one step of reaction, which is in line with green chemistry and medicine. Chemistry requirements and directions.
- the present invention discloses a catalyst-free method for preparing isoxazoline, which avoids the use of transition metals and is favorable for further use in the synthesis of drug molecules and biologically active molecules.
- the aldehyde, olefin, p-toluenesulfonyl hydrazide, alkali, nitrite, catalyst and solvent of the present invention are all marketable commodities and can be purchased directly.
- the specific operation method and test method of the experiment are conventional methods in the field, and the reaction is carried out in a conventional environment.
- test tube was sealed with parafilm, stirred at 65 °C for 24 h, quenched with saturated sodium chloride solution, extracted with ethyl acetate, removed the solvent by rotary evaporator, adsorbed on silica gel, and finally used ethyl acetate and petroleum
- the product isoxazoline 3aa can be obtained by column chromatography with the mixed solvent of ether .
- Example 2 On the basis of Example 1, the reaction conditions were changed by a single factor: the THF (2.0 mL) added for the second time was replaced with acetone (2.0 mL), and the yield was 84%.
- Tetramethylethylenediamine TMEDA was replaced with N,N-dimethylethanolamine DABCO (0.75 mmol), yield: 68%.
- Tetramethylethylenediamine TMEDA was replaced by sodium carbonate (0.75 mmol), yield: 16%.
- Tetramethylethylenediamine TMEDA was replaced with potassium carbonate (0.75 mmol) in ⁇ 1% yield.
- Tetramethylethylenediamine TMEDA was replaced with sodium hydroxide (0.75 mmol) in ⁇ 1% yield.
- Example 3 On the basis of Example 1, omitting the copper catalyst: in the air, to a test tube with a magnetic stirrer, add p-bromobenzaldehyde (0.65 mmol), p-toluenesulfonylhydrazide (0.7 mmol) and MeOH (1 mL), the mixture was stirred at 60 °C for 30 min. After the solvent was removed in vacuo, ethyl acrylate (0.5 mmol), TMEDA (0.75 mmol), TBN (2.0 mmol) and THF (2.0 mL) were added sequentially.
- test tube was sealed with parafilm, stirred at 65 °C for 24 h, quenched with saturated sodium chloride solution, extracted with ethyl acetate, removed the solvent by rotary evaporator, adsorbed on silica gel, and finally used ethyl acetate and petroleum
- the product isoxazoline 3aa can be obtained by column chromatography with the mixed solvent of ether . Yield: 61%.
- R 1 is phenyl.
- benzaldehyde (0.65 mmol), p-toluenesulfonylhydrazide (0.7 mmol) and MeOH (1 mL) were added, and the mixture was stirred at 60 °C for 30 min. After the solvent MeOH was removed in vacuo, CuCl2 (0.05 mmol), THF (2.0 mL), ethyl acrylate (0.5 mmol), TMEDA (0.75 mmol), TBN (2.0 mmol) and THF (2.0 mL) were sequentially added.
- test tube was sealed with parafilm and stirred at 65 °C for 24 h. Quenched with saturated sodium chloride solution, extracted with ethyl acetate, removed the solvent with a rotary evaporator, adsorbed on silica gel, and finally performed column chromatography with a mixed solvent of ethyl acetate and petroleum ether to obtain the product isoxazoline 4 .
- Embodiment 6 On the basis of Embodiment 4, compound 1 and compound 2 are replaced, and the rest remain unchanged to obtain the following product.
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Abstract
Disclosed in the present invention is a simple preparation method for isoxazolines, comprising: using aldehyde, p-toluenesulfonyl hydrazide, olefin, and tert-butyl nitrite as a substrate, using copper chloride as a catalyst, using tetramethylethylenediamine (TMEDA) as an alkali, and efficiently synthesizing a series of isoxazoline compounds buy using a one-pot two-step method. The advantages are as follows: the catalyst is cheap, the reaction is economical, substrate universality is wider, raw materials are easy to obtain, later stage functionalization is more convenient, reaction conditions are mild, and the gram-scale reaction is good; and in particular, in the present invention, a product can be obtained at a moderate yield in the absence of catalyst, post-treatment is simple and convenient, and it is beneficial to an application in drug molecule synthesis and large-scale industrialization, thereby satisfying the requirements and directions of contemporary green chemistry and pharmaceutical chemistry.
Description
本发明涉及一种制备异噁唑啉的方法,属于有机合成技术领域。The invention relates to a method for preparing isoxazoline, belonging to the technical field of organic synthesis.
异噁唑啉是广泛存在于天然产物、药物分子、生物活性分子、农药以及功能材料的核心骨架。另外,它也被用作过渡金属催化的配体。化学家们发展了一系列制备异噁唑啉的方法,但均有明显的缺点,比如:需要大过量的氧化剂或脱水剂;原料昂贵或制备繁琐;反应条件苛刻;需要昂贵有害的过渡金属等。例如:(1)从炔烃和硝酸铜出发原位生成腈氧化物中间体再进一步与烯烃偶极环加成制备异噁唑啉的工作,但是反应必须在氮气氛下才能有着更高的产率,与此同时,该方法不可避免需要使用当量的过渡金属硝酸铜(价格昂贵且有毒有害),不适合药物分子的合成(参见:
Angew. Chem., Int. Ed.
2015
, 54, 8795);(2)亚硝酸叔丁酯引发的重氮化合物与烯烃三组分制备异噁唑啉的反应。但反应中需要用到制备繁琐而且危险的重氮化合物,限制了其在制备生物活性分子中的应用(参见:
Chem.
Sci., 2021,
12, 774)。综上,很有必要开发一种原料来源丰富、成本低廉、安全、操作简便的方法来高效率的合成异噁唑啉类化合物。
Isoxazolines are the core skeletons that widely exist in natural products, drug molecules, bioactive molecules, pesticides and functional materials. In addition, it has also been used as a ligand for transition metal catalysis. Chemists have developed a series of methods for the preparation of isoxazolines, but they all have obvious shortcomings, such as: requiring a large excess of oxidant or dehydrating agent; expensive raw materials or complicated preparation; harsh reaction conditions; expensive and harmful transition metals, etc. . For example: (1) In-situ generation of nitrile oxide intermediates from alkynes and copper nitrate, and further dipolar cycloaddition with alkenes to prepare isoxazolines, but the reaction must be under nitrogen atmosphere to have higher yields At the same time, this method inevitably requires the use of equivalent transition metal copper nitrate (expensive and toxic), which is not suitable for the synthesis of drug molecules (see: Angew. Chem., Int. Ed. 2015 , 54, 8795) ; (2) The reaction of three-component preparation of isoxazoline from diazonium compounds and olefins initiated by t-butyl nitrite. However, the complex and dangerous diazonium compounds are required to be prepared in the reaction, which limits its application in the preparation of biologically active molecules (see: Chem. Sci., 2021, 12 , 774). In conclusion, it is necessary to develop a method with abundant raw material sources, low cost, safety and simple operation to synthesize isoxazolines with high efficiency.
本发明的目的是提供一种制备异噁唑啉的方法,该方法具有原料来源丰富、反应底物普适性广,操作简便,反应条件温和等优点。The purpose of the present invention is to provide a method for preparing isoxazoline, which has the advantages of abundant raw material sources, wide universality of reaction substrates, simple operation, mild reaction conditions and the like.
为达到上述发明目的,本发明采用的技术方案是:一种异噁唑啉的简单制备方法,以醛、对甲苯磺酰肼、烯烃和亚硝酸酯为反应底物,在碱与铜催化剂存在下,在有机溶剂中反应得到异噁唑啉。In order to achieve the above-mentioned purpose of the invention, the technical scheme adopted in the present invention is: a simple preparation method of isoxazoline, using aldehyde, p-toluenesulfonyl hydrazide, alkene and nitrite as reaction substrates, in the presence of alkali and copper catalyst. Under the following conditions, the isoxazoline is obtained by reaction in an organic solvent.
本发明得到的产物为异噁唑啉,其化学结构式为:
。
The product that the present invention obtains is isoxazoline, and its chemical structural formula is: .
本发明中,所述醛的化学结构通式为:
;所述烯烃的化学结构通式为:
;所述亚硝酸酯的化学结构通式为:
。
In the present invention, the general formula of the chemical structure of the aldehyde is: ; The general chemical structure of the alkene is: ; The general formula of chemical structure of described nitrite is: .
上述结构式中,R
1选自芳基、取代芳基、杂芳香基、萘基或者烯基,比如芳基或者取代芳基为:
,R
2、R
3独立的选自氢、烷基、氟、氯、溴、羧酸、酰胺、硫醚、氨基、烷氧基、三氟甲基、硝基、氰基、酯基、羟基或者砜基;R
4、R
5独立的选自氢、烷基、芳基、酯基、醚、酰胺基、羰基、硅基、羟基、缩醛、氰基、卤素、炔基、羧基、磷酸酯基;R
6选自叔丁基、正丁基、异丁基、异丙基。
In the above structural formula, R 1 is selected from aryl, substituted aryl, heteroaryl, naphthyl or alkenyl, such as aryl or substituted aryl: , R 2 and R 3 are independently selected from hydrogen, alkyl, fluorine, chlorine, bromine, carboxylic acid, amide, thioether, amino, alkoxy, trifluoromethyl, nitro, cyano, ester, hydroxyl or sulfone group; R 4 , R 5 are independently selected from hydrogen, alkyl, aryl, ester, ether, amide, carbonyl, silicon, hydroxyl, acetal, cyano, halogen, alkynyl, carboxyl, phosphoric acid Ester group; R 6 is selected from tert-butyl, n-butyl, isobutyl, isopropyl.
上述技术方案中,将醛、对甲苯磺酰肼在醇溶剂中混合后,再加入烯烃、亚硝酸酯、有机溶剂、铜催化剂、碱,反应得到异噁唑啉;优选的,将醛、对甲苯磺酰肼在甲醇中,60℃下搅拌30分钟后,除去甲醇,再加入烯烃、亚硝酸酯、有机溶剂、铜催化剂、碱,反应得到异噁唑啉。In the above technical scheme, after the aldehyde and p-toluenesulfonyl hydrazide are mixed in an alcohol solvent, olefin, nitrite, an organic solvent, a copper catalyst, and a base are added to react to obtain isoxazoline; Tosylhydrazide was stirred in methanol at 60° C. for 30 minutes, methanol was removed, and olefin, nitrite, organic solvent, copper catalyst, and base were added to react to obtain isoxazoline.
上述技术方案中,所述铜催化剂为氯化铜、氯化亚铜、溴化亚铜或者碘化亚铜;优选的,所述铜催化剂为氯化铜。In the above technical solution, the copper catalyst is cupric chloride, cuprous chloride, cuprous bromide or cuprous iodide; preferably, the copper catalyst is cupric chloride.
上述技术方案中,所述铜催化剂用量为烯烃摩尔量的5~20%;优选的铜催化剂用量为烯烃摩尔量的10%。In the above technical solution, the amount of the copper catalyst is 5-20% of the mole of the olefin; the preferred amount of the copper catalyst is 10% of the mole of the olefin.
本发明还公开了一种无金属催化剂制备异噁唑啉的方法,将苯甲醛化合物、对甲苯磺酰肼在甲醇溶剂中混合后,再加入烯烃、亚硝酸酯、有机溶剂、碱,反应得到异噁唑啉;其中,所述苯甲醛化合物的化学结构通式如下:
。
The invention also discloses a method for preparing isoxazoline without metal catalyst. After mixing benzaldehyde compound and p-toluenesulfonyl hydrazide in methanol solvent, olefin, nitrite, organic solvent and alkali are added to react to obtain Isoxazoline; wherein, the general formula of the chemical structure of the benzaldehyde compound is as follows: .
所述烯烃的化学结构通式为R
2-CH
2CH
2;所述亚硝酸酯的化学结构通式为O=N-OR
6。
The general chemical structure of the alkene is R 2 -CH 2 CH 2 ; the general chemical structure of the nitrite is O=N-OR 6 .
所述异噁唑啉的化学结构通式如下:
。
The general formula of the chemical structure of the isoxazoline is as follows: .
式中,R
1选自氢、烷基、氟、氯、溴、羧酸、酰胺、硫醚、氨基、烷氧基、三氟甲基、硝基、氰基、酯基、羟基或者砜基;R
2选自烷基、芳基、酯基、羰基、醚、酰胺基、硅基、羟基、缩苯甲醛化合物、氰基、卤素、炔基、羧基或者磷酸酯基;R
6选自叔丁基、正丁基、异丁基或者异丙基。优选的,R
1选自氢、烷基、氟、氯、溴;R
2选自芳基、酯基,比如苯基、-COOEt、取代苯基。
In the formula, R 1 is selected from hydrogen, alkyl, fluorine, chlorine, bromine, carboxylic acid, amide, thioether, amino, alkoxy, trifluoromethyl, nitro, cyano, ester, hydroxyl or sulfone ; R 2 is selected from alkyl, aryl, ester, carbonyl, ether, amide, silicon, hydroxyl, benzal compound, cyano, halogen, alkynyl, carboxyl or phosphate group; R 6 is selected from tertiary Butyl, n-butyl, isobutyl or isopropyl. Preferably, R 1 is selected from hydrogen, alkyl, fluorine, chlorine, bromine; R 2 is selected from aryl, ester group, such as phenyl, -COOEt, substituted phenyl.
上述技术方案中,将苯甲醛化合物、对甲苯磺酰肼在醇溶剂中,60℃下搅拌30分钟后,除去甲醇溶剂,再加入烯烃、亚硝酸酯、有机溶剂、碱,反应得到异噁唑啉。In the above technical scheme, the benzaldehyde compound and p-toluenesulfonyl hydrazide are stirred in an alcohol solvent at 60° C. for 30 minutes, the methanol solvent is removed, and olefin, nitrite, organic solvent and alkali are added to react to obtain isoxazole. morpholino.
本发明中,所述反应的反应温度为25~80℃;反应时间为12~24小时;优选的反应温度为65℃;反应时间为24小时。In the present invention, the reaction temperature of the reaction is 25-80°C; the reaction time is 12-24 hours; the preferred reaction temperature is 65°C; and the reaction time is 24 hours.
本发明中,所述反应在碱存在下进行,所使用的碱为TMEDA、DABCO、碳酸钠;所述有机溶剂为乙酸乙酯、四氢呋喃、乙腈、丙酮、氯仿、
N,
N-二甲基甲酰胺。优选的,碱优选有机胺,比如为TMEDA,有机溶剂为四氢呋喃。
In the present invention, the reaction is carried out in the presence of a base, and the bases used are TMEDA, DABCO, and sodium carbonate; and the organic solvent is ethyl acetate, tetrahydrofuran, acetonitrile, acetone, chloroform, N , N -dimethylmethane amide. Preferably, the base is preferably an organic amine, such as TMEDA, and the organic solvent is tetrahydrofuran.
本发明中,所述醛化合物用量为烯烃摩尔量的1~1.5倍;对甲苯磺酰肼用量为烯烃摩尔量的1~1.5倍,亚硝酸酯用量为烯烃摩尔量的3~5倍;碱的用量为烯烃摩尔量的1~1.8倍;优选的,所述醛化合物用量为烯烃摩尔量的1.3倍;对甲苯磺酰肼用量为烯烃摩尔量的1.4倍,亚硝酸酯用量为烯烃摩尔量的4倍,碱的用量为烯烃摩尔量的1.5倍。In the present invention, the amount of the aldehyde compound is 1 to 1.5 times the mole of the olefin; the amount of p-toluenesulfonyl hydrazide is 1 to 1.5 times the mole of the olefin, and the amount of nitrite is 3 to 5 times the mole of the olefin; The dosage is 1 to 1.8 times the mole weight of olefin; preferably, the dosage of the aldehyde compound is 1.3 times the mole weight of olefin; the dosage of p-toluenesulfonyl hydrazide is 1.4 times the mole weight of olefin, and the dosage of nitrite is the mole weight of olefin 4 times the amount of the base, and the amount of the base is 1.5 times the molar amount of the olefin.
本发明的反应在空气中进行。反应结束后,用饱和氯化钠溶液淬灭,再用乙酸乙酯萃取后,利用旋转蒸发仪除去溶剂、硅胶吸附,最后用乙酸乙酯和石油醚的混合溶剂进行柱层析即可得产物异噁唑啉。The reaction of the present invention is carried out in air. After the reaction, it was quenched with saturated sodium chloride solution, extracted with ethyl acetate, the solvent was removed by rotary evaporator, adsorbed on silica gel, and finally the product was obtained by column chromatography with a mixed solvent of ethyl acetate and petroleum ether. Isoxazoline.
由于上述技术方案的运用,本发明与现有技术相比具有下列优点:本发明使用CuCl
2为催化剂实现了醛、对甲苯磺酰肼、烯烃和亚硝酸叔丁酯的多组分反应来制备异噁唑啉,与现有技术中的原料预制备难、原料用量大和条件苛刻相比,反应更经济、底物普适性更广、原料易得、后期官能团化更易。本发明公开的方法反应条件温和,催化剂廉价而且用量少,克级规模反应良好,后处理简便,有利于在药物分子合成和大规模工业化中的应用。本发明使用的反应物、添加剂、碱、催化剂等原料廉价易得,反应组成合理,无需配体,反应步骤少,仅需一步反应即可得到官能团化的异噁唑啉,符合绿色化学和药物化学的要求和方向。尤其是,本发明公开了无催化剂制备异噁唑啉的方法,避免了过渡金属的使用,有利于进一步用于药物分子与生物活性分子的合成中。
Due to the application of the above technical solutions, the present invention has the following advantages compared with the prior art: the present invention uses CuCl 2 as a catalyst to realize the multi-component reaction of aldehyde, p-toluenesulfonyl hydrazide, olefin and tert-butyl nitrite to prepare Isoxazoline is more economical in reaction, more widely applicable to substrates, easy to obtain raw materials, and easier to functionalize later, compared with the prior art, which is difficult to prepare raw materials, large amount of raw materials and harsh conditions. The method disclosed by the invention has mild reaction conditions, cheap catalyst and less dosage, good gram-scale reaction, convenient post-processing, and is beneficial to the application in drug molecule synthesis and large-scale industrialization. The reactants, additives, bases, catalysts and other raw materials used in the invention are cheap and easy to obtain, the reaction composition is reasonable, no ligand is required, and the reaction steps are few, and the functionalized isoxazoline can be obtained by only one step of reaction, which is in line with green chemistry and medicine. Chemistry requirements and directions. In particular, the present invention discloses a catalyst-free method for preparing isoxazoline, which avoids the use of transition metals and is favorable for further use in the synthesis of drug molecules and biologically active molecules.
下面结合实施例对本发明作进一步描述:本发明的醛、烯烃、对甲苯磺酰肼、碱、亚硝酸酯、催化剂和溶剂皆为市场化商品,可直接购买。实验具体操作方法以及测试方法为本领域常规方法,反应在常规环境中进行。The present invention will be further described below in conjunction with the examples: the aldehyde, olefin, p-toluenesulfonyl hydrazide, alkali, nitrite, catalyst and solvent of the present invention are all marketable commodities and can be purchased directly. The specific operation method and test method of the experiment are conventional methods in the field, and the reaction is carried out in a conventional environment.
实施例一。Example 1.
空气中,向具有磁力搅拌子的试管中,添加对溴苯甲醛(0.65 mmol),对甲苯磺酰肼(0.7
mmol)和MeOH(1 mL),将混合物在60 ℃下搅拌30分钟。 真空除去溶剂后,依次加入CuCl
2(0.05 mmol),THF(2.0 mL),丙烯酸乙酯(0.5 mmol),TMEDA(0.75 mmol),TBN(2.0 mmol)和THF(2.0 mL)。 将试管用封口膜密封,并在65 ℃下搅拌24 h,用饱和氯化钠溶液淬灭,再用乙酸乙酯萃取后,利用旋转蒸发仪除去溶剂、硅胶吸附,最后用乙酸乙酯和石油醚的混合溶剂进行柱层析即可得产物异噁唑啉
3aa
。产率:88%; mp: 66-68
oC;
1H
NMR (400 MHz, CDCl
3) δ 7.51
(s, 4H), 5.15 (dd,
J = 10.5, 7.9 Hz, 1H), 4.24 (q,
J = 7.1 Hz,
2H), 3.592 (d,
J = 7.9 Hz, 1H), 3.586 (d,
J = 10.5 Hz, 1H), 1.30
(t,
J = 7.1 Hz, 3H);
13C NMR (100 MHz, CDCl
3) δ 169.9, 155.1, 131.9, 128.2, 127.4, 124.7, 78.2, 62.0,
38.5, 14.0; HRMS (ESI-TOF): Anal. Calcd. For C
12H
12
79BrNNaO
3
+:
319.9893, C
12H
12
81BrNNaO
3
+:
321.9872, Found: 319.9881, 321.9890; IR (neat, cm
-1): υ 2972, 2933, 1738, 1195, 1160, 1008, 890, 821。丙烯酸乙酯反应放大到20mmol规模,同样的条件,产率为85%。
In air, to a test tube with a magnetic stirring bar, p-bromobenzaldehyde (0.65 mmol), p-toluenesulfonylhydrazide (0.7 mmol) and MeOH (1 mL) were added, and the mixture was stirred at 60 °C for 30 min. After the solvent was removed in vacuo, CuCl2 (0.05 mmol), THF (2.0 mL), ethyl acrylate (0.5 mmol), TMEDA (0.75 mmol), TBN (2.0 mmol) and THF (2.0 mL) were added sequentially. The test tube was sealed with parafilm, stirred at 65 °C for 24 h, quenched with saturated sodium chloride solution, extracted with ethyl acetate, removed the solvent by rotary evaporator, adsorbed on silica gel, and finally used ethyl acetate and petroleum The product isoxazoline 3aa can be obtained by column chromatography with the mixed solvent of ether . Yield: 88%; mp: 66-68 o C; 1 H NMR (400 MHz, CDCl 3 ) δ 7.51 (s, 4H), 5.15 (dd, J = 10.5, 7.9 Hz, 1H), 4.24 (q, J = 7.1 Hz, 2H), 3.592 (d, J = 7.9 Hz, 1H), 3.586 (d, J = 10.5 Hz, 1H), 1.30 (t, J = 7.1 Hz, 3H); 13 C NMR (100 MHz) , CDCl 3 ) δ 169.9, 155.1, 131.9, 128.2, 127.4, 124.7, 78.2, 62.0, 38.5, 14.0; HRMS (ESI-TOF): Anal. Calcd. For C 12 H 12 79 BrNNaO 3 + : 319.9893 , C H 12 81 BrNNaO 3 + : 321.9872, Found: 319.9881, 321.9890; IR (neat, cm -1 ): υ 2972, 2933, 1738, 1195, 1160, 1008, 890, 821. The ethyl acrylate reaction was scaled up to 20 mmol, and the yield was 85% under the same conditions.
实施例二 在实施例一的基础上,反应条件做单因素变化:将第二次加入的THF(2.0 mL)更换为丙酮(2.0 mL),产率:84%。Example 2 On the basis of Example 1, the reaction conditions were changed by a single factor: the THF (2.0 mL) added for the second time was replaced with acetone (2.0 mL), and the yield was 84%.
将第二次加入的THF(2.0 mL)更换为乙腈(2.0 mL),产率:54%。The second addition of THF (2.0 mL) was replaced with acetonitrile (2.0 mL), yield: 54%.
将亚硝酸叔丁酯TBN更换为亚硝酸异丙酯(2.0 mmol),产率:79%。The tert-butyl nitrite TBN was replaced with isopropyl nitrite (2.0 mmol), yield: 79%.
将亚硝酸叔丁酯TBN更换为亚硝酸正丁酯(2.0 mmol),产率:68%。The tert-butyl nitrite TBN was replaced with n-butyl nitrite (2.0 mmol), yield: 68%.
将CuCl
2(0.05
mmol)更换为CuCl(0.05
mmol),产率:77%。
Replaced CuCl2 ( 0.05 mmol) with CuCl (0.05 mmol), yield: 77%.
将CuCl
2(0.05
mmol)更换为CuBr(0.05
mmol),产率:83%。
Replaced CuCl2 ( 0.05 mmol) with CuBr (0.05 mmol), yield: 83%.
将CuCl
2(0.05
mmol)更换为CuI(0.05
mmol),产率:56%。
Replaced CuCl2 ( 0.05 mmol) with CuI (0.05 mmol), yield: 56%.
将CuCl
2(0.05
mmol)更换为Cu(OAc)
2(0.05 mmol),产率:58%。
CuCl2 (0.05 mmol) was replaced by Cu(OAc) 2 ( 0.05 mmol), yield: 58%.
将四甲基乙二胺TMEDA 更换为N,N-二甲基乙醇胺DABCO(0.75 mmol),产率:68%。Tetramethylethylenediamine TMEDA was replaced with N,N-dimethylethanolamine DABCO (0.75 mmol), yield: 68%.
将四甲基乙二胺TMEDA 更换为碳酸钠(0.75 mmol),产率:16%。Tetramethylethylenediamine TMEDA was replaced by sodium carbonate (0.75 mmol), yield: 16%.
将四甲基乙二胺TMEDA 更换为碳酸钾(0.75 mmol),产率<1%。Tetramethylethylenediamine TMEDA was replaced with potassium carbonate (0.75 mmol) in <1% yield.
将四甲基乙二胺TMEDA 更换为氢氧化钠(0.75 mmol),产率<1%。Tetramethylethylenediamine TMEDA was replaced with sodium hydroxide (0.75 mmol) in <1% yield.
省略TMEDA,产率<1%。Omit TMEDA, yield <1%.
实施例三 在实施例一的基础上,省略铜催化剂:空气中,向具有磁力搅拌子的试管中,添加对溴苯甲醛(0.65
mmol),对甲苯磺酰肼(0.7 mmol)和MeOH(1 mL),将混合物在60 ℃下搅拌30分钟。 真空除去溶剂后,依次加入丙烯酸乙酯(0.5
mmol),TMEDA(0.75
mmol),TBN(2.0
mmol)和THF(2.0
mL)。将试管用封口膜密封,并在65 ℃下搅拌24 h,用饱和氯化钠溶液淬灭,再用乙酸乙酯萃取后,利用旋转蒸发仪除去溶剂、硅胶吸附,最后用乙酸乙酯和石油醚的混合溶剂进行柱层析即可得产物异噁唑啉
3aa
。产率:61%。
Example 3 On the basis of Example 1, omitting the copper catalyst: in the air, to a test tube with a magnetic stirrer, add p-bromobenzaldehyde (0.65 mmol), p-toluenesulfonylhydrazide (0.7 mmol) and MeOH (1 mL), the mixture was stirred at 60 °C for 30 min. After the solvent was removed in vacuo, ethyl acrylate (0.5 mmol), TMEDA (0.75 mmol), TBN (2.0 mmol) and THF (2.0 mL) were added sequentially. The test tube was sealed with parafilm, stirred at 65 °C for 24 h, quenched with saturated sodium chloride solution, extracted with ethyl acetate, removed the solvent by rotary evaporator, adsorbed on silica gel, and finally used ethyl acetate and petroleum The product isoxazoline 3aa can be obtained by column chromatography with the mixed solvent of ether . Yield: 61%.
实施例四。Example four.
以化合物1为苯甲醛为例,即R
1为苯基。空气中,向具有磁力搅拌子的试管中,添加苯甲醛(0.65 mmol),对甲苯磺酰肼(0.7
mmol)和MeOH(1 mL),将混合物在60 ℃下搅拌30分钟。 真空除去溶剂MeOH后,依次加入CuCl
2(0.05 mmol),THF(2.0 mL),丙烯酸乙酯(0.5 mmol),TMEDA(0.75 mmol),TBN(2.0 mmol)和THF(2.0 mL)。将试管用封口膜密封,并在65 ℃下搅拌24 h。用饱和氯化钠溶液淬灭,再用乙酸乙酯萃取后,利用旋转蒸发仪除去溶剂、硅胶吸附,最后用乙酸乙酯和石油醚的混合溶剂进行柱层析即可得产物异噁唑啉
4
。产率:93%;
1H NMR
(400 MHz, CDCl
3) δ 7.69 – 7.63 (m, 2H), 7.43 – 7.35
(m, 3H), 5.14 (dd,
J = 10.4, 7.9 Hz, 1H), 4.24 (q,
J = 7.1 Hz,
2H), 3.623 (d,
J = 7.9 Hz, 1H), 3.617 (d,
J = 10.4 Hz, 1H), 1.30
(t,
J = 7.1 Hz, 3H);
13C NMR (100 MHz, CDCl
3) δ 170.0, 155.9, 130.3, 128.6, 128.4, 126.8, 78.0, 61.8,
38.7, 14.0; Anal. Calcd. For C
12H
13NNaO
3
+:
242.0788, Found: 242.0778; IR (neat, cm
-1): υ 2976, 2936, 2906, 1750, 1209, 1182, 1035, 901, 762, 695。上述产物化合物4的结构式如下:
。
Taking compound 1 as benzaldehyde as an example, that is, R 1 is phenyl. In air, to a test tube with a magnetic stirring bar, benzaldehyde (0.65 mmol), p-toluenesulfonylhydrazide (0.7 mmol) and MeOH (1 mL) were added, and the mixture was stirred at 60 °C for 30 min. After the solvent MeOH was removed in vacuo, CuCl2 (0.05 mmol), THF (2.0 mL), ethyl acrylate (0.5 mmol), TMEDA (0.75 mmol), TBN (2.0 mmol) and THF (2.0 mL) were sequentially added. The test tube was sealed with parafilm and stirred at 65 °C for 24 h. Quenched with saturated sodium chloride solution, extracted with ethyl acetate, removed the solvent with a rotary evaporator, adsorbed on silica gel, and finally performed column chromatography with a mixed solvent of ethyl acetate and petroleum ether to obtain the product isoxazoline 4 . Yield: 93%; 1 H NMR (400 MHz, CDCl 3 ) δ 7.69 - 7.63 (m, 2H), 7.43 - 7.35 (m, 3H), 5.14 (dd, J = 10.4, 7.9 Hz, 1H), 4.24 (q, J = 7.1 Hz, 2H), 3.623 (d, J = 7.9 Hz, 1H), 3.617 (d, J = 10.4 Hz, 1H), 1.30 (t, J = 7.1 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 170.0 , 155.9 , 130.3 , 128.6, 128.4, 126.8, 78.0, 61.8, 38.7, 14.0; , cm -1 ): υ 2976, 2936, 2906, 1750, 1209, 1182, 1035, 901, 762, 695. The structural formula of above-mentioned product compound 4 is as follows: .
保持反应条件不变,仅仅更换化合物1,得到的产物以及表征如下:
。
Keeping the reaction conditions unchanged, only replacing compound 1, the obtained products and their characterizations are as follows: .
产率:87% yield;
1H NMR (400 MHz, CDCl
3) δ 7.56 (d,
J = 8.0 Hz, 2H), 7.20 (d,
J = 8.0
Hz, 2H), 5.13 (dd,
J = 10.5, 7.8 Hz, 1H), 4.25 (q,
J = 7.1 Hz,
2H), 3.615 (d,
J = 7.8 Hz, 1H), 3.608 (d,
J = 10.5 Hz, 1H), 2.37
(s, 3H), 1.31 (t,
J = 7.1 Hz, 3H);
13C NMR (100 MHz, CDCl
3)
δ 170.2, 155.8, 140.7, 129.4, 126.8,
125.7, 77.9, 61.9, 38.9, 21.4, 14.0; HRMS (ESI-TOF): Anal. Calcd. For C
13H
15NNaO
3
+:
256.0944, Found: 256.0956; IR (neat, cm
-1): υ 2978, 2960, 2927, 1752, 1204, 1183, 1030, 901, 819。
Yield: 87% yield; 1 H NMR (400 MHz, CDCl 3 ) δ 7.56 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H), 5.13 (dd, J = 10.5, 7.8 Hz, 1H), 4.25 (q, J = 7.1 Hz, 2H), 3.615 (d, J = 7.8 Hz, 1H), 3.608 (d, J = 10.5 Hz, 1H), 2.37 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 170.2, 155.8, 140.7, 129.4, 126.8, 125.7, 77.9, 61.9, 38.9, 21.4, 14.0; HRMS (ESI-TOF) : Anal. Calcd. For C 13 H 15 NNaO 3 + : 256.0944, Found: 256.0956; IR (neat, cm -1 ): υ 2978, 2960, 2927, 1752, 1204, 1183, 1030, 901, 819.
产率:91%;
1H NMR (400 MHz, CDCl
3) δ 7.60 (d,
J = 8.2 Hz, 2H), 7.41 (d,
J = 8.2
Hz, 2H), 5.12 (dd,
J = 10.2, 8.0 Hz, 1H), 4.23 (q,
J = 7.1 Hz,
2H), 3.64 – 3.59 (m, 2H), 1.32-1.26 (m, 12H);
13C
NMR (100 MHz, CDCl
3) δ
170.1, 155.7, 153.7, 126.6, 125.6, 125.5, 77.8, 61.7, 38.8, 34.7, 31.0, 13.9;
HRMS (ESI-TOF): Anal. Calcd. For C
16H
21NNaO
3
+:
298.1414, Found: 298.1427; IR (neat, cm
-1): υ 2983, 2938, 1735, 1513, 1203, 1158, 893, 836。
Yield: 91%; 1 H NMR (400 MHz, CDCl 3 ) δ 7.60 (d, J = 8.2 Hz, 2H), 7.41 (d, J = 8.2 Hz, 2H), 5.12 (dd, J = 10.2, 8.0 Hz, 1H), 4.23 (q, J = 7.1 Hz, 2H), 3.64 – 3.59 (m, 2H), 1.32-1.26 (m, 12H); 13 C NMR (100 MHz, CDCl 3 ) δ 170.1, 155.7, 153.7, 126.6, 125.6, 125.5, 77.8, 61.7, 38.8, 34.7, 31.0, 13.9; HRMS (ESI-TOF): Anal. Calcd. For C 16 H 21 NNaO 3 + : 298.1414, Found: 298.1427; IR (neat, cm -1 ): υ 2983, 2938, 1735, 1513, 1203, 1158, 893, 836.
产率:85%;
1H NMR (400 MHz, CDCl
3) δ 7.59 (d,
J = 8.9 Hz, 2H), 6.89 (d,
J = 8.9
Hz, 2H), 5.11 (dd,
J = 10.3, 8.0 Hz, 1H), 4.24 (q,
J = 7.1 Hz,
2H), 3.81 (s, 3H), 3.593 (d,
J = 8.0 Hz, 1H), 3.587 (d,
J = 10.3
Hz, 1H), 1.30 (t,
J = 7.1 Hz, 3H);
13C NMR (100 MHz, CDCl
3)
δ 170.3, 161.2, 155.4, 128.4, 121.0,
114.1, 77.8, 61.8, 55.3, 39.0, 14.0; HRMS (ESI-TOF): Anal. Calcd. For C
13H
15NNaO
4
+:
272.0893, Found: 272.0890; IR (neat, cm
-1): υ 2980, 2938, 2840, 1735, 1608, 1516, 1252, 1202, 1177,
1019, 888, 832。
Yield: 85%; 1 H NMR (400 MHz, CDCl 3 ) δ 7.59 (d, J = 8.9 Hz, 2H), 6.89 (d, J = 8.9 Hz, 2H), 5.11 (dd, J = 10.3, 8.0 Hz, 1H), 4.24 (q, J = 7.1 Hz, 2H), 3.81 (s, 3H), 3.593 (d, J = 8.0 Hz, 1H), 3.587 (d, J = 10.3 Hz, 1H), 1.30 ( t, J = 7.1 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 170.3, 161.2, 155.4, 128.4, 121.0, 114.1, 77.8, 61.8, 55.3, 39.0, 14.0; HRMS (ESI-TOF): Anal. Calcd. For C 13 H 15 NNaO 4 + : 272.0893, Found: 272.0890; IR (neat, cm -1 ): υ 2980, 2938, 2840, 1735, 1608, 1516, 1252, 1202, 1177, 1019, 888 , 832.
产率:84%; mp: 63-65
oC;
1H NMR (400 MHz,
CDCl
3) δ 7.54 (d,
J
= 8.6 Hz, 2H), 7.20 (d,
J = 8.6 Hz, 2H), 5.12 (dd,
J = 10.3, 8.1
Hz, 1H), 4.23 (q,
J = 7.1 Hz, 2H), 3.67 – 3.48
(m, 2H), 2.46 (s, 3H), 1.29 (t,
J = 7.1 Hz, 3H);
13C NMR (100
MHz, CDCl
3) δ 170.0, 155.4,
141.9, 127.0, 125.6, 124.7, 77.9, 61.8, 38.6, 14.9, 14.0; HRMS (ESI-TOF): Anal.
Calcd. For C
13H
15NNaO
3S
+: 288.0665,
Found: 288.0675; IR (neat, cm
-1): υ
2989, 2921, 1748, 1199, 1032, 1022, 894, 817。
Yield: 84%; mp: 63-65 oC ; 1 H NMR (400 MHz, CDCl 3 ) δ 7.54 (d, J = 8.6 Hz, 2H), 7.20 (d, J = 8.6 Hz, 2H), 5.12 ( dd, J = 10.3, 8.1 Hz, 1H), 4.23 (q, J = 7.1 Hz, 2H), 3.67 – 3.48 (m, 2H), 2.46 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H) ); 13 C NMR (100 MHz, CDCl 3 ) δ 170.0, 155.4, 141.9, 127.0, 125.6, 124.7, 77.9, 61.8, 38.6, 14.9, 14.0; HRMS (ESI-TOF): Anal. Calcd. For C 13 H 15 NNaO 3 S + : 288.0665, Found: 288.0675; IR (neat, cm -1 ): υ 2989, 2921, 1748, 1199, 1032, 1022, 894, 817.
产率:73%;
1H NMR (400 MHz, CDCl
3) δ7.89 (s, 1H), 7.86 (d,
J = 7.8 Hz, 1H), 7.66 (d,
J
= 7.8 Hz, 1H), 7.53 (t,
J = 7.8 Hz, 1H), 5.20 (dd,
J = 10.5, 7.9
Hz, 1H), 4.26 (q,
J = 7.1 Hz, 2H), 3.65 (d,
J = 7.9 Hz, 1H), 3.65
(d,
J = 10.5 Hz, 1H), 1.31 (t,
J = 7.1 Hz, 3H);
13C
NMR (100 MHz, CDCl
3) δ
169.7, 154.9, 131.2 (q,
J = 32.7 Hz), 129.9, 129.4, 129.3, 126.9 (q,
J
= 3.7 Hz), 123.6 (q,
J = 272.3 Hz), 123.6 (q,
J = 3.8 Hz),
78.4, 62.1, 38.4, 14.0;
19F NMR (376 MHz, CDCl
3) δ -62.9; HRMS (ESI-TOF): Anal. Calcd. For C
13H
12F
3NNaO
3
+:
310.0661, Found: 310.0648; IR (neat, cm
-1): υ 2979, 2938, 2907, 1738, 1311, 1165, 1122, 1098, 900,
803, 693。
Yield: 73%; 1 H NMR (400 MHz, CDCl 3 ) δ 7.89 (s, 1H), 7.86 (d, J = 7.8 Hz, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.53 (t, J = 7.8 Hz, 1H), 5.20 (dd, J = 10.5, 7.9 Hz, 1H), 4.26 (q, J = 7.1 Hz, 2H), 3.65 (d, J = 7.9 Hz, 1H), 3.65 (d, J = 10.5 Hz, 1H), 1.31 (t, J = 7.1 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 169.7, 154.9, 131.2 (q, J = 32.7 Hz), 129.9, 129.4, 129.3, 126.9 (q, J = 3.7 Hz), 123.6 (q, J = 272.3 Hz), 123.6 (q, J = 3.8 Hz), 78.4, 62.1, 38.4, 14.0; 19 F NMR (376 MHz, CDCl 3 ) δ -62.9; HRMS (ESI-TOF): Anal. Calcd. For C 13 H 12 F 3 NNaO 3 + : 310.0661, Found: 310.0648; IR (neat, cm -1 ): υ 2979, 2938, 2907, 1738, 1311, 1165, 1122, 1098, 900, 803, 693.
产率:71%;
1H NMR (400 MHz, CDCl
3) δ 7.87 – 7.82 (m, 1H),
7.43 – 7.35 (m, 1H), 7.18 – 7.13 (m, 1H), 7.12 – 7.06
(m, 1H), 5.14 (dd,
J = 10.0, 8.6 Hz, 1H), 4.25 (q,
J = 7.1 Hz,
2H), 3.72 – 3.68 (m, 2H), 1.30 (t,
J = 7.2
Hz, 3H);
13C NMR (100 MHz, CDCl
3) δ 170.0, 160.3 (d,
J = 252.7 Hz), 152.7 (d,
J
= 3.0 Hz), 132.1 (d,
J = 8.6 Hz), 129.1 (d,
J = 3.0 Hz), 124.4
(d,
J = 3.4 Hz), 116.6 (d,
J = 11.5 Hz), 116.3 (d,
J =
22.0 Hz), 78.1 (d,
J = 2.3 Hz), 61.8, 40.4 (d,
J = 7.7 Hz), 14.0;
19F NMR (376 MHz, CDCl
3) δ
-112.5; HRMS (ESI-TOF): Anal. Calcd. For C
12H
12FNNaO
3
+:
260.0693, Found: 260.0684; IR (neat, cm
-1): υ 2983, 2929, 2854, 1736, 1454, 1203, 1027, 898, 758。
Yield: 71%; 1 H NMR (400 MHz, CDCl 3 ) δ 7.87 – 7.82 (m, 1H), 7.43 – 7.35 (m, 1H), 7.18 – 7.13 (m, 1H), 7.12 – 7.06 (m, 1H), 5.14 (dd, J = 10.0, 8.6 Hz, 1H), 4.25 (q, J = 7.1 Hz, 2H), 3.72 – 3.68 (m, 2H), 1.30 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 170.0, 160.3 (d, J = 252.7 Hz), 152.7 (d, J = 3.0 Hz), 132.1 (d, J = 8.6 Hz), 129.1 (d, J = 3.0 Hz), 124.4 (d, J = 3.4 Hz), 116.6 (d, J = 11.5 Hz), 116.3 (d, J = 22.0 Hz), 78.1 (d, J = 2.3 Hz), 61.8, 40.4 (d, J = 7.7 Hz), 14.0; 19 F NMR (376 MHz, CDCl 3 ) δ -112.5; HRMS (ESI-TOF): Anal. Calcd. For C 12 H 12 FNNaO 3 + : 260.0693, Found: 260.0684; IR (neat , cm -1 ): υ 2983, 2929, 2854, 1736, 1454, 1203, 1027, 898, 758.
产率:83%;
1H NMR (400 MHz, CDCl
3) δ 7.62 (dd,
J = 7.6, 1.3 Hz, 1H), 7.53 (dd,
J
= 7.6, 1.8 Hz, 1H), 7.38 – 7.33 (m, 1H),
7.31 – 7.26 (m, 1H), 5.20 (dd,
J =
11.0, 7.0 Hz, 1H), 4.28 (q,
J = 7.1 Hz, 2H), 3.83 (dd,
J = 17.3,
11.0 Hz, 1H), 3.76 (dd,
J = 17.3, 7.0 Hz, 1H), 1.33 (t,
J = 7.1
Hz, 3H);
13C NMR (100 MHz, CDCl
3) δ 169.9, 156.9, 133.6, 131.2, 130.9, 130.1, 127.5, 121.7,
78.4, 61.8, 41.2, 14.0; HRMS (ESI-TOF): Anal. Calcd. For C
12H
12
79BrNNaO
3
+:
319.9893, C
12H
12
81BrNNaO
3
+:
321.9872, Found: 319.9874, 321.9912; IR (neat, cm
-1): υ 2982, 2938, 1736, 1341, 1200, 1026, 1016, 852, 756。
Yield: 83%; 1 H NMR (400 MHz, CDCl 3 ) δ 7.62 (dd, J = 7.6, 1.3 Hz, 1H), 7.53 (dd, J = 7.6, 1.8 Hz, 1H), 7.38 – 7.33 (m , 1H), 7.31 – 7.26 (m, 1H), 5.20 (dd, J = 11.0, 7.0 Hz, 1H), 4.28 (q, J = 7.1 Hz, 2H), 3.83 (dd, J = 17.3, 11.0 Hz, 1H), 3.76 (dd, J = 17.3, 7.0 Hz, 1H), 1.33 (t, J = 7.1 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 169.9, 156.9, 133.6, 131.2, 130.9, 130.1, 127.5, 121.7, 78.4, 61.8, 41.2, 14.0; HRMS (ESI-TOF): Anal. Calcd. For C 12 H 12 79 BrNNaO 3 + : 319.9893, C 12 H 12 81 BrNNaO 3 + : 321.9872, Found: 319.9874, 321.9912; IR (neat, cm -1 ): υ 2982, 2938, 1736, 1341, 1200, 1026, 1016, 852, 756.
产率:87%;
1H NMR (400 MHz, CDCl
3) δ 7.35 – 7.20 (m, 4H),
5.10 (t,
J = 9.0 Hz, 1H), 4.26 (q,
J = 7.1 Hz, 2H), 3.67 (d,
J
= 9.0 Hz, 2H), 2.55 (s, 3H), 1.31 (t,
J = 7.1 Hz, 3H);
13C
NMR (100 MHz, CDCl
3) δ
170.2, 156.7, 138.1, 131.5, 129.6, 128.8, 127.6, 125.7, 77.0, 61.8, 41.3, 22.8,
14.0; HRMS (ESI-TOF): Anal. Calcd. For C
13H
15NNaO
3
+:
256.0944, Found: 256.0940; IR (neat, cm
-1): υ 2981, 2928, 1735, 1336, 1200, 1030, 889, 852, 758。
Yield: 87%; 1 H NMR (400 MHz, CDCl 3 ) δ 7.35 – 7.20 (m, 4H), 5.10 (t, J = 9.0 Hz, 1H), 4.26 (q, J = 7.1 Hz, 2H), 3.67 (d, J = 9.0 Hz, 2H), 2.55 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 170.2, 156.7, 138.1, 131.5, 129.6, 128.8, 127.6, 125.7, 77.0, 61.8, 41.3, 22.8, 14.0; HRMS (ESI-TOF): Anal. Calcd. For C 13 H 15 NNaO 3 + : 256.0944, Found: 256.0940; IR (neat, cm - 1 ): υ 2981, 2928, 1735, 1336, 1200, 1030, 889, 852, 758.
产率:67%;
1H NMR (400 MHz, CDCl
3) δ7.74 (dd,
J = 7.7, 1.8 Hz, 1H), 7.36 (ddd,
J
= 8.3, 7.4, 1.8 Hz, 1H), 6.99 – 6.88 (m, 2H),
5.08 (dd,
J = 11.3, 7.2 Hz, 1H), 4.24 (q,
J = 7.1 Hz, 2H), 3.83
(s, 3H), 3.74 (d,
J = 11.3 Hz, 1H), 3.70 (d,
J = 7.2 Hz, 1H),
1.30 (t,
J = 7.1 Hz, 3H);
13C NMR (100 MHz, CDCl
3)
δ 170.5, 157.4, 155.4, 131.6, 129.4,
120.7, 117.6, 111.3, 77.9, 61.6, 55.4, 41.4, 14.0; HRMS (ESI-TOF): Anal. Calcd.
For C
13H
15NNaO
4
+: 272.0893, Found:
272.0891; IR (neat, cm
-1): υ
2981, 2940, 2840, 1735, 1600, 1462, 1248, 1199,
1026, 891, 853, 754。
Yield: 67%; 1 H NMR (400 MHz, CDCl 3 ) δ 7.74 (dd, J = 7.7, 1.8 Hz, 1H), 7.36 (ddd, J = 8.3, 7.4, 1.8 Hz, 1H), 6.99 – 6.88 (m, 2H), 5.08 (dd, J = 11.3, 7.2 Hz, 1H), 4.24 (q, J = 7.1 Hz, 2H), 3.83 (s, 3H), 3.74 (d, J = 11.3 Hz, 1H) ), 3.70 (d, J = 7.2 Hz, 1H), 1.30 (t, J = 7.1 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 170.5, 157.4, 155.4, 131.6, 129.4, 120.7, 117.6 , 111.3, 77.9, 61.6, 55.4, 41.4, 14.0; HRMS (ESI-TOF): Anal. Calcd. For C 13 H 15 NNaO 4 + : 272.0893, Found: 272.0891; IR (neat, cm -1 ): υ 2981 , 2940, 2840, 1735, 1600, 1462, 1248, 1199, 1026, 891, 853, 754.
产率:69%;
1H NMR (400 MHz, CDCl
3) δ7.77 (dd,
J = 7.8, 1.7 Hz, 1H), 7.38 – 7.33 (m, 1H), 6.98 – 6.88
(m, 2H), 5.10 (dd,
J = 11.0, 7.2 Hz, 1H), 4.26 (q,
J = 7.1 Hz,
2H), 4.07 (q,
J = 7.0 Hz, 2H), 3.86 – 3.68
(m, 2H), 1.43 (t,
J = 7.0 Hz, 3H), 1.31 (t,
J = 7.1 Hz, 3H);
13C
NMR (100 MHz, CDCl
3) δ
170.6, 156.8, 155.6, 131.5, 129.4, 120.6, 117.6, 112.0, 78.0, 63.9, 61.6, 41.5,
14.6, 14.0; HRMS (ESI-TOF): Anal. Calcd. For C
14H
17NNaO
4
+:
286.1050, Found: 286.1063; IR (neat, cm
-1): υ 2983, 2950, 2939, 2890, 1730, 1453, 1282, 1255, 1030,
888, 760。
Yield: 69%; 1 H NMR (400 MHz, CDCl 3 ) δ 7.77 (dd, J = 7.8, 1.7 Hz, 1H), 7.38 – 7.33 (m, 1H), 6.98 – 6.88 (m, 2H), 5.10 (dd, J = 11.0, 7.2 Hz, 1H), 4.26 (q, J = 7.1 Hz, 2H), 4.07 (q, J = 7.0 Hz, 2H), 3.86 – 3.68 (m, 2H), 1.43 (t , J = 7.0 Hz, 3H), 1.31 (t, J = 7.1 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 170.6, 156.8, 155.6, 131.5, 129.4, 120.6, 117.6, 112.0, 78.0, 63.9, 61.6, 41.5, 14.6, 14.0; HRMS (ESI-TOF): Anal. Calcd. For C 14 H 17 NNaO 4 + : 286.1050, Found: 286.1063; IR (neat, cm -1 ): υ 2983, 2950, 2939, 2890, 1730, 1453, 1282, 1255, 1030, 888, 760.
产率:51%;
1H NMR (400 MHz, CDCl
3) δ 9.54 (s, 1H), 7.37 – 7.30
(m, 1H), 7.19 (d,
J = 7.8 Hz, 1H), 7.03 (d,
J = 8.1 Hz, 1H), 6.95
– 6.89 (m, 1H), 5.13 (dd,
J =
10.8, 7.4 Hz, 1H), 4.27 (q,
J = 7.2 Hz, 2H), 3.79 – 3.68 (m, 2H), 1.32 (t,
J = 7.2 Hz, 3H);
13C
NMR (100 MHz, CDCl
3) δ
169.6, 157.8, 157.3, 132.1, 128.5, 119.6, 117.1, 113.0, 76.7, 62.2, 39.0, 14.0;
HRMS (ESI-TOF): Anal. Calcd. For C
12H
13NNaO
4
+:
258.0737, Found: 258.0730; IR (neat, cm
-1): υ 3211, 3057, 2984, 2939, 1737, 1494, 1258, 1201, 1157,
754, 655。
Yield: 51%; 1 H NMR (400 MHz, CDCl 3 ) δ 9.54 (s, 1H), 7.37 – 7.30 (m, 1H), 7.19 (d, J = 7.8 Hz, 1H), 7.03 (d, J = 8.1 Hz, 1H), 6.95 – 6.89 (m, 1H), 5.13 (dd, J = 10.8, 7.4 Hz, 1H), 4.27 (q, J = 7.2 Hz, 2H), 3.79 – 3.68 (m, 2H) , 1.32 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 169.6, 157.8, 157.3, 132.1, 128.5, 119.6, 117.1, 113.0, 76.7, 62.2, 39.0, 14.0; HRMS ( ESI-TOF): Anal. Calcd. For C 12 H 13 NNaO 4 + : 258.0737, Found: 258.0730; IR (neat, cm -1 ): υ 3211, 3057, 2984, 2939, 1737, 1494, 1258, 1201, 1157, 754, 655.
产率:77%;
1H NMR (400 MHz, CDCl
3) δ 7.55 (d,
J = 8.8 Hz, 2H), 6.88 (d,
J = 8.8
Hz, 2H), 5.09 (dd,
J = 9.8, 8.5 Hz, 1H), 4.22 (q,
J = 7.1 Hz,
2H), 4.09 – 4.04 (m, 2H), 3.94 (t,
J = 4.5
Hz, 2H), 3.67 – 3.45 (m, 2H), 2.65 (s, 1H), 1.28 (t,
J
= 7.1 Hz, 3H);
13C NMR (100 MHz, CDCl
3) δ 170.2, 160.3, 155.4, 128.4, 121.2, 114.6, 77.7, 69.2,
61.8, 61.0, 38.9, 14.0; HRMS (ESI-TOF): Anal. Calcd. For C
14H
17NNaO
5
+:
302.0999, Found: 302.0989; IR (neat, cm
-1): υ 3412, 2993, 2944, 1742, 1257, 1210, 1169, 1076, 1026,
890, 837, 818。
Yield: 77%; 1 H NMR (400 MHz, CDCl 3 ) δ 7.55 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 5.09 (dd, J = 9.8, 8.5 Hz, 1H), 4.22 (q, J = 7.1 Hz, 2H), 4.09 – 4.04 (m, 2H), 3.94 (t, J = 4.5 Hz, 2H), 3.67 – 3.45 (m, 2H), 2.65 (s , 1H), 1.28 (t, J = 7.1 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 170.2, 160.3, 155.4, 128.4, 121.2, 114.6, 77.7, 69.2, 61.8, 61.0, 38.9, 14.0 ; HRMS (ESI-TOF): Anal. Calcd. For C 14 H 17 NNaO 5 + : 302.0999, Found: 302.0989; IR (neat, cm -1 ): υ 3412, 2993, 2944, 1742, 1257, 1210, 1169 , 1076, 1026, 890, 837, 818.
产率:74%;
1H NMR (400 MHz, CDCl
3) δ7.76 – 7.71 (m, 1H),
7.33 – 7.26 (m, 2H), 5.15 (t,
J = 9.3
Hz, 1H), 4.25 (q,
J = 7.1 Hz, 2H), 3.68 (d,
J = 9.3 Hz, 1H), 3.67
(d,
J = 9.3 Hz, 1H), 1.30 (t,
J = 7.1 Hz, 3H);
13C NMR
(100 MHz, CDCl
3) δ 169.8, 159.8
(d,
J = 257.1 Hz), 152.0 (d,
J = 3.3 Hz), 130.0 (d,
J =
3.6 Hz), 128.0 (d,
J = 3.4 Hz), 124.9 (d,
J = 9.8 Hz), 120.0 (d,
J = 25.4 Hz), 115.8 (d,
J = 11.7 Hz), 78.3 (d,
J = 2.5 Hz),
61.9, 40.1 (d,
J = 7.7 Hz), 14.0;
19F NMR (376 MHz, CDCl
3)
δ -100.3; HRMS (ESI-TOF): Anal. Calcd.
For C
12H
11
79BrFNNaO
3
+:
337.9799, C
12H
11
81BrFNNaO
3
+:
339.9778, Found: 337.9795, 339.9771; IR (neat, cm
-1): υ 3072, 2985, 2929, 2855, 1726, 1594, 1203, 1170, 908,
878, 869, 823。
Yield: 74%; 1 H NMR (400 MHz, CDCl 3 ) δ 7.76 – 7.71 (m, 1H), 7.33 – 7.26 (m, 2H), 5.15 (t, J = 9.3 Hz, 1H), 4.25 ( q, J = 7.1 Hz, 2H), 3.68 (d, J = 9.3 Hz, 1H), 3.67 (d, J = 9.3 Hz, 1H), 1.30 (t, J = 7.1 Hz, 3H); 13 C NMR ( 100 MHz, CDCl 3 ) δ 169.8, 159.8 (d, J = 257.1 Hz), 152.0 (d, J = 3.3 Hz), 130.0 (d, J = 3.6 Hz), 128.0 (d, J = 3.4 Hz), 124.9 (d, J = 9.8 Hz), 120.0 (d, J = 25.4 Hz), 115.8 (d, J = 11.7 Hz), 78.3 (d, J = 2.5 Hz), 61.9, 40.1 (d, J = 7.7 Hz) , 14.0; 19 F NMR (376 MHz, CDCl 3 ) δ -100.3; HRMS (ESI-TOF): Anal. Calcd. For C 12 H 11 79 BrFNNaO 3 + : 337.9799, C 12 H 11 81 BrFNNaO 3 + : 339.9778 , Found: 337.9795, 339.9771; IR (neat, cm -1 ): υ 3072, 2985, 2929, 2855, 1726, 1594, 1203, 1170, 908, 878, 869, 823.
产率:62%;
1H NMR (400 MHz, CDCl
3) δ 9.55 (s, 1H), 7.28 (d,
J = 8.9 Hz, 1H), 7.16 (s,
1H), 6.98 (d,
J = 8.9 Hz, 1H), 5.16 (dd,
J = 11.0, 7.2 Hz, 1H),
4.29 (q,
J = 7.1 Hz, 2H), 3.81 – 3.61
(m, 2H), 1.34 (t,
J = 7.1 Hz, 3H);
13C NMR (100 MHz, CDCl
3)
δ 169.3, 156.9, 155.9, 131.9, 127.7,
124.3, 118.6, 114.3, 77.0, 62.4, 38.8, 14.1; HRMS (ESI-TOF): Anal. Calcd. For C
12H
12
35ClNNaO
4
+:
292.0347, Found: 292.0329; IR (neat, cm
-1): υ 3072, 2996, 2967, 2930, 2911, 1751, 1384, 1204, 1193,
1170, 812, 667。
Yield: 62%; 1 H NMR (400 MHz, CDCl 3 ) δ 9.55 (s, 1H), 7.28 (d, J = 8.9 Hz, 1H), 7.16 (s, 1H), 6.98 (d, J = 8.9 Hz, 1H), 5.16 (dd, J = 11.0, 7.2 Hz, 1H), 4.29 (q, J = 7.1 Hz, 2H), 3.81 – 3.61 (m, 2H), 1.34 (t, J = 7.1 Hz, 3H) ); 13 C NMR (100 MHz, CDCl 3 ) δ 169.3, 156.9, 155.9, 131.9, 127.7, 124.3, 118.6, 114.3, 77.0, 62.4, 38.8, 14.1; HRMS (ESI-TOF): Anal. Calcd. For C 12 H 12 35 ClNNaO 4 + : 292.0347, Found: 292.0329; IR (neat, cm -1 ): υ 3072, 2996, 2967, 2930, 2911, 1751, 1384, 1204, 1193, 1170, 812, 667.
产率:76%;
1H NMR (400 MHz, CDCl
3) δ8.99 (d,
J = 8.6 Hz, 1H), 7.91 – 7.85 (m, 2H), 7.62 – 7.57
(m, 1H), 7.56 – 7.50 (m, 2H), 7.45 (dd,
J = 8.1,
7.3 Hz, 1H), 5.17 (dd,
J = 9.8, 8.2 Hz, 1H), 4.29 (q,
J = 7.1 Hz,
2H), 3.85 – 3.78 (m, 2H), 1.33 (t,
J = 7.1
Hz, 3H);
13C NMR (100 MHz, CDCl
3) δ 170.1, 156.4, 133.8, 131.1, 130.4, 128.4, 127.8, 127.5,
126.9, 126.3, 125.4, 124.6, 77.0, 61.9, 41.6, 14.0; HRMS (ESI-TOF): Anal.
Calcd. For C
16H
15NNaO
3
+: 292.0944,
Found: 292.0934; IR (neat, cm
-1): υ
3050, 2982, 2938, 1735, 1318, 1202, 1024, 891, 801, 773。
Yield: 76%; 1 H NMR (400 MHz, CDCl 3 ) δ 8.99 (d, J = 8.6 Hz, 1H), 7.91 – 7.85 (m, 2H), 7.62 – 7.57 (m, 1H), 7.56 – 7.50 (m, 2H), 7.45 (dd, J = 8.1, 7.3 Hz, 1H), 5.17 (dd, J = 9.8, 8.2 Hz, 1H), 4.29 (q, J = 7.1 Hz, 2H), 3.85 – 3.78 (m, 2H), 1.33 (t, J = 7.1 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 170.1, 156.4, 133.8, 131.1, 130.4, 128.4, 127.8, 127.5, 126.9, 126.3, 125.4 , 124.6, 77.0, 61.9, 41.6, 14.0; HRMS (ESI-TOF): Anal. Calcd. For C 16 H 15 NNaO 3 + : 292.0944, Found: 292.0934; IR (neat, cm -1 ): υ 3050, 2982 , 2938, 1735, 1318, 1202, 1024, 891, 801, 773.
产率:77%;
1H NMR (400 MHz, CDCl
3) δ7.31 (s, 1H), 6.45 (s, 1H), 5.02 (dd,
J = 11.2,
7.1 Hz, 1H), 4.20 (q,
J = 7.1 Hz, 2H), 3.86 (s, 3H), 3.79 (s, 3H), 3.78
(s, 3H), 3.75 – 3.63 (m, 2H), 1.26 (t,
J = 7.1
Hz, 3H);
13C NMR (100 MHz, CDCl
3) δ 170.6, 154.9, 152.5, 151.7, 143.0, 111.1, 108.6, 96.9,
77.8, 61.5, 56.14, 56.11, 55.8, 41.4, 13.9; HRMS (ESI-TOF): Anal. Calcd. For C
15H
19NNaO
6
+:
332.1105, Found: 332.1104; IR (neat, cm
-1): υ 3003, 2978, 2939, 2839, 1715, 1462, 1271, 1207, 1162,
1025, 797。
Yield: 77%; 1 H NMR (400 MHz, CDCl 3 ) δ 7.31 (s, 1H), 6.45 (s, 1H), 5.02 (dd, J = 11.2, 7.1 Hz, 1H), 4.20 (q, J = 7.1 Hz, 2H), 3.86 (s, 3H), 3.79 (s, 3H), 3.78 (s, 3H), 3.75 – 3.63 (m, 2H), 1.26 (t, J = 7.1 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 170.6, 154.9, 152.5, 151.7, 143.0, 111.1, 108.6, 96.9, 77.8, 61.5, 56.14, 56.11, 55.8, 41.4, 13.9; HRMS (ESI-TOF) Anal. Calcd. For C 15 H 19 NNaO 6 + : 332.1105, Found: 332.1104; IR (neat, cm -1 ): υ 3003, 2978, 2939, 2839, 1715, 1462, 1271, 1207, 1162, 1025, 797.
产率:69%;
1H NMR (400 MHz, CDCl
3) δ 7.83 – 7.74 (m, 2H),
7.42 – 7.32 (m, 3H), 5.20 (dd,
J =
11.2, 7.2 Hz, 1H), 4.28 (q,
J = 7.0 Hz, 2H), 3.80 – 3.62 (m, 2H), 1.33 (t,
J = 7.0 Hz, 3H);
13C
NMR (100 MHz, CDCl
3) δ
169.7, 152.3, 140.5, 138.8, 131.0, 126.14, 126.12, 124.7, 124.2, 122.4, 78.6,
62.1, 39.0, 14.0; HRMS (EI-TOF): Anal. Calcd. For C
14H
13NO
3S:
275.0616, Found: 275.0614; IR (neat, cm
-1): υ 2983, 2961, 2922, 1747, 1193, 1163, 1153, 898, 832, 749,
727。
Yield: 69%; 1 H NMR (400 MHz, CDCl 3 ) δ 7.83 - 7.74 (m, 2H), 7.42 - 7.32 (m, 3H), 5.20 (dd, J = 11.2, 7.2 Hz, 1H), 4.28 (q, J = 7.0 Hz, 2H), 3.80 – 3.62 (m, 2H), 1.33 (t, J = 7.0 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 169.7, 152.3, 140.5, 138.8 , 131.0, 126.14, 126.12, 124.7, 124.2, 122.4, 78.6, 62.1, 39.0, 14.0; HRMS (EI-TOF): Anal. Calcd. For C 14 H 13 NO 3 S: 275.0616, Found: 275.0614; IR (neat , cm -1 ): υ 2983, 2961, 2922, 1747, 1193, 1163, 1153, 898, 832, 749, 727.
产率:69%;
1H NMR (400 MHz, CDCl
3) δ7.94 (dd,
J = 8.7, 1.8 Hz, 1H), 7.88 (s, 1H), 7.85
– 7.78 (m, 3H), 7.54 – 7.46 (m, 2H), 5.20 (dd,
J = 11.3, 7.1 Hz, 1H),
4.27 (q,
J = 7.1 Hz, 2H), 3.76 (dd,
J = 16.8, 7.1 Hz, 1H), 3.69
(dd,
J = 16.8, 11.3 Hz, 1H), 1.32 (t,
J = 7.1 Hz, 3H);
13C
NMR (100 MHz, CDCl
3) δ
170.1, 156.0, 134.0, 132.7, 128.4, 128.3, 127.7, 127.2, 127.1, 126.6, 126.0,
123.4, 78.1, 61.9, 38.6, 14.0; HRMS (ESI-TOF): Anal. Calcd. For C
16H
15NNaO
3
+:
292.0944, Found: 292.0940; IR (neat, cm
-1): υ 3062, 2983, 2955, 1743, 1200, 1191, 1162, 898, 821, 749。
Yield: 69%; 1 H NMR (400 MHz, CDCl 3 ) δ 7.94 (dd, J = 8.7, 1.8 Hz, 1H), 7.88 (s, 1H), 7.85 – 7.78 (m, 3H), 7.54 – 7.46 (m, 2H), 5.20 (dd, J = 11.3, 7.1 Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H), 3.76 (dd, J = 16.8, 7.1 Hz, 1H), 3.69 (dd , J = 16.8, 11.3 Hz, 1H), 1.32 (t, J = 7.1 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 170.1, 156.0, 134.0, 132.7, 128.4, 128.3, 127.7, 127.2, 127.1, 126.6, 126.0, 123.4, 78.1, 61.9, 38.6, 14.0; HRMS (ESI-TOF): Anal. Calcd. For C 16 H 15 NNaO 3 + : 292.0944, Found: 292.0940; IR (neat, cm -1 ) : υ 3062, 2983, 2955, 1743, 1200, 1191, 1162, 898, 821, 749.
产率:75%;
1H NMR (400 MHz, CDCl
3) δ 8.46 (s, 1H), 8.16 (dd,
J = 8.1, 1.7 Hz, 1H),
7.67 (ddd,
J = 8.7, 7.1, 1.7 Hz, 1H), 7.48 – 7.37 (m, 2H), 5.10 (dd,
J = 11.8, 6.9 Hz, 1H),
4.22 (q,
J = 7.1 Hz, 2H), 3.90 (dd,
J = 18.1, 11.8 Hz, 1H), 3.75
(dd,
J = 18.1, 6.9 Hz, 1H), 1.27 (t,
J = 7.1 Hz, 3H);
13C
NMR (100 MHz, CDCl
3) δ
175.0, 170.0, 155.8, 154.9, 151.7, 134.2, 125.9, 125.8, 123.9, 118.2, 114.4,
77.9, 61.7, 40.4, 14.0; HRMS (ESI-TOF): Anal. Calcd. For C
15H
13NNaO
5
+:
310.0686, Found: 310.0690; IR (neat, cm
-1): υ 2977, 2924, 1754, 1650, 1615, 1465, 1189, 1034, 813, 759。
Yield: 75%; 1 H NMR (400 MHz, CDCl 3 ) δ 8.46 (s, 1H), 8.16 (dd, J = 8.1, 1.7 Hz, 1H), 7.67 (ddd, J = 8.7, 7.1, 1.7 Hz , 1H), 7.48 – 7.37 (m, 2H), 5.10 (dd, J = 11.8, 6.9 Hz, 1H), 4.22 (q, J = 7.1 Hz, 2H), 3.90 (dd, J = 18.1, 11.8 Hz, 1H), 3.75 (dd, J = 18.1, 6.9 Hz, 1H), 1.27 (t, J = 7.1 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 175.0, 170.0, 155.8, 154.9, 151.7, 134.2, 125.9, 125.8, 123.9, 118.2, 114.4, 77.9, 61.7, 40.4, 14.0; HRMS (ESI-TOF): Anal. Calcd. For C 15 H 13 NNaO 5 + : 310.0686, Found: 310.0690; IR ( cm -1 ): υ 2977, 2924, 1754, 1650, 1615, 1465, 1189, 1034, 813, 759.
产率:58%;
1H NMR (400 MHz, CDCl
3) δ 7.49 – 7.42 (m, 2H),
7.39 – 7.29 (m, 3H), 7.06 (d,
J = 16.5
Hz, 1H), 6.77 (d,
J = 16.5 Hz, 1H), 5.10 (dd,
J = 10.8, 7.5 Hz,
1H), 4.26 (q,
J = 7.1 Hz, 2H), 3.49 (d,
J = 7.5 Hz, 1H), 3.48 (d,
J = 10.8 Hz, 1H), 1.32 (t,
J = 7.1 Hz, 3H);
13C NMR
(100 MHz, CDCl
3) δ 170.0, 156.9,
137.4, 135.4, 129.1, 128.8, 127.0, 116.8, 78.0, 61.9, 37.4, 14.0; HRMS
(ESI-TOF): Anal. Calcd. For C
14H
15NNaO
3
+:
268.0944, Found: 268.0936; IR (neat, cm
-1): υ 3069, 2978, 2924, 1737, 1589, 1362, 1340, 1162, 1073,
894, 882, 785, 691。
Yield: 58%; 1 H NMR (400 MHz, CDCl 3 ) δ 7.49 – 7.42 (m, 2H), 7.39 – 7.29 (m, 3H), 7.06 (d, J = 16.5 Hz, 1H), 6.77 (d , J = 16.5 Hz, 1H), 5.10 (dd, J = 10.8, 7.5 Hz, 1H), 4.26 (q, J = 7.1 Hz, 2H), 3.49 (d, J = 7.5 Hz, 1H), 3.48 (d , J = 10.8 Hz, 1H), 1.32 (t, J = 7.1 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 170.0, 156.9, 137.4, 135.4, 129.1, 128.8, 127.0, 116.8, 78.0, 61.9, 37.4, 14.0; HRMS (ESI-TOF): Anal. Calcd. For C 14 H 15 NNaO 3 + : 268.0944, Found: 268.0936; IR (neat, cm -1 ): υ 3069, 2978, 2924, 1737, 1589, 1362, 1340, 1162, 1073, 894, 882, 785, 691.
产率:87%;
1H NMR (400 MHz, CDCl
3) δ 7.48 – 7.42 (m, 2H),
7.36 – 7.27 (m, 3H), 4.96 (dd,
J =
10.5, 7.6 Hz, 1H), 4.19 (q,
J = 7.1 Hz, 2H), 3.85 – 3.76 (m, 2H), 3.23 (s, 3H), 2.56 (s, 3H), 1.25 (t,
J
= 7.1 Hz, 3H);
13C NMR (100 MHz, CDCl
3) δ 170.6, 163.6, 153.4, 151.3, 134.1, 129.3, 127.7, 125.3,
97.0, 76.2, 61.5, 40.7, 34.5, 14.0, 13.1; HRMS (ESI-TOF): Anal. Calcd. For C
17H
20N
3O
4
+:
330.1448, Found: 330.1468; IR (neat, cm
-1): υ 2988, 2918, 2852, 1738, 1650, 1548, 1310, 1281, 1089,
1032, 976, 854, 751。
Yield: 87%; 1 H NMR (400 MHz, CDCl 3 ) δ 7.48 - 7.42 (m, 2H), 7.36 - 7.27 (m, 3H), 4.96 (dd, J = 10.5, 7.6 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 3.85 – 3.76 (m, 2H), 3.23 (s, 3H), 2.56 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H); 13 C NMR ( 100 MHz, CDCl 3 ) δ 170.6, 163.6, 153.4, 151.3, 134.1, 129.3, 127.7, 125.3, 97.0, 76.2, 61.5, 40.7, 34.5, 14.0, 13.1; HRMS (ESI-TOF): Anal. Calcd 17 H 20 N 3 O 4 + : 330.1448, Found: 330.1468; IR (neat, cm -1 ): υ 2988, 2918, 2852, 1738, 1650, 1548, 1310, 1281, 1089, 1032, 976, 854, 75 .
产率:73%;
1H NMR (400 MHz, CDCl
3) δ5.02 (dd,
J = 10.7, 7.5 Hz, 1H), 4.21 (q,
J
= 7.1 Hz, 2H), 3.75 (s, 3H), 3.65 (d,
J = 7.5 Hz, 1H), 3.64 (d,
J
= 10.7 Hz, 1H), 2.36 (s, 3H), 1.27 (t,
J = 7.1 Hz, 3H);
13C
NMR (100 MHz, CDCl
3) δ
170.1, 149.5, 148.3, 127.1, 106.3, 76.9, 61.8, 40.0, 36.1, 15.1, 14.0; HRMS
(ESI-TOF): Anal. Calcd. For C
11H
14
35ClN
3NaO
3
+:
294.0616, C
11H
14
37ClN
3NaO
3
+:
296.0586, Found: 294.0625, 296.0592; IR (neat, cm
-1): υ 2996, 2937, 2851, 1729, 1529, 1367, 1275, 1028, 892, 808。
Yield: 73%; 1 H NMR (400 MHz, CDCl 3 ) δ 5.02 (dd, J = 10.7, 7.5 Hz, 1H), 4.21 (q, J = 7.1 Hz, 2H), 3.75 (s, 3H) , 3.65 (d, J = 7.5 Hz, 1H), 3.64 (d, J = 10.7 Hz, 1H), 2.36 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H); 13 C NMR (100 MHz) , CDCl 3 ) δ 170.1, 149.5, 148.3, 127.1, 106.3, 76.9, 61.8, 40.0, 36.1, 15.1, 14.0; HRMS (ESI-TOF): Anal. Calcd. For C 11 H 14 35 ClN 3 NaO 3 + : 294.0616, C 11 H 14 37 ClN 3 NaO 3 + : 296.0586, Found: 294.0625, 296.0592; IR (neat, cm -1 ): υ 2996, 2937, 2851, 1729, 1529, 1367, 1275, 8028 .
实施例五。Example five.
以丙烯酸丁酯为例,向具有磁力搅拌子的试管中,添加对溴苯甲醛(0.65 mmol),对甲苯磺酰肼(0.7 mmol)和MeOH(1 mL),将混合物在60 ℃下搅拌30分钟。 真空除去溶剂后,依次加入CuCl
2(0.05 mmol),THF(2.0 mL),丙烯酸丁酯(0.5 mmol),TMEDA(0.75 mmol),TBN(2.0 mmol)和THF(2.0 mL)。将试管用封口膜密封,并在65 ℃下搅拌24 h。用饱和氯化钠溶液淬灭,再用乙酸乙酯萃取后,利用旋转蒸发仪除去溶剂、硅胶吸附,最后用乙酸乙酯和石油醚的混合溶剂进行柱层析即可得产物异噁唑啉
4aj。产率:88%;
1H NMR (400 MHz, CDCl
3) δ 7.52 (s, 4H), 5.16 (dd,
J = 10.4, 8.0 Hz, 1H),
4.19 (t,
J = 6.7 Hz, 2H), 3.63 – 3.56
(m, 2H), 1.70 – 1.61 (m, 2H), 1.43– 1.32 (m, 2H), 0.92 (t,
J = 7.4 Hz, 3H);
13C
NMR (100 MHz, CDCl
3) δ
169.9, 155.1, 131.9, 128.2, 127.5, 124.7, 78.2, 65.8, 38.5, 30.4, 18.9, 13.6;
1HRMS
(ESI-TOF): Anal. Calcd. For C
14H
16
79BrNNaO
3
+:
348.0206, C
14H
16
81BrNNaO
3
+:
350.0185, Found: 348.0188, 350.0204; IR (neat, cm
-1): υ 2958, 2931, 2872, 1738, 1210, 1058, 1006, 888, 861, 819.
产物4aj如下:
。
Taking butyl acrylate as an example, to a test tube with a magnetic stirring bar, add p-bromobenzaldehyde (0.65 mmol), p-toluenesulfonylhydrazide (0.7 mmol) and MeOH (1 mL), and the mixture was stirred at 60 °C for 30 minute. After the solvent was removed in vacuo, CuCl2 (0.05 mmol), THF (2.0 mL), butyl acrylate (0.5 mmol), TMEDA (0.75 mmol), TBN (2.0 mmol) and THF (2.0 mL) were added sequentially. The test tube was sealed with parafilm and stirred at 65 °C for 24 h. Quenched with saturated sodium chloride solution, extracted with ethyl acetate, removed the solvent with a rotary evaporator, adsorbed on silica gel, and finally performed column chromatography with a mixed solvent of ethyl acetate and petroleum ether to obtain the product isoxazoline 4aj . Yield: 88%; 1 H NMR (400 MHz, CDCl 3 ) δ 7.52 (s, 4H), 5.16 (dd, J = 10.4, 8.0 Hz, 1H), 4.19 (t, J = 6.7 Hz, 2H), 3.63 – 3.56 (m, 2H), 1.70 – 1.61 (m, 2H), 1.43 – 1.32 (m, 2H), 0.92 (t, J = 7.4 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 169.9, 155.1, 131.9, 128.2, 127.5, 124.7, 78.2, 65.8, 38.5, 30.4, 18.9, 13.6; 1 HRMS (ESI-TOF): Anal. Calcd. For C 14 H 16 79 BrNNaO 3 + 6 C : 348.02 H 16 81 BrNNaO 3 + : 350.0185, Found: 348.0188, 350.0204; IR (neat, cm -1 ): υ 2958, 2931, 2872, 1738, 1210, 1058, 1006, 888, 861, 819. The product 4aj is as follows: .
保持反应条件不变,仅仅更换烯烃化合物2,得到的产物以及表征如下:
。
Keeping the reaction conditions unchanged, only replacing the olefin compound 2, the obtained products and their characterizations are as follows: .
产率:80%;
1H NMR (400 MHz, CDCl
3) δ 7.50 (s, 4H), 5.03 (t,
J = 9.4 Hz, 1H), 3.53 (d,
J
= 9.4 Hz, 2H), 1.48 (s, 9H);
13C NMR (100 MHz, CDCl
3) δ 168.8, 154.9, 131.8, 128.2, 127.6, 124.5, 82.7, 78.9,
38.3, 27.8;
1HRMS (ESI-TOF): Anal. Calcd. For C
14H
16
79BrNNaO
3
+:
348.0206, C
14H
16
81BrNNaO
3
+:
350.0185, Found: 348.0195, 350.0200; IR (neat, cm
-1): υ 2976, 2935, 1733, 1590, 1346, 1149, 1007, 894, 866, 834,
820。
Yield: 80%; 1 H NMR (400 MHz, CDCl 3 ) δ 7.50 (s, 4H), 5.03 (t, J = 9.4 Hz, 1H), 3.53 (d, J = 9.4 Hz, 2H), 1.48 ( s, 9H); 13 C NMR (100 MHz, CDCl 3 ) δ 168.8, 154.9, 131.8, 128.2, 127.6, 124.5, 82.7, 78.9, 38.3, 27.8; 1 HRMS (ESI-TOF): Anal. Calcd. For C 14 H 16 79 BrNNaO 3 + : 348.0206, C 14 H 16 81 BrNNaO 3 + : 350.0185, Found: 348.0195, 350.0200; IR (neat, cm -1 ): υ 2976, 2935, 1733, 1590, 0179 , 894, 866, 834, 820.
产率:83%;
1H NMR (400 MHz, CDCl
3) δ 7.51 (s, 4H), 7.39 – 7.32
(m, 5H), 5.24 – 5.17 (m, 3H), 3.59 (d,
J = 7.7
Hz, 1H), 3.58 (d,
J = 10.7 Hz, 1H);
13C NMR (100 MHz, CDCl
3)
δ 169.6, 155.1, 134.8, 131.8, 128.5,
128.4, 128.2, 127.3, 124.7, 78.1, 67.4, 38.4;
1HRMS (ESI-TOF): Anal.
Calcd. For C
17H
14
79BrNNaO
3
+:
382.0049, C
17H
14
81BrNNaO
3
+:
384.0029, Found: 382.0042, 384.0030; IR (neat, cm
-1): υ 3068, 3037, 2955, 1755, 1174, 1162, 881, 825, 734, 693。
Yield: 83%; 1 H NMR (400 MHz, CDCl 3 ) δ 7.51 (s, 4H), 7.39 – 7.32 (m, 5H), 5.24 – 5.17 (m, 3H), 3.59 (d, J = 7.7 Hz , 1H), 3.58 (d, J = 10.7 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 169.6, 155.1, 134.8, 131.8, 128.5, 128.4, 128.2, 127.3, 124.7, 78.1, 67.4, 38 ; 1 HRMS (ESI-TOF): Anal. Calcd. For C 17 H 14 79 BrNNaO 3 + : 382.0049, C 17 H 14 81 BrNNaO 3 + : 384.0029, Found: 382.0042, 384.0030; IR (neat, cm -1 ) : υ 3068, 3037, 2955, 1755, 1174, 1162, 881, 825, 734, 693.
产率:67%;
1H NMR (400 MHz, CDCl
3) δ 7.59 – 7.50 (m, 4H),
7.43 – 7.33 (m, 2H), 7.28 – 7.21 (m, 1H), 7.16 – 7.10
(m, 2H), 5.41 (dd,
J = 11.3, 7.0 Hz, 1H), 3.77 (dd,
J = 17.0, 7.0
Hz, 1H), 3.70 (dd,
J = 17.0, 11.3 Hz, 1H);
13C NMR (100 MHz,
CDCl
3) δ 168.3, 155.2,
150.1, 131.9, 129.4, 128.3, 126.2, 124.8, 121.0, 78.1, 38.5;
1HRMS
(ESI-TOF): Anal. Calcd. For C
16H
12
79BrNNaO
3
+:
367.9893, C
16H
12
81BrNNaO
3
+:
369.9872, Found: 367.9881, 369.9859; IR (neat, cm
-1): υ 3070, 3043, 2976, 2927, 1773, 1589, 1489, 1193, 1162,
1069, 818, 748。
Yield: 67%; 1 H NMR (400 MHz, CDCl 3 ) δ 7.59 – 7.50 (m, 4H), 7.43 – 7.33 (m, 2H), 7.28 – 7.21 (m, 1H), 7.16 – 7.10 (m, 2H), 5.41 (dd, J = 11.3, 7.0 Hz, 1H), 3.77 (dd, J = 17.0, 7.0 Hz, 1H), 3.70 (dd, J = 17.0, 11.3 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 168.3, 155.2, 150.1, 131.9, 129.4, 128.3, 126.2, 124.8, 121.0, 78.1, 38.5; 1 HRMS (ESI-TOF): Anal. Calcd. For C 16 H 12 79 BrNNaO 3 + : 367.9893, C 16 H 12 81 BrNNaO 3 + : 369.9872, Found: 367.9881, 369.9859; IR (neat, cm -1 ): υ 3070, 3043, 2976, 2927, 1773, 1589, 1168, 109, 83, , 748.
产率:60%;
1H NMR (400 MHz, CDCl
3) δ 7.58 – 7.52 (m, 4H),
5.28 (dd,
J = 11.1, 7.0 Hz, 1H), 4.65 (dq,
J = 12.6, 8.3 Hz, 1H),
4.53 (dq,
J = 12.6, 8.3 Hz, 1H), 3.76 – 3.56
(m, 2H);
13C NMR (100 MHz, CDCl
3) δ 168.4, 155.1, 132.1, 128.4, 127.1, 125.1, 122.5 (q,
J
= 277.2 Hz), 77.5, 61.2 (q,
J = 37.1 Hz), 38.7;
19F NMR (376
MHz, CDCl
3) δ -73.7; HRMS
(ESI-TOF): Anal. Calcd. For C
12H
9
79BrF
3NNaO
3
+:
373.9610, C
12H
9
81BrF
3NNaO
3
+:
375.9590, Found: 373.9605, 375.9593; IR (neat, cm
-1): υ 2991, 2977, 2923, 1772, 1274, 1176, 1161, 1054, 971,
894, 824。
Yield: 60%; 1 H NMR (400 MHz, CDCl 3 ) δ 7.58 – 7.52 (m, 4H), 5.28 (dd, J = 11.1, 7.0 Hz, 1H), 4.65 (dq, J = 12.6, 8.3 Hz) , 1H), 4.53 (dq, J = 12.6, 8.3 Hz, 1H), 3.76 – 3.56 (m, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 168.4, 155.1, 132.1, 128.4, 127.1, 125.1, 122.5 (q, J = 277.2 Hz), 77.5, 61.2 (q, J = 37.1 Hz), 38.7; 19 F NMR (376 MHz, CDCl 3 ) δ -73.7; HRMS (ESI-TOF): Anal. Calcd. For C 12 H 9 79 BrF 3 NNaO 3 + : 373.9610, C 12 H 9 81 BrF 3 NNaO 3 + : 375.9590, Found: 373.9605, 375.9593; IR (neat, cm -1 ): υ 2991, 2977, 2923, 1772 1274, 1176, 1161, 1054, 971, 894, 824.
产率:60%;
1H NMR (400 MHz, CDCl
3) δ 7.51 (s, 4H), 5.21 (t,
J = 9.2 Hz, 1H), 4.81 (dd,
J = 15.5, 2.5 Hz, 1H), 4.75 (dd,
J = 15.5, 2.5 Hz, 1H), 3.62 (d,
J
= 9.2 Hz, 2H), 2.52 (t,
J = 2.5 Hz, 1H);
13C NMR (100 MHz,
CDCl
3) δ 169.1, 155.1,
132.0, 128.3, 127.2, 124.8, 77.8, 76.6, 75.8, 53.2, 38.5; HRMS (ESI-TOF): Anal.
Calcd. For C
13H
10
79BrNNaO
3
+:
329.9736, C
13H
10
81BrNNaO
3
+:
331.9716, Found: 329.9721, 331.9710; IR (neat, cm
-1): υ 3277, 2977, 2945, 1742, 1219, 1204, 1069, 1021, 895,
884, 821, 638。
Yield: 60%; 1 H NMR (400 MHz, CDCl 3 ) δ 7.51 (s, 4H), 5.21 (t, J = 9.2 Hz, 1H), 4.81 (dd, J = 15.5, 2.5 Hz, 1H), 4.75 (dd, J = 15.5, 2.5 Hz, 1H), 3.62 (d, J = 9.2 Hz, 2H), 2.52 (t, J = 2.5 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 169.1 , 155.1, 132.0, 128.3, 127.2, 124.8, 77.8, 76.6, 75.8, 53.2, 38.5; HRMS (ESI-TOF): Anal. Calcd. For C 13 H 10 79 BrNNaO 3 + : 329.9736, C 13 H BrNNaO 10 8 3 + : 331.9716, Found: 329.9721, 331.9710; IR (neat, cm -1 ): υ 3277, 2977, 2945, 1742, 1219, 1204, 1069, 1021, 895, 884, 821, 638.
产率:81%;
1H NMR (400 MHz, DMSO-d6) δ 7.67 (d,
J = 8.6 Hz, 2H), 7.64 (d,
J = 8.6
Hz, 2H), 5.60 (dd,
J = 11.3, 7.2 Hz, 1H), 3.78 (dd,
J = 17.0, 7.2
Hz, 1H), 3.54 (dd,
J = 17.0, 11.3 Hz, 1H), 3.11 (s, 3H), 2.88 (s, 3H);
13C
NMR (100 MHz, DMSO-d6) δ 167.4, 156.1,
131.9, 128.7, 128.1, 123.7, 77.4, 36.72, 36.70, 35.4; HRMS (ESI-TOF): Anal.
Calcd. For C
12H
13
79BrN
2NaO
2
+:
319.0053, C
12H
13
81BrN
2NaO
2
+:
321.0032, Found: 319.0041, 321.0030; IR (neat, cm
-1): υ 2925, 2860, 1649, 1396, 1151, 1003, 897, 824。
Yield: 81%; 1 H NMR (400 MHz, DMSO-d6) δ 7.67 (d, J = 8.6 Hz, 2H), 7.64 (d, J = 8.6 Hz, 2H), 5.60 (dd, J = 11.3, 7.2 Hz, 1H), 3.78 (dd, J = 17.0, 7.2 Hz, 1H), 3.54 (dd, J = 17.0, 11.3 Hz, 1H), 3.11 (s, 3H), 2.88 (s, 3H); 13 C NMR (100 MHz, DMSO-d6) δ 167.4, 156.1, 131.9, 128.7, 128.1, 123.7, 77.4, 36.72, 36.70, 35.4; HRMS (ESI-TOF): Anal. Calcd. For C 12 H 13 79 BrN 2 NaO 2 + : 319.0053, C 12 H 13 81 BrN 2 NaO 2 + : 321.0032, Found: 319.0041, 321.0030; IR (neat, cm -1 ): υ 2925, 2860, 1649, 1396, 1151, 1003, 897.
产率:85% yield (137.9 mg); mp: 114-116
oC;
1H
NMR (400 MHz, Benzene-d6) δ 7.22 (d,
J
= 8.4 Hz, 2H), 7.14 (d,
J = 8.4 Hz, 2H), 4.78 (dd,
J = 11.2, 7.7
Hz, 1H), 4.11 (dd,
J = 16.6, 7.7 Hz, 1H), 3.18 – 3.07 (m, 3H), 3.00 (dq,
J = 14.4, 7.1 Hz, 1H),
2.63 (dd,
J = 16.6, 11.2 Hz, 1H), 0.93 (t,
J = 7.1 Hz, 3H), 0.88
(t,
J = 7.1 Hz, 3H);
13C NMR (100 MHz, Benzene-d6) δ 166.3, 156.3, 132.0, 128.7, 128.6, 124.3, 78.8, 41.8,
40.7, 36.7, 14.4, 12.8; HRMS (ESI-TOF): Anal. Calcd. For C
14H
17
79BrN
2NaO
2
+:
347.0366, C
14H
17
81BrN
2NaO
2
+:
349.0345, Found: 347.0332, 349.0329; IR (neat, cm
-1): υ 2968, 2930, 2871, 1633, 1261, 1068, 1005, 895, 830。
Yield: 85% yield (137.9 mg); mp: 114-116 oC ; 1 H NMR (400 MHz, Benzene-d6) δ 7.22 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 8.4 Hz , 2H), 4.78 (dd, J = 11.2, 7.7 Hz, 1H), 4.11 (dd, J = 16.6, 7.7 Hz, 1H), 3.18 – 3.07 (m, 3H), 3.00 (dq, J = 14.4, 7.1 Hz, 1H), 2.63 (dd, J = 16.6, 11.2 Hz, 1H), 0.93 (t, J = 7.1 Hz, 3H), 0.88 (t, J = 7.1 Hz, 3H); 13 C NMR (100 MHz, Benzene-d6) δ 166.3, 156.3, 132.0, 128.7, 128.6, 124.3, 78.8, 41.8, 40.7, 36.7, 14.4, 12.8; HRMS (ESI-TOF): Anal. Calcd. For C 14 H 17 79 BrN 2 NaO 2 + : 347.0366, C 14 H 17 81 BrN 2 NaO 2 + : 349.0345, Found: 347.0332, 349.0329; IR (neat, cm -1 ): υ 2968, 2930, 2871, 1633, 1261, 1068, 1005, 8 .
产率:45%;
1H NMR (400 MHz, DMSO-d6) δ 8.14 (t,
J = 5.7 Hz, 1H), 7.68 – 7.60 (m, 4H), 5.12 (dd,
J = 11.6, 7.0 Hz, 1H),
4.71 (t,
J = 5.5 Hz, 1H), 3.68 (dd,
J = 17.2, 11.6 Hz, 1H), 3.54
(dd,
J = 17.2, 7.0 Hz, 1H), 3.45 – 3.40
(m, 2H), 3.26 – 3.10 (m, 2H);
13C NMR (100
MHz, DMSO-d6) δ 169.7, 156.0, 131.9, 128.8, 128.0,
123.8, 79.4, 59.6, 41.6, 38.5; HRMS (ESI-TOF): Anal. Calcd. For C
12H
13
79BrN
2NaO
3
+:
335.0002, C
12H
13
81BrN
2NaO
3
+:
336.9981, Found: 334.9983, 336.9962; IR (neat, cm
-1): υ 3240, 2950, 2924, 2887, 1641, 1535, 1204, 1058, 1038,
902, 825。
Yield: 45%; 1 H NMR (400 MHz, DMSO-d6) δ 8.14 (t, J = 5.7 Hz, 1H), 7.68 – 7.60 (m, 4H), 5.12 (dd, J = 11.6, 7.0 Hz, 1H), 4.71 (t, J = 5.5 Hz, 1H), 3.68 (dd, J = 17.2, 11.6 Hz, 1H), 3.54 (dd, J = 17.2, 7.0 Hz, 1H), 3.45 – 3.40 (m, 2H) ), 3.26 – 3.10 (m, 2H); 13 C NMR (100 MHz, DMSO-d6) δ 169.7, 156.0, 131.9, 128.8, 128.0, 123.8, 79.4, 59.6, 41.6, 38.5; HRMS (ESI-TOF): Anal. Calcd. For C 12 H 13 79 BrN 2 NaO 3 + : 335.0002, C 12 H 13 81 BrN 2 NaO 3 + : 336.9981, Found: 334.9983, 336.9962; IR (neat, cm -1 ): υ 3240, 2950 , 2924, 2887, 1641, 1535, 1204, 1058, 1038, 902, 825.
产率:75%;
1H NMR (400 MHz, DMSO-d6) δ 7.73 – 7.59 (m, 4H),
5.62 (dd,
J = 11.4, 7.2 Hz, 1H), 3.83 (dd,
J = 17.0, 7.2 Hz, 1H),
3.73 – 3.43 (m, 9H);
13C NMR (100
MHz, DMSO-d6) δ 166.2, 156.2, 131.9, 128.8, 128.0,
123.8, 77.2, 66.2, 66.1, 45.8, 42.3, 36.6; HRMS (ESI-TOF): Anal. Calcd. For C
14H
15
79BrN
2NaO
3
+:
361.0158, C
14H
15
81BrN
2NaO
3
+:
363.0138, Found: 361.0139, 363.0139; IR (neat, cm
-1): υ 2969, 2930, 2860, 1637, 1422, 1234, 1113, 1024, 891, 826。
Yield: 75%; 1 H NMR (400 MHz, DMSO-d6) δ 7.73 - 7.59 (m, 4H), 5.62 (dd, J = 11.4, 7.2 Hz, 1H), 3.83 (dd, J = 17.0, 7.2 Hz, 1H), 3.73 – 3.43 (m, 9H); 13 C NMR (100 MHz, DMSO-d6) δ 166.2, 156.2, 131.9, 128.8, 128.0, 123.8, 77.2, 66.2, 66.1, 45.8, 42.3, 36.6; HRMS (ESI-TOF): Anal. Calcd. For C 14 H 15 79 BrN 2 NaO 3 + : 361.0158, C 14 H 15 81 BrN 2 NaO 3 + : 363.0138, Found: 361.0139, 363.0139; IR (neat, cm - 1 ): υ 2969, 2930, 2860, 1637, 1422, 1234, 1113, 1024, 891, 826.
产率:53%;
1H NMR (400 MHz, DMSO-d6) δ 7.71 – 7.58 (s, 5H),
7.44 (s, 1H), 5.07 (dd,
J = 11.6, 7.0 Hz, 1H), 3.66 (dd,
J =
17.3, 11.7 Hz, 1H), 3.53 (dd,
J = 17.3, 7.0 Hz, 1H);
13C NMR
(100 MHz, DMSO-d6) δ 171.9, 155.8,
131.9, 128.8, 128.0, 123.8, 79.3, 38.3; HRMS (ESI-TOF): Anal. Calcd. For C
10H
9
79BrN
2NaO
2
+:
290.9740, C
10H
9
81BrN
2NaO
2
+:
292.9719, Found: 290.9724, 292.9711; IR (neat, cm
-1): υ 3410, 3185, 2969, 2928, 1650, 1591, 1401, 1010, 896, 820。
Yield: 53%; 1 H NMR (400 MHz, DMSO-d6) δ 7.71 – 7.58 (s, 5H), 7.44 (s, 1H), 5.07 (dd, J = 11.6, 7.0 Hz, 1H), 3.66 ( dd, J = 17.3, 11.7 Hz, 1H), 3.53 (dd, J = 17.3, 7.0 Hz, 1H); 13 C NMR (100 MHz, DMSO-d6) δ 171.9, 155.8, 131.9, 128.8, 128.0, 123.8, 79.3, 38.3; HRMS (ESI-TOF): Anal. Calcd. For C 10 H 9 79 BrN 2 NaO 2 + : 290.9740, C 10 H 9 81 BrN 2 NaO 2 + : 292.9719, Found: 290.9724, 292.9711; IR ( neat, cm -1 ): υ 3410, 3185, 2969, 2928, 1650, 1591, 1401, 1010, 896, 820.
产率:56%;
1H NMR (400 MHz, CDCl
3) δ 7.58 – 7.51 (m, 4H),
7.41 – 7.30 (m, 5H), 5.75 (dd,
J =
11.0, 8.3 Hz, 1H), 3.75 (dd,
J = 16.6, 11.0 Hz, 1H), 3.31 (dd,
J
= 16.6, 8.3 Hz, 1H);
13C NMR (100 MHz, CDCl
3) δ 155.3, 140.6, 131.9, 128.8, 128.4, 128.3, 128.1, 125.8,
124.4, 82.8, 42.9; HRMS (ESI-TOF): Anal. Calcd. For C
15H
12
79BrNNaO
+:
323.9994, C
15H
12
81BrNNaO
+:
325.9974, Found: 323.9984, 325.9967; IR (neat, cm
-1): υ 3068, 3041, 2968, 2921, 2851, 1587, 1335, 1159, 1007,
901, 830, 757, 697, 671。
Yield: 56%; 1 H NMR (400 MHz, CDCl 3 ) δ 7.58 - 7.51 (m, 4H), 7.41 - 7.30 (m, 5H), 5.75 (dd, J = 11.0, 8.3 Hz, 1H), 3.75 (dd, J = 16.6, 11.0 Hz, 1H), 3.31 (dd, J = 16.6, 8.3 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 155.3, 140.6, 131.9, 128.8, 128.4, 128.3, 128.1 , 125.8 , 124.4 , 82.8 , 42.9 ; HRMS ( ESI - TOF): Anal. Calcd. neat, cm -1 ): υ 3068, 3041, 2968, 2921, 2851, 1587, 1335, 1159, 1007, 901, 830, 757, 697, 671.
产率:52%;
1H NMR (400 MHz, CDCl
3) δ 7.55 (s, 4H), 7.40 – 7.32
(m, 2H), 7.10 – 7.02 (m, 2H), 5.73 (dd,
J =
11.0, 8.3 Hz, 1H), 3.74 (dd,
J = 16.6, 11.0 Hz, 1H), 3.27 (dd,
J
= 16.6, 8.3 Hz, 1H);
13C NMR (100 MHz, CDCl
3) δ 162.6 (d,
J = 247.0 Hz), 155.3, 136.4 (d,
J
= 3.2 Hz), 132.0, 128.3, 128.1, 127.7 (d,
J = 8.2 Hz), 124.5, 115.7 (d,
J
= 21.6 Hz), 82.2, 42.9;
19F NMR (376 MHz, CDCl
3) δ -113.6; HRMS (ESI-TOF): Anal. Calcd. For C
15H
11
79BrFNNaO
+:
341.9900, C
15H
11
81BrFNNaO
+:
343.9880, Found: 341.9896, 343.9894; IR (neat, cm
-1): υ 2975, 2927, 1591, 1347, 1193, 1161, 1009, 889, 820。
Yield: 52%; 1 H NMR (400 MHz, CDCl 3 ) δ 7.55 (s, 4H), 7.40 – 7.32 (m, 2H), 7.10 – 7.02 (m, 2H), 5.73 (dd, J = 11.0, 8.3 Hz, 1H), 3.74 (dd, J = 16.6, 11.0 Hz, 1H), 3.27 (dd, J = 16.6, 8.3 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 162.6 (d, J = 247.0 Hz), 155.3, 136.4 (d, J = 3.2 Hz), 132.0, 128.3, 128.1, 127.7 (d, J = 8.2 Hz), 124.5, 115.7 (d, J = 21.6 Hz), 82.2, 42.9; 19 F NMR (376 MHz, CDCl 3 ) δ -113.6; HRMS (ESI-TOF): Anal. Calcd. For C 15 H 11 79 BrFNNaO + : 341.9900, C 15 H 11 81 BrFNNaO + : 343.9880, Found: 341.9896, 343.9894 ; IR (neat, cm -1 ): υ 2975, 2927, 1591, 1347, 1193, 1161, 1009, 889, 820.
产率:46%;
1H NMR (400 MHz, CDCl
3) δ 7.53 (s, 4H), 7.37 – 7.28
(m, 4H), 5.71 (dd,
J = 11.0, 8.2 Hz, 1H), 3.74 (dd,
J = 16.6,
11.0 Hz, 1H), 3.25 (dd,
J = 16.6, 8.2 Hz, 1H);
13C NMR (100
MHz, CDCl
3) δ 155.2, 139.1,
134.1, 131.9, 128.9, 128.1, 127.2, 124.5, 82.0, 42.9; HRMS (ESI-TOF): Anal.
Calcd. For C
15H
12
79BrClNO
+:
335.9785, C
15H
12
81BrClNO
+:
337.9765, Found: 335.9819, 337.9777; IR (neat, cm
-1): υ 3068, 2959, 2922, 1589, 1488, 1348, 1093, 1009, 908,
837, 823。
Yield: 46%; 1 H NMR (400 MHz, CDCl 3 ) δ 7.53 (s, 4H), 7.37 - 7.28 (m, 4H), 5.71 (dd, J = 11.0, 8.2 Hz, 1H), 3.74 (dd , J = 16.6, 11.0 Hz, 1H), 3.25 (dd, J = 16.6, 8.2 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 155.2, 139.1, 134.1, 131.9, 128.9, 128.1, 127.2, 124.5, 82.0, 42.9; HRMS (ESI-TOF): Anal. Calcd. For C 15 H 12 79 BrClNO + : 335.9785, C 15 H 12 81 BrClNO + : 337.9765, Found: 335.9819, 337.9777; IR (neat, cm - 1 ): υ 3068, 2959, 2922, 1589, 1488, 1348, 1093, 1009, 908, 837, 823.
产率:50%;
1H NMR (400 MHz, CDCl
3) δ 7.52 (s, 4H), 7.48 (d,
J = 8.4 Hz, 2H), 7.24 (d,
J
= 8.4 Hz, 2H), 5.68 (dd,
J = 11.0, 8.1 Hz, 1H), 3.74 (dd,
J =
16.7, 11.0 Hz, 1H), 3.24 (dd,
J = 16.7, 8.1 Hz, 1H);
13C NMR
(100 MHz, CDCl
3) δ 155.2, 139.6,
131.9, 131.8, 128.09, 128.07, 127.5, 124.5, 122.2, 82.0, 42.8; HRMS (ESI-TOF):
Anal. Calcd. For C
15H
12
79Br
79Br NO
+:
379.9280, C
15H
12
79Br
81Br NO
+:
381.9260, C
15H
12
81Br
81Br NO
+:
383.9239, Found: 379.9261, 381.9252, 383.9222; IR (neat, cm
-1): υ 3062, 2969, 2917, 1589, 1488, 1348, 1071, 1008, 909,
837, 820。
Yield: 50%; 1 H NMR (400 MHz, CDCl 3 ) δ 7.52 (s, 4H), 7.48 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.4 Hz, 2H), 5.68 ( dd, J = 11.0, 8.1 Hz, 1H), 3.74 (dd, J = 16.7, 11.0 Hz, 1H), 3.24 (dd, J = 16.7, 8.1 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 155.2, 139.6, 131.9, 131.8, 128.09, 128.07, 127.5, 124.5, 122.2, 82.0, 42.8; HRMS (ESI-TOF): Anal. Calcd. For C 15 H 12 79 Br 79 Br NO + : 159.928 H 12 79 Br 81 Br NO + : 381.9260, C 15 H 12 81 Br 81 Br NO + : 383.9239, Found: 379.9261, 381.9252, 383.9222; IR (neat, cm -1 ): υ 3062, 2969, 5917, 1488, 1348, 1071, 1008, 909, 837, 820.
产率:55%;
1H NMR (400 MHz, CDCl
3) δ 7.60 – 7.48 (m, 4H),
7.26 (d,
J = 8.0 Hz, 2H), 7.18 (d,
J = 8.0 Hz, 2H), 5.70 (dd,
J
= 11.0, 8.5 Hz, 1H), 3.70 (dd,
J = 16.7, 11.0 Hz, 1H), 3.28 (dd,
J
= 16.7, 8.5 Hz, 1H), 2.34 (s, 3H);
13C NMR (100 MHz, CDCl
3)
δ 155.3, 138.1, 137.5, 131.9, 129.4,
128.5, 128.1, 125.8, 124.3, 82.9, 42.7, 21.1; HRMS (ESI-TOF): Anal. Calcd. For
C
16H
14
79BrNNaO
+: 338.0151, C
16H
14
81BrNNaO
+:
340.0131, Found: 338.0157, 340.0122; IR (neat, cm
-1): υ 2977, 2917, 2860, 1587, 1397, 1344, 1070, 1006, 905,
831, 813。
Yield: 55%; 1 H NMR (400 MHz, CDCl 3 ) δ 7.60 – 7.48 (m, 4H), 7.26 (d, J = 8.0 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 5.70 (dd, J = 11.0, 8.5 Hz, 1H), 3.70 (dd, J = 16.7, 11.0 Hz, 1H), 3.28 (dd, J = 16.7, 8.5 Hz, 1H), 2.34 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 155.3, 138.1, 137.5, 131.9, 129.4, 128.5, 128.1, 125.8, 124.3, 82.9, 42.7, 21.1; HRMS (ESI-TOF): Anal. Calcd. For C 16 H 14 79 BrNNaO + : 338.0151, C 16 H 14 81 BrNNaO + : 340.0131, Found: 338.0157, 340.0122; IR (neat, cm -1 ): υ 2977, 2917, 2860, 1587, 1397, 1344, 9010 831, 813.
产率:57%;
1H NMR (400 MHz, CDCl
3) δ 7.54 (s, 4H), 7.37 – 7.31
(m, 1H), 7.18 – 7.07 (m, 2H), 7.04 – 6.98 (m, 1H), 5.74 (dd,
J = 11.1, 8.0 Hz, 1H),
3.77 (dd,
J = 16.6, 11.1 Hz, 1H), 3.28 (dd,
J = 16.6, 8.0 Hz,
1H);
13C NMR (100 MHz, CDCl
3) δ 163.0 (d,
J = 246.7 Hz), 155.2, 143.3 (d,
J
= 6.9 Hz), 132.0 , 130.4 (d,
J = 8.1 Hz), 128.14 , 128.10 , 124.5, 121.3
(d,
J = 3.0 Hz), 115.2 (d,
J = 21.2 Hz), 112.8 (d,
J =
22.4 Hz), 81.9 (d,
J = 1.8 Hz), 42.9;
19F NMR (376 MHz, CDCl
3)
δ -112.0; HRMS (ESI-TOF): Anal. Calcd.
For C
15H
11
79BrFNNaO
+: 341.9900, C
15H
11
81BrFNNaO
+:
343.9880, Found: 341.9906, 343.9900; IR (neat, cm
-1): υ 2974, 2925, 2891, 1588, 1485, 1454, 1251, 1143, 1071,
1053, 897, 873, 830, 784, 692。
Yield: 57%; 1 H NMR (400 MHz, CDCl 3 ) δ 7.54 (s, 4H), 7.37 – 7.31 (m, 1H), 7.18 – 7.07 (m, 2H), 7.04 – 6.98 (m, 1H) , 5.74 (dd, J = 11.1, 8.0 Hz, 1H), 3.77 (dd, J = 16.6, 11.1 Hz, 1H), 3.28 (dd, J = 16.6, 8.0 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 163.0 (d, J = 246.7 Hz), 155.2, 143.3 (d, J = 6.9 Hz), 132.0 , 130.4 (d, J = 8.1 Hz), 128.14 , 128.10 , 124.5, 121.3 (d, J = 8.1 Hz) 3.0 Hz), 115.2 (d, J = 21.2 Hz), 112.8 (d, J = 22.4 Hz), 81.9 (d, J = 1.8 Hz), 42.9; 19 F NMR (376 MHz, CDCl 3 ) δ -112.0; HRMS (ESI-TOF): Anal. Calcd. For C 15 H 11 79 BrFNNaO + : 341.9900, C 15 H 11 81 BrFNNaO + : 343.9880, Found: 341.9906, 343.9900; IR (neat, cm -1 ): υ 2974, 2925, 2891, 1588, 1485, 1454, 1251, 1143, 1071, 1053, 897, 873, 830, 784, 692.
产率:57%;
1H NMR (400 MHz, CDCl
3) δ 7.53 (s, 5H), 7.46 – 7.42
(m, 1H), 7.32 – 7.28 (m, 1H), 7.26 – 7.21 (m, 1H), 5.70 (dd,
J = 11.1, 8.0 Hz, 1H),
3.75 (dd,
J = 16.7, 11.1 Hz, 1H), 3.27 (dd,
J = 16.7, 8.0 Hz,
1H);
13C NMR (100 MHz, CDCl
3) δ 155.2, 143.0, 131.9, 131.3, 130.3, 128.8, 128.1, 128.0,
124.5, 124.3, 122.8, 81.8, 42.9; HRMS (ESI-TOF): Anal. Calcd. For C
15H
12
79Br
79Br
NO
+: 379.9280, C
15H
12
79Br
81Br
NO
+: 381.9260, C
15H
12
81Br
81Br
NO
+: 383.9239, Found: 379.9266, 381.9236, 383.9210; IR (neat, cm
-1):
υ 3093, 3071, 2974, 2919, 1589, 1569,
1340, 1161, 1072, 894, 881, 830, 818, 785, 691, 661。
Yield: 57%; 1 H NMR (400 MHz, CDCl 3 ) δ 7.53 (s, 5H), 7.46 – 7.42 (m, 1H), 7.32 – 7.28 (m, 1H), 7.26 – 7.21 (m, 1H) , 5.70 (dd, J = 11.1, 8.0 Hz, 1H), 3.75 (dd, J = 16.7, 11.1 Hz, 1H), 3.27 (dd, J = 16.7, 8.0 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 155.2, 143.0, 131.9 , 131.3, 130.3, 128.8, 128.1, 128.0, 124.5, 124.3, 122.8, 81.8, 42.9; HRMS (ESI-TOF): Anal. Calcd. For C 15 HBr 12 79 NO + : 379.9280, C 15 H 12 79 Br 81 Br NO + : 381.9260, C 15 H 12 81 Br 81 Br NO + : 383.9239, Found: 379.9266, 381.9236, 383.9210; IR (neat, cm -1 ): υ30 , 3071, 2974, 2919, 1589, 1569, 1340, 1161, 1072, 894, 881, 830, 818, 785, 691, 661.
产率:56%;
1H NMR (400 MHz, CDCl
3) δ 7.65 (s, 1H), 7.60 – 7.47
(m, 7H), 5.80 (dd,
J = 11.1, 8.1 Hz, 1H), 3.81 (dd,
J = 16.7,
11.1 Hz, 1H), 3.30 (dd,
J = 16.7, 8.1 Hz, 1H);
13C NMR (100
MHz, CDCl
3) δ 155.2, 141.7,
132.0, 131.1 (q,
J = 32.5 Hz), 129.3, 129.1, 128.1, 128.0, 125.1 (q,
J
= 3.7 Hz), 124.6, 122.6 (q,
J = 4.0 Hz), 81.9, 43.0;
19F NMR
(376 MHz, CDCl
3) δ -62.6; HRMS
(ESI-TOF): Anal. Calcd. For C
16H
11
79BrF
3NNaO
+:
391.9868, C
16H
11
81BrF
3NNaO
+:
393.9848, Found: 391.9885, 393.9844; IR (neat, cm
-1): υ 3062, 3006, 2949, 1324, 1171, 1117, 1072, 905, 895, 837,
802, 701, 661。
Yield: 56%; 1 H NMR (400 MHz, CDCl 3 ) δ 7.65 (s, 1H), 7.60 - 7.47 (m, 7H), 5.80 (dd, J = 11.1, 8.1 Hz, 1H), 3.81 (dd , J = 16.7, 11.1 Hz, 1H), 3.30 (dd, J = 16.7, 8.1 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 155.2, 141.7, 132.0, 131.1 (q, J = 32.5 Hz ), 129.3, 129.1, 128.1, 128.0, 125.1 (q, J = 3.7 Hz), 124.6, 122.6 (q, J = 4.0 Hz), 81.9, 43.0; 19 F NMR (376 MHz, CDCl 3 ) δ -62.6; HRMS (ESI-TOF): Anal. Calcd. For C 16 H 11 79 BrF 3 NNaO + : 391.9868, C 16 H 11 81 BrF 3 NNaO + : 393.9848, Found: 391.9885, 393.9844; IR (neat, cm -1 ) : υ 3062, 3006, 2949, 1324, 1171, 1117, 1072, 905, 895, 837, 802, 701, 661.
产率:60%;
1H NMR (400 MHz, CDCl
3) δ 7.55 (s, 4H), 6.03 (dd,
J = 12.0, 8.5 Hz, 1H),
3.78 (dd,
J = 16.8, 12.0 Hz, 1H), 3.50 (dd,
J = 16.8, 8.5 Hz,
1H);
13C NMR (100 MHz, CDCl
3) δ 154.9, 132.0, 128.2, 127.6, 124.8, 72.4, 40.6;
19F
NMR (376 MHz, CDCl
3) δ
-141.35 – -142.79 (m, 2F), -152.46 – -152.70 (m, 1F), -160.98 – -161.22
(m, 2F); HRMS (ESI-TOF): Anal. Calcd. For C
15H
7
79BrF
5NNaO
+:
413.9523, C
15H
7
81BrF
5NNaO
+:
415.9503, Found: 413.9508, 415.9506; IR (neat, cm
-1): υ 3061, 2977, 2930, 1523, 1503, 1130, 1012, 964, 894, 840,
824。
Yield: 60%; 1 H NMR (400 MHz, CDCl 3 ) δ 7.55 (s, 4H), 6.03 (dd, J = 12.0, 8.5 Hz, 1H), 3.78 (dd, J = 16.8, 12.0 Hz, 1H) ), 3.50 (dd, J = 16.8, 8.5 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 154.9, 132.0, 128.2, 127.6, 124.8, 72.4, 40.6; 19 F NMR (376 MHz, CDCl 3 ) ) δ -141.35 – -142.79 (m, 2F), -152.46 – -152.70 (m, 1F), -160.98 – -161.22 (m, 2F); HRMS (ESI-TOF): Anal. Calcd. For C 15 H 7 79 BrF 5 NNaO + : 413.9523, C 15 H 7 81 BrF 5 NNaO + : 415.9503, Found: 413.9508, 415.9506; IR (neat, cm -1 ): υ 3061, 2977, 2930, 1523, 10503, 1 , 964, 894, 840, 824.
实施例六:在实施例四的基础上,更换化合物1与化合物2,其余不变,得到如下产物。Embodiment 6: On the basis of Embodiment 4, compound 1 and compound 2 are replaced, and the rest remain unchanged to obtain the following product.
产率:60%;
1H NMR (400 MHz, DMSO-d6) δ 8.32 (d,
J = 7.6 Hz, 1H), 8.16 – 7.95 (m, 3H), 7.60 (d,
J = 8.8 Hz, 2H), 7.00 (d,
J
= 8.8 Hz, 2H), 5.10 – 5.01 (m, 1H),
3.97 (dd,
J = 15.1, 7.4 Hz, 1H), 3.89 – 3.76
(m, 4H), 3.56 (dd,
J = 17.1, 10.5 Hz, 1H), 3.37 – 3.29 (m, 1H);
13C NMR (100 MHz, DMSO-d6) δ 160.8, 159.0, 156.2, 136.8, 136.0, 135.4, 128.3, 126.3,
125.3, 121.7, 121.6, 114.3, 77.1, 55.4, 41.7, 38.3; HRMS (ESI-TOF): Anal.
Calcd. For C
18H
17N
2O
5S
+:
373.0853, Found: 373.0859; IR (neat, cm
-1): υ 3069, 2963, 2920, 2848, 1739, 1321, 1300, 1248, 1178,
1162, 1018, 839, 747, 671.
4bz
产率:36%;
1H
NMR (400 MHz, CDCl
3) δ 7.57
– 7.45 (m, 1H), 7.34 – 7.28 (m, 1H), 7.21 – 7.13
(m, 1H), 6.14 (s, 1H), 4.91 – 4.83 (m, 1H),
3.63 – 3.46 (m, 2H), 3.34 (dd,
J = 16.9,
10.7 Hz, 1H), 3.07 (dd,
J = 16.9, 7.5 Hz, 1H), 1.97 (s, 3H);
13C
NMR (100 MHz, CDCl
3) δ
170.8, 155.4, 151.5 (dd,
J = 253.5, 12.6 Hz), 150.3 (dd,
J =
249.8, 13.2 Hz), 126.2 (dd,
J = 6.3, 4.0 Hz), 123.2 (dd,
J = 6.7,
3.7 Hz), 117.7 (d,
J = 17.9 Hz), 115.6 (d,
J = 18.8 Hz), 80.3,
42.2, 37.3, 23.1;
19F NMR (376 MHz, CDCl
3) δ -134.0 (d,
J = 22.0 Hz, 1F), -136.2 (d,
J
= 22.0 Hz, 1F); HRMS (ESI-TOF): Anal. Calcd. For C
12H
12F
2N
2NaO
2
+:
277.0759, Found: 277.0756; IR (neat, cm
-1): υ 3294, 2988, 2942, 2926, 1738, 1651, 1225, 1192, 1026,
1009, 822。
Yield: 60%; 1 H NMR (400 MHz, DMSO-d6) δ 8.32 (d, J = 7.6 Hz, 1H), 8.16 - 7.95 (m, 3H), 7.60 (d, J = 8.8 Hz, 2H) , 7.00 (d, J = 8.8 Hz, 2H), 5.10 – 5.01 (m, 1H), 3.97 (dd, J = 15.1, 7.4 Hz, 1H), 3.89 – 3.76 (m, 4H), 3.56 (dd, J = 17.1, 10.5 Hz, 1H), 3.37 – 3.29 (m, 1H); 13 C NMR (100 MHz, DMSO-d6) δ 160.8, 159.0, 156.2, 136.8, 136.0, 135.4, 128.3, 126.3, 125.3, 121.7, 121.6, 114.3, 77.1, 55.4, 41.7, 38.3; HRMS (ESI-TOF): Anal. Calcd. For C 18 H 17 N 2 O 5 S + : 373.0853, Found: 373.0859; IR (neat, cm -1 ): υ 3069, 2963, 2920, 2848, 1739, 1321, 1300, 1248, 1178, 1162, 1018, 839, 747, 671. 4bz yield: 36%; 1 H NMR (400 MHz, CDCl 3 ) δ 7.57 – 7.45 (m, 1H), 7.34 – 7.28 (m, 1H), 7.21 – 7.13 (m, 1H), 6.14 (s, 1H), 4.91 – 4.83 (m, 1H), 3.63 – 3.46 (m, 2H), 3.34 (dd, J = 16.9, 10.7 Hz, 1H), 3.07 (dd, J = 16.9, 7.5 Hz, 1H), 1.97 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 170.8, 155.4, 151.5 (dd, J = 253.5, 12.6 Hz), 150.3 (dd, J = 249.8, 13.2 Hz), 126.2 (dd, J = 6.3, 4.0 Hz), 123.2 (dd, J = 6.7, 3.7 Hz), 11 7.7 (d, J = 17.9 Hz), 115.6 (d, J = 18.8 Hz), 80.3, 42.2, 37.3, 23.1; 19 F NMR (376 MHz, CDCl 3 ) δ -134.0 (d, J = 22.0 Hz, 1F ), -136.2 (d, J = 22.0 Hz, 1F); HRMS (ESI-TOF): Anal. Calcd. For C 12 H 12 F 2 N 2 NaO 2 + : 277.0759, Found: 277.0756; IR (neat, cm -1 ): υ 3294, 2988, 2942, 2926, 1738, 1651, 1225, 1192, 1026, 1009, 822.
Claims (10)
- 一种异噁唑啉的简单制备方法,其特征在于:以醛、对甲苯磺酰肼、烯烃和亚硝酸酯为反应底物,在碱与铜催化剂存在下,在有机溶剂中反应得到异噁唑啉;A simple preparation method of isoxazoline is characterized in that: taking aldehyde, p-toluenesulfonyl hydrazide, alkene and nitrite as reaction substrates, in the presence of alkali and copper catalyst, reacting in an organic solvent to obtain isoxazoline oxazoline;其中,所述醛的化学结构通式为: ;式中,R 1选自芳基、取代芳基、杂芳香基、萘基或者烯基; Wherein, the general chemical structure of the aldehyde is: ; In the formula, R 1 is selected from aryl, substituted aryl, heteroaryl, naphthyl or alkenyl;所述烯烃的化学结构通式为: ;式中R 4、R 5独立的选自氢、烷基、芳基、酯基、醚、酰胺基、羰基、硅基、羟基、缩醛、氰基、卤素、炔基、羧基或者磷酸酯基; The general chemical structure of the alkene is: In the formula, R 4 and R 5 are independently selected from hydrogen, alkyl, aryl, ester, ether, amide, carbonyl, silicon, hydroxyl, acetal, cyano, halogen, alkynyl, carboxyl or phosphate base;所述亚硝酸酯的化学结构通式为: ;式中R 6选自叔丁基、正丁基、异丁基或者异丙基; The general formula of the chemical structure of the nitrite is: ; R in the formula is selected from tert-butyl, n-butyl, isobutyl or isopropyl;
- 根据权利要求1所述异噁唑啉的简单制备方法,其特征在于:所述反应的反应温度为25~80℃,时间为12~48小时。The simple preparation method of isoxazoline according to claim 1 is characterized in that: the reaction temperature of the reaction is 25-80 DEG C, and the time is 12-48 hours.
- 根据权利要求1所述异噁唑啉的简单制备方法,其特征在于:碱的用量为烯烃摩尔量的1~1.8倍;所述铜催化剂用量为烯烃摩尔量的5~20%。The simple preparation method of isoxazoline according to claim 1 is characterized in that: the consumption of alkali is 1-1.8 times of the mole of olefin; the consumption of the copper catalyst is 5-20% of the mole of olefin.
- 根据权利要求1所述异噁唑啉的简单制备方法,其特征在于:所述有机溶剂为乙酸乙酯、四氢呋喃、乙腈、丙酮、氯仿或者 N, N-二甲基甲酰胺;所述铜催化剂为氯化铜、氯化亚铜、溴化亚铜或者碘化亚铜。 The simple preparation method of isoxazoline according to claim 1, characterized in that: the organic solvent is ethyl acetate, tetrahydrofuran, acetonitrile, acetone, chloroform or N , N -dimethylformamide; the copper catalyst It is cupric chloride, cuprous chloride, cuprous bromide or cuprous iodide.
- 根据权利要求1所述异噁唑啉的简单制备方法,其特征在于:所述醛化合物用量为烯烃摩尔量的1~1.5倍;对甲苯磺酰肼用量为烯烃摩尔量的1~1.5倍,亚硝酸酯用量为烯烃摩尔量的3~5倍。The simple preparation method of isoxazoline according to claim 1 is characterized in that: the amount of the aldehyde compound is 1-1.5 times the molar amount of the olefin; the amount of p-toluenesulfonyl hydrazide is 1-1.5 times the molar amount of the olefin, The amount of nitrite is 3 to 5 times the molar amount of olefin.
- 根据权利要求5所述异噁唑啉的简单制备方法,其特征在于:所述醛化合物用量为烯烃摩尔量的1.3倍;对甲苯磺酰肼用量为烯烃摩尔量的1.4倍,亚硝酸酯用量为烯烃摩尔量的4倍。The simple preparation method of isoxazoline according to claim 5 is characterized in that: the amount of the aldehyde compound is 1.3 times the molar amount of olefin; the amount of p-toluenesulfonyl hydrazide is 1.4 times the molar amount of olefin, and the amount of nitrite is It is 4 times the molar amount of olefin.
- 根据权利要求1所述异噁唑啉的简单制备方法,其特征在于:芳基或者取代芳基的化学结构通式为: ,其中,R 2、R 3独立的选自氢、烷基、氟、氯、溴、羧酸、酰胺、硫醚、氨基、烷氧基、三氟甲基、硝基、氰基、酯基、羟基或者砜基。 The simple preparation method of isoxazoline according to claim 1, is characterized in that: the general formula of chemical structure of aryl or substituted aryl is: , wherein R 2 and R 3 are independently selected from hydrogen, alkyl, fluorine, chlorine, bromine, carboxylic acid, amide, thioether, amino, alkoxy, trifluoromethyl, nitro, cyano, ester , hydroxyl or sulfone group.
- 一种无金属催化剂制备异噁唑啉的方法,其特征在于:将苯甲醛化合物、对甲苯磺酰肼在甲醇溶剂中混合后,再加入烯烃、亚硝酸酯、有机溶剂、碱,反应得到异噁唑啉;A method for preparing isoxazoline without metal catalyst, which is characterized in that: after mixing benzaldehyde compound and p-toluenesulfonyl hydrazide in methanol solvent, then adding olefin, nitrite, organic solvent and alkali, and reacting to obtain isoxazoline oxazoline;其中,所述苯甲醛化合物的化学结构通式如下:Wherein, the general formula of the chemical structure of the benzaldehyde compound is as follows:所述烯烃的化学结构通式为R 2-CH 2CH 2; The general chemical structure of the alkene is R 2 -CH 2 CH 2 ;所述亚硝酸酯的化学结构通式为O=N-OR 6; The general chemical structure of the nitrite is O=N-OR 6 ;所述异噁唑啉的化学结构通式如下:The general formula of the chemical structure of the isoxazoline is as follows:式中,R 1选自氢、烷基、氟、氯、溴、羧酸、酰胺、硫醚、氨基、烷氧基、三氟甲基、硝基、氰基、酯基、羟基或者砜基;R 2选自烷基、芳基、酯基、羰基、醚、酰胺基、硅基、羟基、缩苯甲醛化合物、氰基、卤素、炔基、羧基或者磷酸酯基;R 6选自叔丁基、正丁基、异丁基或者异丙基。 In the formula, R 1 is selected from hydrogen, alkyl, fluorine, chlorine, bromine, carboxylic acid, amide, thioether, amino, alkoxy, trifluoromethyl, nitro, cyano, ester, hydroxyl or sulfone ; R 2 is selected from alkyl, aryl, ester, carbonyl, ether, amide, silicon, hydroxyl, benzal compound, cyano, halogen, alkynyl, carboxyl or phosphate group; R 6 is selected from tertiary Butyl, n-butyl, isobutyl or isopropyl.
- 铜催化剂在催化醛、对甲苯磺酰肼、烯烃和亚硝酸酯为反应底物制备异噁唑啉中的应用。Application of copper catalyst in catalyzing aldehyde, p-toluenesulfonyl hydrazide, alkene and nitrite as reaction substrates to prepare isoxazoline.
- 根据权利要求1所述异噁唑啉的简单制备方法制备的异噁唑啉。The isoxazoline prepared by the simple preparation method of isoxazoline according to claim 1.
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Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2008239611A (en) * | 2007-02-27 | 2008-10-09 | Nissan Chem Ind Ltd | Isoxazoline-substituted benzamide compound and pesticide |
US20110144334A1 (en) * | 2005-09-02 | 2011-06-16 | Nissan Chemical Industries, Ltd. | Isoxazoline-substituted benzamide compound and pesticide |
CN103588720A (en) * | 2013-11-20 | 2014-02-19 | 河北科技大学 | Synthesis method of benzo [c] isoxazole-3(1H)-ketone |
CN104039149A (en) * | 2011-11-21 | 2014-09-10 | 安纳考尔医药公司 | Boron-containing small molecules |
CN105198824A (en) * | 2015-10-09 | 2015-12-30 | 苏州大学 | Dihydroisooxazoline compounds, and preparation method and application thereof |
CN107118171A (en) * | 2017-04-01 | 2017-09-01 | 苏州大学 | A kind of preparation method of isoxazoline derivative |
CN107721941A (en) * | 2017-10-10 | 2018-02-23 | 浦拉司科技(上海)有限责任公司 | A kind of preparation method of the methyl-isoxazole of 3 amino 5 |
CN113149924A (en) * | 2021-03-29 | 2021-07-23 | 苏州大学 | Simple preparation method of isoxazoline |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003022824A1 (en) * | 2001-09-11 | 2003-03-20 | Astrazeneca Ab | Oxazolidinone and/or isoxazoline as antibacterial agents |
EP1567532A1 (en) * | 2002-11-28 | 2005-08-31 | Astrazeneca AB | Oxazolidinone and / or isoxazoline derivatives as antibacterial agents |
CN112028848B (en) * | 2020-09-09 | 2022-12-16 | 苏州大学 | Method for preparing isoxazoline |
-
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- 2021-12-07 WO PCT/CN2021/136208 patent/WO2022206010A1/en active Application Filing
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20110144334A1 (en) * | 2005-09-02 | 2011-06-16 | Nissan Chemical Industries, Ltd. | Isoxazoline-substituted benzamide compound and pesticide |
JP2008239611A (en) * | 2007-02-27 | 2008-10-09 | Nissan Chem Ind Ltd | Isoxazoline-substituted benzamide compound and pesticide |
CN104039149A (en) * | 2011-11-21 | 2014-09-10 | 安纳考尔医药公司 | Boron-containing small molecules |
CN103588720A (en) * | 2013-11-20 | 2014-02-19 | 河北科技大学 | Synthesis method of benzo [c] isoxazole-3(1H)-ketone |
CN105198824A (en) * | 2015-10-09 | 2015-12-30 | 苏州大学 | Dihydroisooxazoline compounds, and preparation method and application thereof |
CN107118171A (en) * | 2017-04-01 | 2017-09-01 | 苏州大学 | A kind of preparation method of isoxazoline derivative |
CN107721941A (en) * | 2017-10-10 | 2018-02-23 | 浦拉司科技(上海)有限责任公司 | A kind of preparation method of the methyl-isoxazole of 3 amino 5 |
CN113149924A (en) * | 2021-03-29 | 2021-07-23 | 苏州大学 | Simple preparation method of isoxazoline |
Non-Patent Citations (3)
Title |
---|
DATABASE REGISTRY 16 November 1984 (1984-11-16), ANONYMOUS : "-Isoxazole, 3-(4-bromophenyl)-4,5-dihydro-5-phenyl- (CA INDEX NAME) ", XP055972135, retrieved from STN Database accession no. 20822-01-9 * |
MA LIANG, JIN FENG, CHENG XIONGLVE, TAO SUYAN, JIANG GANGZHONG, LI XINGXING, YANG JINWEI, BAO XIAOGUANG, WAN XIAOBING: "[2 + 2 + 1] Cycloaddition of N -tosylhydrazones, tert -butyl nitrite and alkenes: a general and practical access to isoxazolines", CHEMICAL SCIENCE, ROYAL SOCIETY OF CHEMISTRY, UNITED KINGDOM, vol. 12, no. 28, 21 July 2021 (2021-07-21), United Kingdom , pages 9823 - 9830, XP055972131, ISSN: 2041-6520, DOI: 10.1039/D1SC02352G * |
WANG DANJUN, BEI-YI CHEN,YI-QI WANG,XIAO-WEI ZHANG: "Ruthenium-Catalyzed Direct Transformation of Alkenyl Oximes to 5-Cyanated Isoxazolines: A Cascade Approach Based on Non-Stabilized Radical Intermediate", EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, vol. 2018, no. 11, 31 January 2018 (2018-01-31), pages 1342 - 1346, XP055972134, ISSN: 1099-0690, DOI: 10.1002/ejoc.201701651 * |
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