CN113149924B - 一种异噁唑啉的简单制备方法 - Google Patents
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- WEQPBCSPRXFQQS-UHFFFAOYSA-N 4,5-dihydro-1,2-oxazole Chemical compound C1CC=NO1 WEQPBCSPRXFQQS-UHFFFAOYSA-N 0.000 title claims abstract description 31
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 150000001336 alkenes Chemical class 0.000 claims abstract description 33
- 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 32
- 238000000034 method Methods 0.000 claims abstract description 22
- 239000003054 catalyst Substances 0.000 claims abstract description 19
- ICGLPKIVTVWCFT-UHFFFAOYSA-N 4-methylbenzenesulfonohydrazide Chemical compound CC1=CC=C(S(=O)(=O)NN)C=C1 ICGLPKIVTVWCFT-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000003513 alkali Substances 0.000 claims abstract description 14
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 claims abstract description 10
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims abstract description 7
- 239000000758 substrate Substances 0.000 claims abstract description 6
- IOGXOCVLYRDXLW-UHFFFAOYSA-N tert-butyl nitrite Chemical compound CC(C)(C)ON=O IOGXOCVLYRDXLW-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000012414 tert-butyl nitrite Substances 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 36
- 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 26
- -1 nitrous acid ester Chemical class 0.000 claims description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 15
- 239000000126 substance Substances 0.000 claims description 13
- 239000010949 copper Substances 0.000 claims description 12
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 11
- 229910052802 copper Inorganic materials 0.000 claims description 11
- 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
- 239000003960 organic solvent Substances 0.000 claims description 9
- 150000001299 aldehydes Chemical class 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 150000001408 amides Chemical class 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 150000002148 esters Chemical class 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 claims description 5
- 150000002431 hydrogen Chemical class 0.000 claims description 5
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 claims description 5
- ZRYZBQLXDKPBDU-UHFFFAOYSA-N 4-bromobenzaldehyde Chemical compound BrC1=CC=C(C=O)C=C1 ZRYZBQLXDKPBDU-UHFFFAOYSA-N 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- 125000003107 substituted aryl group Chemical group 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 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
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 claims description 3
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 125000000304 alkynyl group Chemical group 0.000 claims description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 3
- 229960003280 cupric chloride Drugs 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 229910052710 silicon Inorganic materials 0.000 claims description 3
- 239000010703 silicon Substances 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 150000003568 thioethers Chemical class 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 125000003342 alkenyl group Chemical group 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
- 125000001072 heteroaryl group Chemical group 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 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
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical class [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 150000003457 sulfones Chemical class 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 8
- 239000003814 drug Substances 0.000 abstract description 5
- 150000002547 isoxazolines Chemical class 0.000 abstract description 5
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 230000009286 beneficial effect Effects 0.000 abstract description 2
- 238000007306 functionalization reaction Methods 0.000 abstract description 2
- 238000005580 one pot reaction Methods 0.000 abstract description 2
- 125000002485 formyl group Chemical class [H]C(*)=O 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 36
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzenecarboxaldehyde Natural products O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 7
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 6
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 6
- 238000007789 sealing Methods 0.000 description 6
- 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
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 5
- 239000003208 petroleum Substances 0.000 description 5
- 238000010791 quenching Methods 0.000 description 5
- 230000000171 quenching effect Effects 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 229910052723 transition metal Inorganic materials 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000000975 bioactive effect Effects 0.000 description 3
- 229940125904 compound 1 Drugs 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003365 glass fiber Substances 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
- 229940125782 compound 2 Drugs 0.000 description 2
- 239000012973 diazabicyclooctane Substances 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
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 125000001174 sulfone group Chemical group 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
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 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
- 239000002585 base Substances 0.000 description 1
- 150000001875 compounds Chemical class 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
- 230000002939 deleterious effect Effects 0.000 description 1
- 150000008049 diazo compounds Chemical class 0.000 description 1
- 150000001989 diazonium salts Chemical class 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
- 230000002349 favourable effect Effects 0.000 description 1
- 238000010952 in-situ formation 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
- 239000008204 material by function Substances 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
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- SMQUZDBALVYZAC-UHFFFAOYSA-N salicylaldehyde Chemical compound OC1=CC=CC=C1C=O SMQUZDBALVYZAC-UHFFFAOYSA-N 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Classifications
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- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明公开了一种异噁唑啉的简单制备方法：以醛、对甲苯磺酰肼、烯烃、亚硝酸叔丁酯为底物，氯化铜为催化剂，四甲基乙二胺（TMEDA）为碱，一锅两步法高效地合成了一系列异恶唑啉化合物。具有如下优点：催化剂廉价、反应经济、底物普适性更广、原料易得、后期官能团化更便利，反应条件温和，克级规模反应良好，尤其是，本发明可在无催化剂存在下，中等收率获得产物，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，符合当代绿色化学和药物化学的要求和方向。
Description
技术领域
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。
背景技术
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。
发明内容
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。
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。
本发明得到的产物为异噁唑啉，其化学结构式为：
。
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：/>。
上述结构式中，R1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：，R2、R3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；R4、R5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；R6选自叔丁基、正丁基、异丁基、异丙基。
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。
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。
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%。
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：
所述烯烃的化学结构通式为R2-CH2CH2；
所述亚硝酸酯的化学结构通式为O=N-OR6；
所述异噁唑啉的化学结构通式如下：
式中，R1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；R2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；R6选自叔丁基、正丁基、异丁基或者异丙基。优选的，R1选自氢、烷基、氟、氯、溴；R2选自芳基、酯基，比如苯基、-COOEt、取代苯基。
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。
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。
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。
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。
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。
本发明的制备方法示意如下：
本发明还公开了根据上述方法制备得到的异噁唑啉。
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CuCl2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。
具体实施方式
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。
实施例一
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（2.0mmol）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 (400MHz, CDCl3) δ 7.51 (s, 4H), 5.15 (dd, J = 10.5, 7.9 Hz, 1H), 4.24 (q, J = 7.1Hz, 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, CDCl3) 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 C12H12 79BrNNaO3 +: 319.9893, C12H12 81BrNNaO3 +: 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%。
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%。
将第二次加入的THF（2.0 mL）更换为乙腈（2.0 mL），产率：54%。
将亚硝酸叔丁酯TBN更换为亚硝酸异丙酯（2.0 mmol），产率：79%。
将亚硝酸叔丁酯TBN更换为亚硝酸正丁酯（2.0 mmol），产率：68%。
将CuCl 2（0.05 mmol）更换为CuCl（0.05 mmol），产率：77%。
将CuCl 2（0.05 mmol）更换为CuBr（0.05 mmol），产率：83%。
将CuCl 2（0.05 mmol）更换为CuI（0.05 mmol），产率：56%。
将CuCl 2（0.05 mmol）更换为Cu(OAc)2（0.05 mmol），产率：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%。
将四甲基乙二胺TMEDA 更换为碳酸钠（0.75 mmol），产率：16%。
将四甲基乙二胺TMEDA 更换为碳酸钾（0.75 mmol），产率<1%。
将四甲基乙二胺TMEDA 更换为氢氧化钠（0.75 mmol），产率<1%。
省略TMEDA，产率<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%。
实施例四
以化合物1为苯甲醛为例，即R1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（0.5mmol），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, CDCl3) 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,CDCl3) δ 170.0, 155.9, 130.3, 128.6, 128.4, 126.8, 78.0, 61.8, 38.7, 14.0;Anal. Calcd. For C12H13NNaO3 +: 242.0788, Found: 242.0778; IR (neat, cm-1): υ2976, 2936, 2906, 1750, 1209, 1182, 1035, 901, 762, 695。上述产物化合物4的结构式如下：
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：
产率：87% yield; 1H NMR (400 MHz, CDCl3) 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 = 7.1Hz, 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, CDCl3) 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 C13H15NNaO3 +: 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, CDCl3) 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, CDCl3) 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 C16H21NNaO3 +: 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, CDCl3) 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, CDCl3) 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. ForC13H15NNaO4 +: 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, CDCl3) 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); 13CNMR (100 MHz, CDCl3) 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 C13H15NNaO3S+: 288.0665,Found: 288.0675; IR (neat, cm-1): υ 2989, 2921, 1748, 1199, 1032, 1022, 894,817.
产率：87%; mp: 45-47 oC; 1H NMR (400 MHz, CDCl3) δ 7.72 – 7.60 (m, 2H),7.12 – 7.03 (m, 2H), 5.14 (dd, J = 10.4, 8.0 Hz, 1H), 4.24 (q, J = 7.1 Hz,2H), 3.69 – 3.47 (m, 2H), 1.30 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ170.0, 163.8 (d, J = 251.3 Hz), 154.9, 128.8 (d, J = 8.6 Hz), 124.8 (d, J =3.4 Hz), 115.8 (d, J = 22.0 Hz), 78.1, 61.9, 38.7, 14.0; 19F NMR (376 MHz,CDCl3) δ -109.3; HRMS (ESI-TOF): Anal. Calcd. For C12H12FNNaO3 +: 260.0693,Found: 260.0683; IR (neat, cm-1): υ 2983, 2938, 1735, 1603, 1513, 1203, 1158,894, 836.
产率：84%; mp: 57-58 oC; 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 8.6 Hz,2H), 7.35 (d, J = 8.6 Hz, 2H), 5.15 (dd, J = 10.5, 7.9 Hz, 1H), 4.24 (q, J =7.1 Hz, 2H), 3.60 (d, J = 7.9 Hz, 1H), 3.59 (d, J = 10.5 Hz, 1H), 1.30 (t, J= 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 169.9, 155.0, 136.3, 128.9, 128.0,127.0, 78.2, 62.0, 38.5, 14.0; HRMS (ESI-TOF): Anal. Calcd. For C12H12 35ClNNaO3 +: 276.0398, Found: 276.0393; IR (neat, cm-1): υ 2987, 2963, 2906, 1749, 1340,1215, 1203, 1032, 908, 839, 827.
产率：60%; 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.2 Hz, 2H), 7.66 (d,J = 8.2 Hz, 2H), 5.21 (dd, J = 11.0, 7.5 Hz, 1H), 4.27 (q, J = 7.2 Hz, 2H),3.65 (d, J = 7.5 Hz, 1H), 3.64 (d, J = 11.0 Hz, 1H), 1.32 (t, J = 7.2 Hz,3H); 13C NMR (100 MHz, CDCl3) δ 169.8, 155.0, 132.1 (q, J = 32.7 Hz), 132.0,127.1, 125.7 (q, J = 3.7 Hz), 123.7 (q, J = 272.2 Hz), 78.5, 62.1, 38.4,14.0; 19F NMR (376 MHz, CDCl3) δ -63.0; HRMS (ESI-TOF): Anal. Calcd. ForC13H12F3NNaO3 +: 310.0661, Found: 310.0674; IR (neat, cm-1): υ 2977, 2939, 1739,1321, 1161, 1120, 1066, 886, 840.
产率：85%; 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 8.7 Hz, 2H), 7.31 –7.23 (m, 4H), 7.15 – 6.99 (m, 8H), 5.12 (dd, J = 10.5, 7.5 Hz, 1H), 4.26 (q,J = 7.1 Hz, 2H), 3.59 (d, J = 7.5 Hz, 1H), 3.58 (d, J = 10.5 Hz, 1H), 1.32(t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 170.3, 155.5, 149.8, 146.9,129.4, 127.9, 125.2, 123.9, 121.7, 121.3, 77.8, 61.8, 39.0, 14.1; HRMS (ESI-TOF): Anal. Calcd. For C24H23N2O3 +: 387.1703, Found: 387.1706; IR (neat, cm-1):υ 2952, 2939, 1736, 1589, 1487, 1272, 1028, 754, 696.
产率：60%; 1H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 8.5 Hz, 2H), 7.81 (d,J = 8.5 Hz, 2H), 5.19 (t, J = 9.3 Hz, 1H), 4.23 (q, J = 7.1 Hz, 2H), 3.63 (d,J = 9.3 Hz, 2H), 3.03 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz,CDCl3) δ 169.5, 154.7, 141.6, 133.6, 127.7, 127.5, 78.6, 62.0, 44.2, 38.1,13.9; HRMS (ESI-TOF): Anal. Calcd. For C13H15NNaO5S+: 320.0563, Found:320.0565; IR (neat, cm-1): υ 3026, 3007, 2927, 1731, 1308, 1225, 1150, 892,846, 777.
产率：54%; 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.1 Hz, 2H), 7.69 (d,J = 8.1 Hz, 2H), 5.21 (dd, J = 11.0, 7.6 Hz, 1H), 4.26 (q, J = 7.2 Hz, 2H),3.71 – 3.57 (m, 2H), 1.31 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ169.5, 154.7, 132.8, 132.5, 127.3, 118.1, 113.7, 78.7, 62.2, 38.0, 14.0; HRMS(ESI-TOF): Anal. Calcd. For C13H12N2NaO3 +: 267.0740, Found: 267.0751; IR (neat,cm-1): υ 2985, 2936, 2226, 1721, 1284, 1018, 889, 868, 849, 832.
产率：41%; 1H NMR (400 MHz, CDCl3) δ 8.25 (d, J = 8.8 Hz, 2H), 7.84 (d,J = 8.8 Hz, 2H), 5.24 (dd, J = 11.0, 7.6 Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H),3.68 (d, J = 7.6 Hz, 1H), 3.66 (d, J = 11.0 Hz, 1H), 1.32 (t, J = 7.1 Hz,3H); 13C NMR (100 MHz, CDCl3) δ 169.5, 154.5, 148.6, 134.5, 127.6, 124.0,78.9, 62.2, 38.1, 14.0; HRMS (ESI-TOF): Anal. Calcd. For C12H12N2NaO5 +:287.0638, Found: 287.0649; IR (neat, cm-1): υ 3115, 2988, 2965, 1728, 1513,1342, 1256, 910, 848.
产率：72%; 1H NMR (400 MHz, DMSO-d6) δ 8.00 (d, J = 8.1 Hz, 2H), 7.81(d, J = 8.1 Hz, 2H), 5.31 (dd, J = 11.8, 6.8 Hz, 1H), 4.17 (q, J = 7.1 Hz,2H), 3.81 (dd, J = 17.4, 11.8 Hz, 1H), 3.66 (dd, J = 17.4, 6.8 Hz, 1H), 1.23(t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, DMSO-d6) δ 169.9, 166.8, 156.0, 132.4,132.3, 129.8, 127.1, 78.1, 61.4, 38.3, 14.0; HRMS (ESI-TOF): Anal. Calcd. ForC13H13NNaO5 +: 286.0686, Found: 286.0673; IR (neat, cm-1): υ 3071, 2980, 2921,2673, 2553, 1754, 1681, 1288, 1197, 1025, 862, 771.
产率：53%; 1H NMR (400 MHz, DMSO-d6) δ 10.15 (s, 1H), 7.68 (d, J = 8.6Hz, 2H), 7.62 (d, J = 8.6 Hz, 2H), 5.22 (dd, J = 11.6, 6.6 Hz, 1H), 4.16 (q,J = 7.1 Hz, 2H), 3.72 (dd, J = 17.2, 11.6 Hz, 1H), 3.58 (dd, J = 17.2, 6.6Hz, 1H), 2.07 (s, 3H), 1.22 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, DMSO-d6) δ170.2, 168.8, 155.8, 141.3, 127.7, 122.9, 118.9, 77.5, 61.3, 38.7, 24.2,14.0; HRMS (ESI-TOF): Anal. Calcd. For C14H16N2NaO4 +: 299.1002, Found:299.1001; IR (neat, cm-1): υ 3305, 3039, 2994, 2947, 1749, 1668, 1522, 1201,1022, 896, 829.
产率：75%; 1H NMR (400 MHz, CDCl3) δ 7.27 – 7.19 (m, 3H), 7.09 (d, J =8.0 Hz, 1H), 6.94 (dd, J = 8.0, 2.5 Hz, 1H), 5.15 (dd, J = 10.0, 8.4 Hz, 1H),4.25 (q, J = 7.1 Hz, 2H), 3.65 – 3.57 (m, 2H), 1.29 (t, J = 7.1 Hz, 3H); 13CNMR (100 MHz, CDCl3) δ 170.5, 156.4, 156.3, 130.0, 129.2, 119.1, 118.2,113.5, 77.9, 62.2, 39.0, 14.0; HRMS (ESI-TOF): Anal. Calcd. For C12H13NNaO4 +:258.0737, Found: 258.0724; IR (neat, cm-1): υ 3451, 2987, 2960, 1737, 1450,1191, 1160, 1024, 837, 789, 685.
产率：49%; 1H NMR (400 MHz, CDCl3) δ 8.43 – 8.41 (m, 1H), 8.28 – 8.24(m, 1H), 8.08 – 8.04 (m, 1H), 7.63 – 7.58 (m, 1H), 5.24 (dd, J = 10.8, 7.7Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H), 3.69 (d, J = 7.7 Hz, 1H), 3.68 (d, J =10.8 Hz, 1H), 1.32 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 169.5,154.4, 148.3, 132.4, 130.4, 129.9, 124.9, 121.6, 78.7, 62.2, 38.2, 14.0; HRMS(ESI-TOF): Anal. Calcd. For C12H12N2NaO5 +: 287.0638, Found: 287.0627; IR (neat,cm-1): υ 3089, 2974, 2924, 1745, 1528, 1352, 1337, 1205, 891, 739, 679.
产率：73%; 1H NMR (400 MHz, CDCl3) 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, CDCl3) 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; 19FNMR (376 MHz, CDCl3) δ -62.9; HRMS (ESI-TOF): Anal. Calcd. For C13H12F3NNaO3 +: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, CDCl3) 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, 8.6Hz, 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, CDCl3) 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, CDCl3) δ -112.5; HRMS (ESI-TOF):Anal. Calcd. For C12H12FNNaO3 +: 260.0693, Found: 260.0684; IR (neat, cm-1): υ2983, 2929, 2854, 1736, 1454, 1203, 1027, 898, 758.
产率：83%; 1H NMR (400 MHz, CDCl3) 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, CDCl3) 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. ForC12H12 79BrNNaO3 +: 319.9893, C12H12 81BrNNaO3 +: 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, CDCl3) 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, CDCl3) 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 C13H15NNaO3 +: 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, CDCl3) 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 = 11.3Hz, 1H), 3.70 (d, J = 7.2 Hz, 1H), 1.30 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz,CDCl3) 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 C13H15NNaO4 +: 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, CDCl3) 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, CDCl3) δ170.6, 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 C14H17NNaO4 +: 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, CDCl3) 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, CDCl3) 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 C12H13NNaO4 +: 258.0737, Found: 258.0730; IR (neat, cm-1): υ3211, 3057, 2984, 2939, 1737, 1494, 1258, 1201, 1157, 754, 655.
产率：77%; 1H NMR (400 MHz, CDCl3) 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, CDCl3) 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 C14H17NNaO5 +: 302.0999, Found: 302.0989; IR (neat, cm-1): υ3412, 2993, 2944, 1742, 1257, 1210, 1169, 1076, 1026, 890, 837, 818.
产率：74%; 1H NMR (400 MHz, CDCl3) 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 = 9.3Hz, 1H), 3.67 (d, J = 9.3 Hz, 1H), 1.30 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz,CDCl3) 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 = 25.4Hz), 115.8 (d, J = 11.7 Hz), 78.3 (d, J = 2.5 Hz), 61.9, 40.1 (d, J = 7.7Hz), 14.0; 19F NMR (376 MHz, CDCl3) δ -100.3; HRMS (ESI-TOF): Anal. Calcd. ForC12H11 79BrFNNaO3 +: 337.9799, C12H11 81BrFNNaO3 +: 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, CDCl3) 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); 13CNMR (100 MHz, CDCl3) 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 C12H12 35ClNNaO4 +: 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, CDCl3) 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, CDCl3) 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 C16H15NNaO3 +: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, CDCl3) 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 (100MHz, CDCl3) 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. ForC15H19NNaO6 +: 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, CDCl3) 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, CDCl3) 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 C14H13NO3S: 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, CDCl3) 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,CDCl3) 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. ForC16H15NNaO3 +: 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, CDCl3) 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); 13CNMR (100 MHz, CDCl3) 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 C15H13NNaO5 +: 310.0686, Found: 310.0690; IR (neat, cm-1): υ 2977,2924, 1754, 1650, 1615, 1465, 1189, 1034, 813, 759.
产率：58%; 1H NMR (400 MHz, CDCl3) 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, CDCl3) δ170.0, 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 C14H15NNaO3 +: 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, CDCl3) 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, CDCl3) 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. ForC17H20N3O4 +: 330.1448, Found: 330.1468; IR (neat, cm-1): υ 2988, 2918, 2852,1738, 1650, 1548, 1310, 1281, 1089, 1032, 976, 854, 751.
产率：73%; 1H NMR (400 MHz, CDCl3) 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,CDCl3) 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 C11H14 35ClN3NaO3 +: 294.0616,C11H14 37ClN3NaO3 +: 296.0586, Found: 294.0625, 296.0592; IR (neat, cm-1): υ 2996,2937, 2851, 1729, 1529, 1367, 1275, 1028, 892, 808.
实施例五
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（0.75mmol），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 (400MHz, CDCl3) δ 7.52 (s, 4H), 5.16 (dd, J = 10.4, 8.0 Hz, 1H), 4.19 (t, J = 6.7Hz, 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, CDCl3) 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 C14H16 79BrNNaO3 +: 348.0206, C14H16 81BrNNaO3 +: 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：
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：
产率：80%; 1H NMR (400 MHz, CDCl3) 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, CDCl3) 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 C14H16 79BrNNaO3 +: 348.0206, C14H16 81BrNNaO3 +: 350.0185, Found:348.0195, 350.0200; IR (neat, cm-1): υ 2976, 2935, 1733, 1590, 1346, 1149,1007, 894, 866, 834, 820.
产率：83%; 1H NMR (400 MHz, CDCl3) 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); 13CNMR (100 MHz, CDCl3) 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. ForC17H14 79BrNNaO3 +: 382.0049, C17H14 81BrNNaO3 +: 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, CDCl3) 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, 7.0Hz, 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, CDCl3) 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 C16H12 79BrNNaO3 +:367.9893, C16H12 81BrNNaO3 +: 369.9872, Found: 367.9881, 369.9859; IR (neat, cm-1): υ 3070, 3043, 2976, 2927, 1773, 1589, 1489, 1193, 1162, 1069, 818, 748.
产率：60%; 1H NMR (400 MHz, CDCl3) 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, 8.3Hz, 1H), 3.76 – 3.56 (m, 2H); 13C NMR (100 MHz, CDCl3) 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, CDCl3) δ -73.7; HRMS (ESI-TOF): Anal. Calcd. ForC12H9 79BrF3NNaO3 +: 373.9610, C12H9 81BrF3NNaO3 +: 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, CDCl3) 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, CDCl3) δ169.1, 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 C13H10 79BrNNaO3 +: 329.9736, C13H10 81BrNNaO3 +: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, 7.2Hz, 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 C12H13 79BrN2NaO2 +: 319.0053,C12H13 81BrN2NaO2 +: 321.0032, Found: 319.0041, 321.0030; IR (neat, cm-1): υ 2925,2860, 1649, 1396, 1151, 1003, 897, 824.
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 C14H17 79BrN2NaO2 +: 347.0366, C14H17 81BrN2NaO2 +: 349.0345,Found: 347.0332, 349.0329; IR (neat, cm-1): υ 2968, 2930, 2871, 1633, 1261,1068, 1005, 895, 830.
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 C12H13 79BrN2NaO3 +: 335.0002, C12H13 81BrN2NaO3 +: 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 C14H15 79BrN2NaO3 +: 361.0158, C14H15 81BrN2NaO3 +: 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. ForC10H9 79BrN2NaO2 +: 290.9740, C10H9 81BrN2NaO2 +: 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, CDCl3) 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, CDCl3) 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 C15H12 79BrNNaO+: 323.9994, C15H12 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.
产率：52%; 1H NMR (400 MHz, CDCl3) 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, CDCl3) δ162.6 (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 (376MHz, CDCl3) δ -113.6; HRMS (ESI-TOF): Anal. Calcd. For C15H11 79BrFNNaO+:341.9900, C15H11 81BrFNNaO+: 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, CDCl3) 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, CDCl3) 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. ForC15H12 79BrClNO+: 335.9785, C15H12 81BrClNO+: 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, CDCl3) 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, CDCl3)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 C15H12 79Br79Br NO+: 379.9280, C15H12 79Br81BrNO+: 381.9260, C15H12 81Br81Br 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.
产率：55%; 1H NMR (400 MHz, CDCl3) 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, CDCl3) 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 C16H14 79BrNNaO+: 338.0151, C16H14 81BrNNaO+: 340.0131, Found: 338.0157, 340.0122; IR (neat, cm-1): υ 2977, 2917, 2860, 1587, 1397, 1344, 1070, 1006, 905, 831, 813.
产率：57%; 1H NMR (400 MHz, CDCl3) 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, CDCl3) 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 = 3.0Hz), 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, CDCl3) δ -112.0; HRMS (ESI-TOF): Anal. Calcd. ForC15H11 79BrFNNaO+: 341.9900, C15H11 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.
产率：57%; 1H NMR (400 MHz, CDCl3) 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, CDCl3) 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 C15H12 79Br79BrNO+: 379.9280, C15H12 79Br81Br NO+: 381.9260, C15H12 81Br81Br 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.
产率：56%; 1H NMR (400 MHz, CDCl3) 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, CDCl3) 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, CDCl3) δ -62.6; HRMS(ESI-TOF): Anal. Calcd. For C16H11 79BrF3NNaO+: 391.9868, C16H11 81BrF3NNaO+: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, CDCl3) 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, CDCl3) δ 154.9, 132.0, 128.2, 127.6, 124.8, 72.4, 40.6;19F NMR (376 MHz, CDCl3) δ -141.35 – -142.79 (m, 2F), -152.46 – -152.70 (m,1F), -160.98 – -161.22 (m, 2F); HRMS (ESI-TOF): Anal. Calcd. ForC15H7 79BrF5NNaO+: 413.9523, C15H7 81BrF5NNaO+: 415.9503, Found: 413.9508, 415.9506;IR (neat, cm-1): υ 3061, 2977, 2930, 1523, 1503, 1130, 1012, 964, 894, 840,824.
产率：44%; 1H NMR (400 MHz, CDCl3) δ 7.53 (s, 4H), 6.63 (dd, J = 9.9,3.5 Hz, 1H), 3.51 (dd, J = 17.6, 9.9 Hz, 1H), 3.35 – 3.27 (m, 1H), 3.20 –3.14 (m, 1H), 3.11 (dd, J = 17.6, 3.5 Hz, 1H), 2.42 – 2.36 (m, 2H), 2.08 –1.92 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 175.3, 154.6, 132.0, 128.1, 127.5,124.8, 82.2, 41.5, 36.8, 30.9, 17.6; HRMS (ESI-TOF): Anal. Calcd. ForC13H13 79BrN2NaO2 +: 331.0053, C13H13 81BrN2NaO2 +: 333.0032, Found: 331.0036,333.0051; IR (neat, cm-1): υ 2980, 2921, 2890, 1683, 1397, 1283, 1261, 1238,886, 816, 790.
产率：77%; 1H NMR (400 MHz, CDCl3) δ 7.65 – 7.60 (m, 2H), 7.55 – 7.48(m, 4H), 7.46 – 7.36 (m, 3H), 4.32 (dd, J = 15.6, 11.3 Hz, 1H), 3.39 (dd, J =15.6, 11.3 Hz, 1H), 3.09 (t, J = 15.6 Hz, 1H), 0.49 (s, 3H), 0.47 (s, 3H); 13CNMR (100 MHz, CDCl3) δ 155.7, 135.2, 133.9, 131.7, 129.7, 128.5, 128.2,128.0, 123.9, 74.2, 37.7, -5.1, -5.7; HRMS (ESI-TOF): Anal. Calcd. ForC17H18 79BrNNaOSi+: 382.0233, C17H18 81BrNNaOSi+: 384.0213, Found: 382.0235,384.0212; IR (neat, cm-1): υ 3052, 2956, 2902, 1588, 1251, 1115, 896, 821,779, 736, 697.
产率：37%; 1H NMR (400 MHz, CDCl3) δ 7.51 (s, 4H), 4.90 – 4.82 (m, 1H),3.87 (dd, J = 12.3, 3.2 Hz, 1H), 3.67 (dd, J = 12.3, 4.4 Hz, 1H), 3.34 (dd, J= 16.6, 10.7 Hz, 1H), 3.26 (dd, J = 16.6, 8.0 Hz, 1H), 2.41 (s, 1H); 13C NMR(100 MHz, CDCl3) δ 156.2, 131.9, 128.2, 128.1, 124.4, 81.5, 63.5, 36.0; HRMS(ESI-TOF): Anal. Calcd. For C10H11 79BrNO+: 255.9968, C10H11 81BrNO+: 257.9947,Found: 255.9970, 257.9933; IR (neat, cm-1): υ 3375, 2936, 2922, 2852, 1592,1399, 1007, 927, 907, 827, 820, 805.
产率：53%; 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 7.5 Hz, 2H), 7.71 –7.65 (m, 1H), 7.61 – 7.50 (m, 4H), 7.46 (d, J = 8.5 Hz, 2H), 5.56 (dd, J =10.9, 4.5 Hz, 1H), 4.02 (dd, J = 18.3, 4.5 Hz, 1H), 3.77 (dd, J = 18.3, 10.9Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 156.1, 135.1, 134.6, 132.1, 129.7, 129.2,128.4, 126.2, 125.5, 93.3, 36.5; HRMS (ESI-TOF): Anal. Calcd. ForC15H12 79BrNNaO3S+: 387.9613, C15H12 81BrNNaO3S+: 389.9593, Found: 387.9625,389.9600; IR (neat, cm-1): υ 3006, 2940, 2895, 1592, 1310, 1089, 1010, 612.
产率：38%; 1H NMR (400 MHz, CDCl3) δ 7.55 (s, 4H), 6.82 (dd, J = 6.9,1.4 Hz, 1H), 3.58 (dd, J = 17.8, 6.9 Hz, 1H), 3.31 (dd, J = 17.8, 1.4 Hz,1H), 2.07 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 169.6, 156.1, 132.1, 128.4,127.2, 125.2, 95.9, 41.0, 21.0; HRMS (ESI-TOF): Anal. Calcd. ForC11H10 79BrNNaO3 +: 305.9736, C11H10 81BrNNaO3 +: 307.9716, Found: 305.9746, 307.9719;IR (neat, cm-1): υ 2956, 2919, 2851, 1750, 1363, 1218, 1172, 1063, 1029, 949,845, 818.
产率：54%; 1H NMR (400 MHz, CDCl3) δ 7.59 – 7.49 (m, 4H), 5.67 (dd, J =6.7, 1.7 Hz, 1H), 3.85 (dt, J = 9.4, 6.6 Hz, 1H), 3.53 (dt, J = 9.4, 6.7 Hz,1H), 3.36 (dd, J = 17.3, 6.7 Hz, 1H), 3.16 (dd, J = 17.3, 1.7 Hz, 1H), 1.60 –1.51 (m, 2H), 1.41 – 1.30 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz,CDCl3) δ 156.1, 131.9, 128.22, 128.16, 124.5, 103.4, 68.2, 41.2, 31.5, 19.1,13.8; HRMS (ESI-TOF): Anal. Calcd. For C13H17 79BrNO2 +: 298.0437, C13H17 81BrNO2 +:300.0417, Found: 298.0426, 300.0415; IR (neat, cm-1): υ 2957, 2930, 2871,1591, 1350, 1189, 1093, 1071, 1009, 886, 841.
产率：39%; 1H NMR (400 MHz, CDCl3) δ 7.54 (s, 4H), 5.05 (dd, J = 11.9,6.3 Hz, 1H), 3.63 (dd, J = 17.0, 6.3 Hz, 1H), 3.45 (dd, J = 17.0, 11.9 Hz,1H), 2.71 (t, J = 7.4 Hz, 2H), 1.66 – 1.55 (m, 2H), 1.36 – 1.24 (m, 4H), 0.88(t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 209.2, 155.8, 132.0, 128.3,124.9, 84.4, 38.9, 36.9, 31.3, 22.7, 22.4, 13.9; HRMS (ESI-TOF): Anal. Calcd.For C15H18 79BrNNaO2 +: 346.0413, C15H18 81BrNNaO2 +: 348.0393, Found: 346.0391,348.0421; IR (neat, cm-1): υ 2949, 2924, 2867, 2855, 1707, 1591, 896, 888,823.
产率：96%; 1H NMR (400 MHz, CDCl3) δ 7.59 – 7.48 (m, 4H), 4.10 (dd, J =15.6, 11.4 Hz, 1H), 3.41 (dd, J = 15.6, 11.4 Hz, 1H), 3.06 (t, J = 15.6 Hz,1H), 0.16 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 155.6, 131.8, 128.8, 128.2,124.0, 74.7, 37.5, -3.9; HRMS (ESI-TOF): Anal. Calcd. For C12H16 79BrNNaOSi+:320.0077, C12H16 81BrNNaOSi+: 322.0056, Found: 320.0066, 322.0051; IR (neat, cm-1): υ 2958, 2924, 1399, 1247, 1195, 1071, 1008, 889, 863, 823.
产率：49%; 1H NMR (400 MHz, CDCl3) δ 7.56 – 7.47 (m, 4H), 7.44 – 7.38(m, 2H), 7.34 – 7.28 (m, 2H), 7.27 – 7.20 (m, 1H), 4.88 (dddd, J = 11.0, 8.7,6.7, 4.5 Hz, 1H), 3.45 – 3.33 (m, 2H), 3.22 (dd, J = 16.8, 6.7 Hz, 1H), 2.99(dd, J = 13.6, 8.7 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 155.4, 134.6, 131.9,130.1, 129.1, 128.3, 128.1, 126.8, 124.4, 79.8, 39.2, 37.7; HRMS (ESI-TOF):Anal. Calcd. For C16H14 79BrNNaOS+: 369.9872, C16H14 81BrNNaOS+: 371.9851, Found:369.9858, 371.9852; IR (neat, cm-1): υ 3058, 3020, 2924, 1583, 1436, 1071,1006, 895, 822, 735, 689.
产率：66%; mp: 65-67 oC; 1H NMR (400 MHz, CDCl3) δ 7.51 (s, 4H), 4.89 –4.82 (m, 1H), 4.27 – 4.15 (m, 4H), 3.68 – 3.52 (m, 2H), 1.33 (t, J = 5.8 Hz,3H), 1.30 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 155.4 (d, J = 6.3Hz), 131.9, 128.2, 127.4, 124.8, 76.1, 74.5, 63.5 (d, J = 7.0 Hz), 63.1 (d, J= 6.8 Hz), 37.4, 16.4 (d, J = 5.6 Hz); HRMS (ESI-TOF): Anal. Calcd. ForC13H17 79BrNNaO4P+: 383.9971, C13H17 81BrNNaO4P+: 385.9950, Found: 383.9956,385.9958; IR (neat, cm-1): υ 2949, 2917, 1617, 1540, 1372, 1311, 1124, 1031,911, 802, 694.
4bn产率：34%; 1H NMR (400 MHz, CDCl3) δ7.52 (s, 4H), 4.76 (ddd, J =11.1, 7.1, 4.4 Hz, 1H), 4.54 (d, J = 4.4 Hz, 1H), 3.82 – 3.69 (m, 2H), 3.69 –3.56 (m, 2H), 3.39 (dd, J = 16.9, 7.1 Hz, 1H), 3.28 (dd, J = 16.9, 11.1 Hz,1H), 1.25 (t, J = 7.0 Hz, 3H), 1.16 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz,CDCl3) δ155.9, 131.8, 128.4, 128.1, 124.2, 102.1, 81.6, 64.5, 63.6, 35.5,15.3, 15.2; HRMS (ESI-TOF): Anal. Calcd. For C14H18 79BrNNaO3 +: 350.0362,C14H18 81BrNNaO3 +: 352.0342, Found: 350.0352, 352.0329; IR (neat, cm-1): υ 2976,2929, 2882, 1592, 1399, 1349, 1120, 1061, 1009, 899, 823.
4bo产率：47%; 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 8.4 Hz, 2H), 7.63– 7.56 (m, 4H), 7.43 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 6.8 Hz, 1H), 3.70 (dd,J = 17.7, 6.8 Hz, 1H), 3.47 (d, J = 17.7 Hz, 1H), 1.32 (s, 9H); 13C NMR (100MHz, CDCl3) δ 165.2, 157.5, 156.2, 132.2, 129.8, 128.5, 127.3, 126.2, 125.4,125.2, 96.7, 41.4, 35.1, 31.0; HRMS (EI-TOF): Anal. Calcd. For C20H20 79BrNO3:401.0627, C20H20 81BrNO3: 403.0606, Found: 401.0621, 403.0600; IR (neat, cm-1): υ2964, 2924, 2871, 1723, 1265, 1087, 1073, 1009, 948, 845, 821, 773, 706.
4bp产率：41%; 1H NMR (400 MHz, CDCl3) δ 7.50 (s, 4H), 4.98 (s, 1H),4.89 – 4.80 (m, 1H), 3.50 – 3.26 (m, 3H), 3.11 (dd, J = 16.9, 7.5 Hz, 1H),1.38 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 156.2, 156.1, 131.9, 128.2, 128.1,124.4, 80.4, 79.7, 43.5, 37.1, 28.2; HRMS (ESI-TOF): Anal. Calcd. ForC15H19 79BrN2NaO3 +: 377.0471, C15H19 81BrN2NaO3 +: 379.0451, Found: 377.0466,379.0445; IR (neat, cm-1): υ 3374, 2978, 2941, 2872, 1708, 1512, 1492, 1245,1157, 1009, 917, 885, 819.
4bq产率：36%; 1H NMR (400 MHz, CDCl3) δ 7.51 (s, 4H), 4.97 – 4.88 (m,1H), 3.84 (t, J = 5.9 Hz, 2H), 3.43 (dd, J = 16.5, 10.4 Hz, 1H), 3.03 (dd, J= 16.5, 8.0 Hz, 1H), 2.22 (s, 1H), 2.08 – 1.85 (m, 2H); 13C NMR (100 MHz,CDCl3) δ 156.0, 131.9, 128.4, 128.0, 124.3, 79.6, 59.6, 40.2, 37.7; HRMS(ESI-TOF): Anal. Calcd. For C11H12 79BrNNaO2 +: 291.9944, C11H12 81BrNNaO2 +:293.9923, Found: 291.9949, 293.9922; IR (neat, cm-1): υ 3293, 2937, 2880,1591, 1399, 1348, 1041, 1033, 899, 824, 795.
4br产率：44%; 1H NMR (400 MHz, DMSO-d6) δ 8.32 (d, J = 7.6 Hz, 1H),8.12 (d, J = 7.5 Hz, 1H), 8.09 – 8.04 (m, 1H), 8.03 – 7.97 (m, 1H), 7.65 (d,J = 8.6 Hz, 2H), 7.60 (d, J = 8.6 Hz, 2H), 5.16 – 5.06 (m, 1H), 4.01 (dd, J =15.2, 7.4 Hz, 1H), 3.88 (dd, J = 15.2, 4.8 Hz, 1H), 3.60 (dd, J = 17.2, 10.6Hz, 1H), 3.39 – 3,31 (m, 1H); 13C NMR (100 MHz, DMSO-d6) δ 159.0, 156.2,136.7, 136.0, 135.4, 131.9, 128.7, 128.4, 126.2, 125.3, 123.6, 121.7, 77.8,41.7, 37.9; HRMS (ESI-TOF): Anal. Calcd. For C17H13 79BrN2NaO4S+: 442.9672,C17H13 81BrN2NaO4S+: 444.9651, Found: 442.9660, 444.9621; IR (neat, cm-1): υ 3088,3027, 1732, 1326, 1265, 1179, 1160, 906, 869, 816, 754, 676.
4bs产率：40%; 1H NMR (400 MHz, CDCl3) δ 7.84 – 7.79 (m, 2H), 7.73 –7.66 (m, 2H), 7.48 (s, 4H), 4.83 – 4.74 (m, 1H), 3.93 – 3.77 (m, 2H), 3.45(dd, J = 16.6, 10.5 Hz, 1H), 3.01 (dd, J = 16.6, 8.1 Hz, 1H), 2.24 – 2.13 (m,1H), 2.04 – 1.95 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 168.1, 155.4, 133.9,131.9, 131.8, 128.4, 128.0, 124.2, 123.2, 79.4, 39.9, 34.7, 33.9; HRMS (ESI-TOF): Anal. Calcd. For C19H15 79BrN2NaO3 +: 421.0158, C19H15 81BrN2NaO3 +: 423.0138,Found: 421.0133, 423.0146; IR (neat, cm-1): υ 3066, 2930, 2847, 1703, 1395,1007, 906, 814, 716, 706.
4bt产率：33%; 1H NMR (400 MHz, CDCl3) δ 7.54 – 7.41 (m, 12H), 5.20 –5.06 (m, 3H), 4.23 – 4.09 (m, 6H), 3.66 – 3.47 (m, 6H), 1.51 (q, J = 7.3 Hz,2H), 0.87 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 169.4, 155.3, 131.9,128.2, 127.2, 124.8, 78.0, 64.9, 41.1, 38.3, 23.1, 7.2; IR (neat, cm-1): υ2965, 2926, 1740, 1591, 1347, 1193, 1161, 1008, 891, 864, 820.
4bu产率：70%; 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 8.4 Hz, 2H), 7.49(d, J = 8.4 Hz, 2H), 4.62 (d, J = 8.3 Hz, 1H), 3.43 (d, J = 8.3 Hz, 1H), 2.62– 2.58 (m, 1H), 2.50 – 2.43 (m, 1H), 1.62 – 1.51 (m, 2H), 1.50 – 1.44 (m,1H), 1.39 – 1.29 (m, 1H), 1.23 – 1.11 (m, 2H); 13C NMR (100 MHz, CDCl3) δ156.0, 131.8, 128.3, 128.2, 123.8, 88.1, 56.7, 42.9, 39.1, 32.2, 27.3, 22.6;HRMS (ESI-TOF): Anal. Calcd. For C14H14 79BrNNaO+: 314.0151, C14H14 81BrNNaO+:316.0131, Found: 314.0153, 316.0113; IR (neat, cm-1): υ 2960, 2948, 2872,1588, 1399, 1068, 1007, 881, 814.
4bv产率：85%; 1H NMR (400 MHz, DMSO-d6) δ 7.68 (d, J = 8.3 Hz, 2H),7.62 (d, J = 8.3 Hz, 2H), 4.41 (t, J = 6.8 Hz, 2H), 3.76 (d, J = 17.6 Hz,1H), 3.70 (d, J = 17.6 Hz, 1H), 2.66 – 2.53 (m, 2H); 13C NMR (100 MHz, DMSO-d6) δ 174.5, 156.0, 132.0, 128.8, 127.6, 124.1, 85.1, 66.1, 41.6, 33.9; HRMS(ESI-TOF): Anal. Calcd. For C12H10 79BrNNaO3 +: 317.9736, C12H10 81BrNNaO3 +:319.9716, Found: 317.9756, 319.9706; IR (neat, cm-1): υ 2942, 2927, 1741,1592, 1350, 1199, 1008, 892, 821.
4bw产率：40%; 1H NMR (400 MHz, CDCl3) δ7.54 (d, J = 8.7 Hz, 2H), 7.51(d, J = 8.7 Hz, 2H), 3.54 (s, 2H), 3.23 – 3.12 (m, 1H), 2.99 (dd, J = 13.3,9.8 Hz, 2H), 2.67 (dd, J = 13.3, 5.1 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ156.0,132.0, 128.0, 127.9, 124.7, 122.1, 84.5, 45.8, 40.8, 15.2; HRMS (ESI-TOF):Anal. Calcd. For C13H11 79BrN2NaO+: 312.9947, C13H11 81BrN2NaO+: 314.9927, Found:312.9927, 314.9941; IR (neat, cm-1): υ 2976, 2923, 2875, 2852, 2239, 1699,1400, 1363, 1160, 1084, 1008, 894, 819.
4bx产率：42%; 1H NMR (400 MHz, CDCl3) δ7.54 – 7.47 (m, 4H), 3.74 (d, J= 12.0 Hz, 1H), 3.57 (d, J = 12.0 Hz, 1H), 3.47 (d, J = 16.6 Hz, 1H), 2.97(d, J = 16.6 Hz, 1H), 2.36 (s, 1H), 1.42 (s, 3H); 13C NMR (100 MHz, CDCl3) δ156.1, 131.8, 128.7, 128.0, 124.2, 87.9, 67.2, 41.7, 22.6; HRMS (ESI-TOF):Anal. Calcd. For C11H12 79BrNNaO2 +: 291.9944, C11H12 81BrNNaO2 +: 293.9923, Found:291.9952, 293.9929; IR (neat, cm-1): υ 3396, 2975, 2928, 2869, 1591, 1490,1399, 1354, 1055, 1009, 909, 821, 795.
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：
4by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) δ160.8, 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 C18H17N2O5S+: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, CDCl3) 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, CDCl3) 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, CDCl3) δ -134.0 (d, J = 22.0 Hz,1F), -136.2 (d, J = 22.0 Hz, 1F); HRMS (ESI-TOF): Anal. Calcd. ForC12H12F2N2NaO2 +: 277.0759, Found: 277.0756; IR (neat, cm-1): υ 3294, 2988, 2942,2926, 1738, 1651, 1225, 1192, 1026, 1009, 822.
4ca产率：52%; 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 8.8 Hz, 2H), 7.45(d, J = 8.8 Hz, 1H), 6.89 (d, J = 8.8 Hz, 2H), 6.84 (dd, J = 8.8, 2.5 Hz,1H), 6.76 (d, J = 2.5 Hz, 1H), 6.08 (s, 1H), 5.12 – 5.04 (m, 1H), 4.17 (dd, J= 10.0, 5.3 Hz, 1H), 4.11 (dd, J = 10.0, 4.9 Hz, 1H), 3.81 (s, 3H), 3.50 (dd,J = 16.7, 10.7 Hz, 1H), 3.32 (dd, J = 16.7, 7.0 Hz, 1H), 2.35 (s, 3H); 13C NMR(100 MHz, CDCl3) δ 161.2, 161.1, 161.0, 155.9, 154.9, 152.4, 128.2, 125.5,121.5, 114.0, 113.9, 112.3, 112.1, 101.6, 78.1, 69.0, 55.3, 37.6, 18.5; HRMS(ESI-TOF): Anal. Calcd. For C21H20NO5 +: 366.1336, Found: 366.1354; IR (neat,cm-1): υ 2961, 2932, 1731, 1607, 1251, 1155, 1071, 891, 827.
4cb产率：46% yield (110.6 mg); mp: 113-115 oC; 1H NMR (400 MHz, CDCl3) δ7.81 – 7.71 (m, 3H), 7.54 – 7.42 (m, 3H), 7.40 – 7.31 (m, 2H), 7.25 – 7.19(m, 1H), 7.18 – 7.13 (m, 1H), 4.75 – 4.61 (m, 1H), 4.43 – 4.23 (m, 2H), 4.01– 3.85 (m, 4H), 3.14 – 3.03 (m, 1H), 2.84 – 2.73 (m, 1H), 2.19 – 2.05 (m,1H), 2.03 – 1.89 (m, 1H), 1.68 – 1.62 (m, 3H); 13C NMR (100 MHz, CDCl3) δ174.4, 174.3, 157.61, 157.59, 155.66, 155.64, 135.54, 135.49, 133.6, 131.7,129.13, 129.12, 128.78, 128.77, 128.31, 128.28, 127.84, 127.83, 127.15,127.12, 126.1, 126.0, 125.9, 125.8, 124.07, 124.06, 119.06, 119.04, 105.54,105.50, 78.9, 78.6, 61.3, 61.2, 55.20, 55.19, 45.4, 45.3, 39.53, 39.50,33.89, 33.87, 18.5, 18.3; HRMS (EI-TOF): Anal. Calcd. For C25H24 79BrNO4:481.0889, C25H24 81BrNO4: 483.0868, Found: 481.0893, 483.0891; IR (neat, cm-1): υ2960, 2937, 1728, 1604, 1176, 1159, 1026, 858, 823, 813.
4cc产率：45%; 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 8.3 Hz, 2H), 7.49(d, J = 8.3 Hz, 2H), 7.46 – 7.41 (m, 4H), 6.96 (d, J = 2.4 Hz, 1H), 6.87 (d,J = 9.0 Hz, 1H), 6.66 (dd, J = 9.0, 2.4 Hz, 1H), 4.76 – 4.67 (m, 1H), 4.34 –4.22 (m, 2H), 3.81 (s, 3H), 3.67 (s, 2H), 3.26 (dd, J = 16.5, 10.4 Hz, 1H),2.88 (dd, J = 16.5, 8.0 Hz, 1H), 2.37 (s, 3H), 2.14 – 2.01 (m, 1H), 2.01 –1.88 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 170.6, 168.1, 155.9, 155.6, 139.2,135.8, 133.7, 131.8, 131.0, 130.7, 130.5, 129.0, 128.3, 127.9, 124.2, 114.9,112.3, 111.4, 101.2, 78.4, 61.5, 55.6, 39.7, 34.1, 30.2, 13.3; HRMS (EI-TOF):Anal. Calcd. For C30H26 79BrClN2O5: 608.0714, C30H26 81BrClN2O5: 610.0693, Found:608.0717, 610.0674; IR (neat, cm-1): υ 2978, 2957, 2929, 2832, 1733, 1679,1591, 1477, 1355, 1315, 1219, 1068, 826, 751.
4cd产率：71%; 1H NMR (400 MHz, CDCl3) δ 7.57 – 7.50 (m, 4H), 7.28 (s,1H), 6.95 – 6.81 (m, 2H), 5.39 (dd, J = 11.2, 7.2 Hz, 1H), 3.83 – 3.63 (m,2H), 2.92 – 2.84 (m, 2H), 2.54 – 2.45 (m, 1H), 2.41 – 2.34 (m, 1H), 2.29 –2.20 (m, 1H), 2.17 – 1.94 (m, 4H), 1.66 – 1.42 (m, 6H), 0.89 (s, 3H); 13C NMR(100 MHz, CDCl3) δ 220.5, 168.5, 155.1, 147.9, 138.0, 137.8, 131.8, 128.2,127.2, 126.3, 124.7, 120.9, 118.1, 78.1, 50.1, 47.7, 43.9, 38.5, 37.7, 35.6,31.3, 29.1, 26.0, 25.5, 21.4, 13.6; HRMS (ESI-TOF): Anal. Calcd. ForC28H29 79BrNO4 +: 522.1274, C28H29 81BrNO4 +: 524.1254, Found: 522.1256, 524.1250; IR(neat, cm-1): υ 2930, 2876, 2854, 2820, 1766, 1744, 1220, 1189, 1176, 1002,886, 817.
4ce产率：46%; 1H NMR (400 MHz, CDCl3) δ 7.54 (s, 4H), 7.32 (d, J = 8.3Hz, 2H), 7.27 – 7.24 (m, 2H), 7.21 – 7.12 (m, 4H), 7.00 – 6.94 (m, 2H), 6.93– 6.87 (m, 2H), 5.39 (dd, J = 10.9, 7.3 Hz, 1H), 4.68 (t, J = 6.0 Hz, 1H),4.62 (d, J = 2.3 Hz, 1H), 3.80 – 3.67 (m, 2H), 3.14 – 2.93 (m, 2H), 1.99 –1.84 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 168.2, 167.2, 162.0 (d, J = 245.5Hz), 158.9 (d, J = 243.6 Hz), 155.3, 150.2, 139.9 (d, J = 3.1 Hz), 135.6,133.5 (d, J = 2.8 Hz), 132.0, 128.3, 127.3 (d, J = 8.0 Hz), 127.1, 127.0,125.0, 122.0, 118.3 (d, J = 7.8 Hz), 115.8 (d, J = 22.7 Hz), 115.2 (d, J =21.3 Hz), 78.1, 72.9, 60.6, 60.2, 38.6, 36.4, 24.9; 19F NMR (376 MHz, CDCl3) δ-114.9, -117.5; IR (neat, cm-1): υ 3418, 3063, 2926, 2855, 1740, 1507, 1216,1198, 1169, 1154, 831, 729.
4cf产率：62%; 1H NMR (400 MHz, CDCl3) δ 7.48 (s, 4H), 5.35 – 5.30 (m,1H), 5.10 (t, J = 9.3 Hz, 1H), 4.71 – 4.60 (m, 1H), 3.56 (d, J = 9.3 Hz, 2H),2.48 (t, J = 8.7 Hz, 1H), 2.36 – 2.29 (m, 2H), 2.25 – 1.84 (m, 8H), 1.68 –1.51 (m, 5H), 1.46 – 1.38 (m, 3H), 1.20 – 1.08 (m, 3H), 1.00 – 0.92 (m, 4H),0.57 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 209.2, 169.1, 155.0, 139.0, 131.8,128.2, 127.4, 124.5, 122.5, 78.2, 75.5, 63.4, 56.6, 49.6, 43.7, 38.5, 38.4,37.64, 37.60, 36.7, 36.4, 31.6, 31.3, 27.3, 24.3, 22.6, 20.8, 19.1, 13.0; IR(neat, cm-1): υ 2943, 2931, 2853, 1733, 1702, 1508, 1214, 1169, 1155, 1010,904, 832。
Claims (4)
1.一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；
其中，所述醛的化学结构通式为：；式中，R1选自芳基、取代芳基、杂芳香基、萘基或者烯基；
所述烯烃的化学结构通式为：；式中R4、R5独立的选自氢、烷基、芳基、酯基、醚、酰胺基、羰基、硅基、羟基、氰基、卤素、炔基、羧基或者磷酸酯基；
所述亚硝酸酯的化学结构通式为：；式中R6选自叔丁基、正丁基、异丁基或者异丙基；
所述异噁唑啉的化学结构式为：；
所述反应的反应温度为25～80℃，时间为12～48小时；
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%；
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；
芳基或者取代芳基的化学结构通式为：，其中，R2、R3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。
2.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。
3.根据权利要求2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。
4.一种无金属催化剂制备异噁唑啉的方法，其特征在于：将对溴苯甲醛、对甲苯磺酰肼在甲醇溶剂中混合后，再加入丙烯酸乙酯、亚硝酸叔丁酯、四氢呋喃、四甲基乙二胺，反应得到异噁唑啉。
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