CN117945821A - Nitration method of aromatic compound - Google Patents
Nitration method of aromatic compound Download PDFInfo
- Publication number
- CN117945821A CN117945821A CN202410099621.3A CN202410099621A CN117945821A CN 117945821 A CN117945821 A CN 117945821A CN 202410099621 A CN202410099621 A CN 202410099621A CN 117945821 A CN117945821 A CN 117945821A
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- Prior art keywords
- nmr
- cdcl
- reaction
- nitrate
- nitration
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- 238000006396 nitration reaction Methods 0.000 title claims abstract description 81
- 150000001491 aromatic compounds Chemical class 0.000 title claims abstract description 67
- 238000000034 method Methods 0.000 title claims abstract description 40
- BYEAHWXPCBROCE-UHFFFAOYSA-N 1,1,1,3,3,3-hexafluoropropan-2-ol Chemical compound FC(F)(F)C(O)C(F)(F)F BYEAHWXPCBROCE-UHFFFAOYSA-N 0.000 claims abstract description 131
- 239000002904 solvent Substances 0.000 claims abstract description 119
- 230000001546 nitrifying effect Effects 0.000 claims abstract description 47
- 229910002651 NO3 Inorganic materials 0.000 claims abstract description 36
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 35
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims abstract description 34
- 229940079593 drug Drugs 0.000 claims abstract description 16
- 239000003814 drug Substances 0.000 claims abstract description 16
- -1 aromatic nitro compounds Chemical class 0.000 claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims description 140
- 125000003118 aryl group Chemical group 0.000 claims description 38
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 25
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 18
- CHPZKNULDCNCBW-UHFFFAOYSA-N gallium nitrate Chemical compound [Ga+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O CHPZKNULDCNCBW-UHFFFAOYSA-N 0.000 claims description 18
- SZQUEWJRBJDHSM-UHFFFAOYSA-N iron(3+);trinitrate;nonahydrate Chemical compound O.O.O.O.O.O.O.O.O.[Fe+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O SZQUEWJRBJDHSM-UHFFFAOYSA-N 0.000 claims description 18
- 125000001424 substituent group Chemical group 0.000 claims description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 17
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 16
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 16
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 claims description 16
- BJRNKVDFDLYUGJ-RMPHRYRLSA-N hydroquinone O-beta-D-glucopyranoside Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=CC=C(O)C=C1 BJRNKVDFDLYUGJ-RMPHRYRLSA-N 0.000 claims description 16
- VCJMYUPGQJHHFU-UHFFFAOYSA-N iron(3+);trinitrate Chemical compound [Fe+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O VCJMYUPGQJHHFU-UHFFFAOYSA-N 0.000 claims description 16
- YNPNZTXNASCQKK-UHFFFAOYSA-N phenanthrene Chemical compound C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 claims description 16
- 230000008569 process Effects 0.000 claims description 14
- BBEAQIROQSPTKN-UHFFFAOYSA-N pyrene Chemical compound C1=CC=C2C=CC3=CC=CC4=CC=C1C2=C43 BBEAQIROQSPTKN-UHFFFAOYSA-N 0.000 claims description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 12
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 12
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 10
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 9
- 150000001413 amino acids Chemical class 0.000 claims description 9
- 229940044658 gallium nitrate Drugs 0.000 claims description 9
- 229930182470 glycoside Chemical class 0.000 claims description 9
- 229960000271 arbutin Drugs 0.000 claims description 8
- FBXVOTBTGXARNA-UHFFFAOYSA-N bismuth;trinitrate;pentahydrate Chemical compound O.O.O.O.O.[Bi+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O FBXVOTBTGXARNA-UHFFFAOYSA-N 0.000 claims description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 8
- RTIXKCRFFJGDFG-UHFFFAOYSA-N chrysin Chemical compound C=1C(O)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=CC=C1 RTIXKCRFFJGDFG-UHFFFAOYSA-N 0.000 claims description 8
- 150000002148 esters Chemical class 0.000 claims description 8
- GVEPBJHOBDJJJI-UHFFFAOYSA-N fluoranthrene Natural products C1=CC(C2=CC=CC=C22)=C3C2=CC=CC3=C1 GVEPBJHOBDJJJI-UHFFFAOYSA-N 0.000 claims description 8
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 claims description 8
- BJRNKVDFDLYUGJ-UHFFFAOYSA-N p-hydroxyphenyl beta-D-alloside Natural products OC1C(O)C(O)C(CO)OC1OC1=CC=C(O)C=C1 BJRNKVDFDLYUGJ-UHFFFAOYSA-N 0.000 claims description 8
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 8
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 8
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 7
- 125000006575 electron-withdrawing group Chemical group 0.000 claims description 7
- 150000002338 glycosides Chemical class 0.000 claims description 7
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 claims description 6
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 6
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 6
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- 229930192474 thiophene Natural products 0.000 claims description 6
- FTNJQNQLEGKTGD-UHFFFAOYSA-N 1,3-benzodioxole Chemical compound C1=CC=C2OCOC2=C1 FTNJQNQLEGKTGD-UHFFFAOYSA-N 0.000 claims description 5
- XNDZQQSKSQTQQD-UHFFFAOYSA-N 3-methylcyclohex-2-en-1-ol Chemical compound CC1=CC(O)CCC1 XNDZQQSKSQTQQD-UHFFFAOYSA-N 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 125000004104 aryloxy group Chemical group 0.000 claims description 5
- HKVFISRIUUGTIB-UHFFFAOYSA-O azanium;cerium;nitrate Chemical compound [NH4+].[Ce].[O-][N+]([O-])=O HKVFISRIUUGTIB-UHFFFAOYSA-O 0.000 claims description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 229960005235 piperonyl butoxide Drugs 0.000 claims description 5
- 125000004591 piperonyl group Chemical group C(C1=CC=2OCOC2C=C1)* 0.000 claims description 5
- DNXHEGUUPJUMQT-UHFFFAOYSA-N (+)-estrone Natural products OC1=CC=C2C3CCC(C)(C(CC4)=O)C4C3CCC2=C1 DNXHEGUUPJUMQT-UHFFFAOYSA-N 0.000 claims description 4
- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 claims description 4
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 4
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 claims description 4
- NYCXYKOXLNBYID-UHFFFAOYSA-N 5,7-Dihydroxychromone Natural products O1C=CC(=O)C=2C1=CC(O)=CC=2O NYCXYKOXLNBYID-UHFFFAOYSA-N 0.000 claims description 4
- DNXHEGUUPJUMQT-CBZIJGRNSA-N Estrone Chemical compound OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 DNXHEGUUPJUMQT-CBZIJGRNSA-N 0.000 claims description 4
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 claims description 4
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims description 4
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 claims description 4
- BLXXJMDCKKHMKV-UHFFFAOYSA-N Nabumetone Chemical compound C1=C(CCC(C)=O)C=CC2=CC(OC)=CC=C21 BLXXJMDCKKHMKV-UHFFFAOYSA-N 0.000 claims description 4
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 claims description 4
- 239000005927 Pyriproxyfen Substances 0.000 claims description 4
- LZCDAPDGXCYOEH-UHFFFAOYSA-N adapalene Chemical compound C1=C(C(O)=O)C=CC2=CC(C3=CC=C(C(=C3)C34CC5CC(CC(C5)C3)C4)OC)=CC=C21 LZCDAPDGXCYOEH-UHFFFAOYSA-N 0.000 claims description 4
- 229960002916 adapalene Drugs 0.000 claims description 4
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 4
- 229940043370 chrysin Drugs 0.000 claims description 4
- 235000015838 chrysin Nutrition 0.000 claims description 4
- KNHUKKLJHYUCFP-UHFFFAOYSA-N clofibrate Chemical compound CCOC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 KNHUKKLJHYUCFP-UHFFFAOYSA-N 0.000 claims description 4
- 229960001214 clofibrate Drugs 0.000 claims description 4
- 229960001259 diclofenac Drugs 0.000 claims description 4
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 claims description 4
- 229960005309 estradiol Drugs 0.000 claims description 4
- 229930182833 estradiol Natural products 0.000 claims description 4
- 229960003399 estrone Drugs 0.000 claims description 4
- YMTINGFKWWXKFG-UHFFFAOYSA-N fenofibrate Chemical compound C1=CC(OC(C)(C)C(=O)OC(C)C)=CC=C1C(=O)C1=CC=C(Cl)C=C1 YMTINGFKWWXKFG-UHFFFAOYSA-N 0.000 claims description 4
- 229960002297 fenofibrate Drugs 0.000 claims description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 4
- 229960001680 ibuprofen Drugs 0.000 claims description 4
- 229960000905 indomethacin Drugs 0.000 claims description 4
- JMZOMFYRADAWOG-UHFFFAOYSA-N methyl 7-methoxy-4-(7-methoxy-5-methoxycarbonyl-1,3-benzodioxol-4-yl)-1,3-benzodioxole-5-carboxylate Chemical compound COC(=O)C1=CC(OC)=C2OCOC2=C1C1=C2OCOC2=C(OC)C=C1C(=O)OC JMZOMFYRADAWOG-UHFFFAOYSA-N 0.000 claims description 4
- 229960004270 nabumetone Drugs 0.000 claims description 4
- 229960002009 naproxen Drugs 0.000 claims description 4
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 claims description 4
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 claims description 4
- 235000013824 polyphenols Nutrition 0.000 claims description 4
- NHDHVHZZCFYRSB-UHFFFAOYSA-N pyriproxyfen Chemical compound C=1C=CC=NC=1OC(C)COC(C=C1)=CC=C1OC1=CC=CC=C1 NHDHVHZZCFYRSB-UHFFFAOYSA-N 0.000 claims description 4
- RZJQGNCSTQAWON-UHFFFAOYSA-N rofecoxib Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=C(C=2C=CC=CC=2)C(=O)OC1 RZJQGNCSTQAWON-UHFFFAOYSA-N 0.000 claims description 4
- 229960000371 rofecoxib Drugs 0.000 claims description 4
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 claims description 4
- ZDZHCHYQNPQSGG-UHFFFAOYSA-N binaphthyl group Chemical group C1(=CC=CC2=CC=CC=C12)C1=CC=CC2=CC=CC=C12 ZDZHCHYQNPQSGG-UHFFFAOYSA-N 0.000 claims description 3
- 235000010290 biphenyl Nutrition 0.000 claims description 3
- 239000004305 biphenyl Substances 0.000 claims description 3
- RMBPEFMHABBEKP-UHFFFAOYSA-N fluorene Chemical compound C1=CC=C2C3=C[CH]C=CC3=CC2=C1 RMBPEFMHABBEKP-UHFFFAOYSA-N 0.000 claims description 3
- 125000001041 indolyl group Chemical group 0.000 claims description 3
- 150000002823 nitrates Chemical class 0.000 claims description 3
- NIHNNTQXNPWCJQ-UHFFFAOYSA-N o-biphenylenemethane Natural products C1=CC=C2CC3=CC=CC=C3C2=C1 NIHNNTQXNPWCJQ-UHFFFAOYSA-N 0.000 claims description 3
- 229960005489 paracetamol Drugs 0.000 claims description 2
- 239000000463 material Substances 0.000 claims 1
- 239000012046 mixed solvent Substances 0.000 claims 1
- 239000003960 organic solvent Substances 0.000 claims 1
- 239000003054 catalyst Substances 0.000 abstract description 11
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- 238000003786 synthesis reaction Methods 0.000 abstract description 7
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- 230000002194 synthesizing effect Effects 0.000 abstract description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 288
- 239000000758 substrate Substances 0.000 description 100
- 239000000047 product Substances 0.000 description 90
- 229910002554 Fe(NO3)3·9H2O Inorganic materials 0.000 description 87
- 239000011521 glass Substances 0.000 description 87
- 238000005160 1H NMR spectroscopy Methods 0.000 description 86
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 85
- 239000000203 mixture Substances 0.000 description 85
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- 238000003818 flash chromatography Methods 0.000 description 80
- 239000007787 solid Substances 0.000 description 58
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 56
- 239000007788 liquid Substances 0.000 description 21
- 238000002360 preparation method Methods 0.000 description 19
- 239000003795 chemical substances by application Substances 0.000 description 14
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 12
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 10
- 229910017604 nitric acid Inorganic materials 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
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- 125000006527 (C1-C5) alkyl group Chemical group 0.000 description 7
- 238000004293 19F NMR spectroscopy Methods 0.000 description 7
- 229930195733 hydrocarbon Natural products 0.000 description 6
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 239000004215 Carbon black (E152) Substances 0.000 description 5
- RXPAJWPEYBDXOG-UHFFFAOYSA-N hydron;methyl 4-methoxypyridine-2-carboxylate;chloride Chemical compound Cl.COC(=O)C1=CC(OC)=CC=N1 RXPAJWPEYBDXOG-UHFFFAOYSA-N 0.000 description 5
- 230000000802 nitrating effect Effects 0.000 description 5
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- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 description 2
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- 229940117389 dichlorobenzene Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000003912 environmental pollution Methods 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- SNHMUERNLJLMHN-UHFFFAOYSA-N iodobenzene Chemical compound IC1=CC=CC=C1 SNHMUERNLJLMHN-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 229910001960 metal nitrate Inorganic materials 0.000 description 2
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 description 2
- 150000002790 naphthalenes Chemical class 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
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- 150000002987 phenanthrenes Chemical class 0.000 description 2
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- 235000010333 potassium nitrate Nutrition 0.000 description 2
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- 238000005286 illumination Methods 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 239000002608 ionic liquid Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 1
- 150000002826 nitrites Chemical class 0.000 description 1
- ODUCDPQEXGNKDN-UHFFFAOYSA-N nitroxyl Chemical compound O=N ODUCDPQEXGNKDN-UHFFFAOYSA-N 0.000 description 1
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- 239000000575 pesticide Substances 0.000 description 1
- 230000001699 photocatalysis Effects 0.000 description 1
- 230000009145 protein modification Effects 0.000 description 1
- INCIMLINXXICKS-UHFFFAOYSA-M pyronin Y Chemical compound [Cl-].C1=CC(=[N+](C)C)C=C2OC3=CC(N(C)C)=CC=C3C=C21 INCIMLINXXICKS-UHFFFAOYSA-M 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
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- 238000007086 side reaction Methods 0.000 description 1
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- 229910002027 silica gel Inorganic materials 0.000 description 1
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- 238000001577 simple distillation Methods 0.000 description 1
- XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- SHRKDVQQQPFSIY-UHFFFAOYSA-M tetrabutylazanium;nitrite Chemical compound [O-]N=O.CCCC[N+](CCCC)(CCCC)CCCC SHRKDVQQQPFSIY-UHFFFAOYSA-M 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B43/00—Formation or introduction of functional groups containing nitrogen
- C07B43/02—Formation or introduction of functional groups containing nitrogen of nitro or nitroso groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/08—Preparation of nitro compounds by substitution of hydrogen atoms by nitro groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/61—Halogen atoms or nitro radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/70—Nitro radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/42—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms with nitro or nitroso radicals directly attached to ring carbon atoms
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Abstract
The application belongs to the technical field of organic synthesis, and particularly discloses a nitration method of an aromatic compound. The method takes unactivated aromatic compounds as raw materials, hexafluoroisopropanol which is easy to recycle as a solvent, nitrate as a nitrifying reagent, and the nitrified aromatic compounds are obtained under relatively simple and mild conditions, and particularly, the method can be applied to synthesis of the dinitrated aromatic compounds and post-nitrifying modification of various drug molecules. The method avoids the use of corrosive acid and an additional catalyst, realizes the green nitration of the unactivated aromatic compounds by directly taking the nitrate which is cheap and easy to obtain as a nitration reagent, has important application prospect in the field of synthesizing the aromatic nitro compounds, and provides a new method for large-scale industrialized production of nitroaromatics.
Description
Technical Field
The application belongs to the technical field of organic synthesis, and particularly relates to a nitration method of an aromatic compound.
Background
The nitration reaction of aromatic compounds is an important organic reaction, and has wide application value in the fields of medicines, pesticides, dyes, fragrances, explosives and the like. The traditional nitration reaction method is a mixed acid method, namely, the nitration reaction is carried out by taking concentrated nitric acid as a nitration reagent under the catalysis of concentrated sulfuric acid. The traditional synthesis method has mature process and low cost, but also has the problems of more side reactions, low selectivity, high requirements on reaction equipment, serious environmental pollution and the like. Therefore, development of a new efficient "green" nitration reaction for exploring aromatic compounds is of great research importance.
More novel nitration processes have been developed in recent years (CHEMISTRYSELECT 2021,6,1337-1356). (1) Transition metal catalysis nitroaromatics were synthesized by cross-coupling of aryl halides and sodium nitrite catalyzed by transition metal Pd as reported in the s.l. buchwald task group (j.am. Chem. Soc.2009,131, 12898-12899), pyronine task group uses tert-butylnitroso (TBN) as the nitrating reagent and uses Pd to catalyze the activation of hydrocarbon bonds of aromatics to effect nitration of aromatics (ACS catalyst.2015, 1956-1963). The Jianping task group reports the use of transition metal Cu catalysis to effect nitration of special heterocyclic aromatic hydrocarbons with N-directing groups (org. Chem. Front.2021,8, 5821-5830). Transition metal catalysis generally involves the use of expensive transition metals or is limited to aromatic hydrocarbons having directing groups. (2) The nitrification of indazole rings can be achieved by using nitrate as the nitrifying reagent, and more than equivalent amount of oxidant or ionic liquid acid as the co-catalyst (ChemSusChem 2021,14,5340-5358, CHEMISTRYSELECT 2021,6,1337-1356) such as ferric nitrate nonahydrate as the nitrifying reagent, TEMPO as the co-oxidant (org. Biomol. Chem.,2018,16,5113-5118). (3) The nitrate is used as the nitrifying agent, and no co-catalyst is added, so that the nitrifying of special substrates such as highly activated aromatic hydrocarbon can be realized (J.org.chem.2023, 88, 4649-4661), for example, patent CN1854114A discloses that the nitrate is used as the nitrifying agent, but the method of the patent is limited to aromatic hydrocarbon rich in electrons such as phenol, benzenediol, substituted phenol and naphthol. (4) Novel organic nitration reagents (Nat. Commun.2019,10,3410, JACS Au.2022,2, 2152-2161) generally require additional steps to synthesize the organic nitration reagent and additional catalyst, increase the cost of the reaction system, and are therefore not well suited for large-scale production. (5) Electrochemical methods, such as using tetrabutylammonium nitrite as the nitrating reagent, achieve the nitration of electron rich aromatic hydrocarbons under electrochemical conditions (ChemSusChem, 2021,14,4936-4940). (6) Photocatalytic nitration, and nitration modification of proteins is achieved under illumination (Angew.chem.int.ed., 2021,60,13414-13422). (7) Biochemical nitration (chem. Rev,2018,118,1338-1408). (8) Nitration by fluid chemistry (Beilstein J.org.chem., 2014,10,405-424).
The method has the advantages of high catalyst cost, poor substrate universality, strong pollution or corrosiveness, or the need of an additional step for synthesizing a nitrifying reagent, and the like, and is still very important industrial application value in developing and exploring a novel green and economic nitrifying synthetic method on the basis of the existing nitrifying system.
Disclosure of Invention
Aiming at the defects of the prior art, the application aims to provide a nitrifying method of an aromatic compound, which aims to solve the problems of high substrate limitation, harsh reaction conditions, low atomic economy, large environmental pollution and the like in the nitrifying method of the aromatic compound in the prior art.
In order to achieve the above purpose, the present application provides a nitration method of an aromatic compound, wherein an aromatic compound is used as a raw material, nitrate is used as a nitration reagent, and after nitration reaction is performed in a solvent system containing hexafluoroisopropanol, the aromatic nitro compound is obtained by purification and separation; the aromatic compound is a C6-C60 substituted or unsubstituted aromatic ring or a C6-C60 substituted or unsubstituted heterocyclic aromatic ring.
Preferably, the substituted aromatic ring and the substituted heterocyclic aromatic ring are each mono-or poly-substituted, and the substituents thereof are each independently selected from the group consisting of hydrogen, halogen, trifluoromethyl, trifluoromethoxy, nitro, cyano, phenolic hydroxyl, aldehyde, carbonyl, carboxyl, sulfonic acid, amino, acetamido, C1-C10 alkyl, C1-C10 alkoxy, C6-C30 aryloxy, C1-C10 carbonyl-containing alkyl chain, C6-C30 arylcarbonyl, C1-C10 ester, C6-C30 aryl, and C6-C30 heterocyclic aryl.
Further preferably, the aromatic ring is selected from benzene, biphenyl, fluorene, naphthalene, anthracene, phenanthrene, pyrene, piperonyl (1, 2-methylenedioxybenzene) and binaphthyl skeleton; the heterocyclic aromatic ring is selected from furan, thiophene, pyridine and indole.
Preferably, the substituted heterocyclic aromatic ring is selected from furan, thiophene, pyridine and indole bearing an electron withdrawing group, wherein the electron withdrawing group is further preferably halogen, ester, carbonyl, aldehyde, carboxyl, sulfonic acid, trifluoromethyl, trifluoromethoxy, nitro.
Preferably, the aromatic compound is a drug molecule with an aromatic ring, an amino acid with an aromatic ring, or a glycoside with an aromatic ring, wherein the drug molecule with an aromatic ring is selected from ibuprofen, adapalene, naproxen, nabumetone, estrone, estradiol, acetaminophen, chrysin, diclofenac, pyriproxyfen, clofibrate, fenofibrate, bifendate, indomethacin, arbutin, and rofecoxib;
The amino acid with an aromatic ring is selected from tyrosine and phenylalanine.
The glycoside with an aromatic ring is selected from arbutin and lactoside.
Preferably, the nitrate salt is one or more of ferric nitrate, bismuth nitrate pentahydrate, ferric nitrate nonahydrate, gallium nitrate hydrate, aluminum nitrate nonahydrate, and ammonium cerium nitrate.
Further preferably, the nitrate is bismuth nitrate pentahydrate, ferric nitrate nonahydrate, gallium nitrate hydrate.
In general, compared with the prior art, the above technical solution conceived by the present application mainly has the following technical advantages:
(1) The application provides a novel green and economic preparation method for nitrifying an aromatic compound, which can realize direct nitrifying of nitrate such as ferric nitrate, bismuth nitrate and the like serving as nitrifying agents on unactivated aromatic compounds in hexafluoroisopropanol solvent and in later nitrifying modification of various drug molecules. Simple aromatic hydrocarbon is used as a raw material, hexafluoroisopropanol is used as a solvent, nitrate which is cheap and easy to obtain is used as a nitrifying reagent, the reaction solvent is removed after full reaction under simple and mild conditions, and the nitrified aromatic compound is obtained through purification and separation. The preparation method has the advantages of high reaction efficiency, mild reaction conditions, low-cost and easily available raw materials, simple and safe operation, wide universality of substrates, easy separation of products, higher economy of atoms and steps of the reaction and the like.
(2) Compared with a nitration system which takes sulfuric acid as a catalyst and nitric acid as a nitration reagent in the traditional method, the nitration reagent provided by the application has the advantages of no strong acid system, no need of additional catalyst, mild reaction condition, high reaction speed, simple and safe reaction operation. In addition, the inorganic salts are low in price, easy to obtain, stable in chemical property and easy to store. Nitrate such as ferric nitrate and bismuth nitrate is used as a nitrifying agent, and can be recycled as the nitrifying agent after the nitrifying reaction is finished by simply treating the nitrate with nitric acid, so that no waste is generated, and the only byproduct is water, thus the method is a green reaction system.
(3) The nitration reaction of the aromatic compound provided by the application utilizes the characteristic that the solvent hexafluoroisopropanol enhances the inherent nitration capability of the metal nitrate, and provides C-H nitration which is easy to operate and is universally applicable. After the reaction is finished, the solvent hexafluoroisopropanol can be recovered by simple distillation, and the recovered solvent can be repeatedly used for the nitration reaction of the aromatic compound.
(4) The aromatic compound in the nitration preparation method of the aromatic compound provided by the application has wide universality, can be benzene, toluene, piperonyl (1, 2-methylenedioxybenzene), polysubstituted alkylbenzene, polysubstituted alkoxybenzene, phenol, substituted phenol, naphthalene, substituted naphthalene, anthracene, substituted anthracene, phenanthrene, substituted phenanthrene, pyrene, substituted pyrene and other electron-rich aromatic compounds, and can also be chlorobenzene, bromobenzene, fluorobenzene, iodobenzene, dichlorobenzene, dibromobenzene, difluorobenzene, diiodobenzene, benzotrifluoride, nitrobenzene, p-toluenesulfonic acid, piperonic acid, benzene with an electron-withdrawing substituent, phenol with a strong electron-withdrawing substituent, naphthalene with an electron-withdrawing substituent, anthracene with an electron-withdrawing substituent, phenanthrene with an electron-withdrawing substituent, pyrene and other electron-poor aromatic compounds with an electron-withdrawing substituent. The aromatic compound may be a heterocyclic aromatic hydrocarbon having a electron withdrawing substituent such as 2-acetylfuran, 5-bromoindole or the like.
(5) The nitration preparation method of the aromatic compound provided by the application has wide application, and can be applied to nitration modification of various drug molecules, such as nitration of aromatic rings in any one of the drug molecules, such as ibuprofen, adapalene, naproxen, nabumetone, estrone, estradiol, paracetamol (acetaminophen), chrysin, diclofenac, pyriproxyfen, clofibrate, fenofibrate, bifendate, indomethacin, arbutin, rofecoxib and the like. The method can also be applied to the nitration of amino acid molecules, such as the nitration of aromatic rings in any one of amino acid molecules such as tyrosine, phenylalanine, tyrosine derivatives, phenylalanine derivatives and the like. The preparation method of the nitrification can also be used for nitrifying glycoside molecule derivatives, such as the nitrifying of aromatic rings in any one of arbutin and lactose glycoside derivative molecules.
(6) The nitrifying preparation method of the aromatic compound can prepare the dinitrated aromatic compound, and when the substituent on the aromatic ring of the aromatic compound is an electron donating group such as hydroxyl or alkoxy, the dinitrated aromatic hydrocarbon can be obtained by controlling the reaction time and the equivalent of the nitrifying reagent.
(7) The nitrifying preparation method of the aromatic compound can be used for preparing the aromatic compound by reaction from a large scale to more than gram scale, the solvent hexafluoroisopropanol of the reaction system can be recovered by a distillation method during large-scale production, the nitrate can be recycled as a nitrifying agent after the reaction is finished by simply treating the nitrate with dilute nitric acid, no waste is generated, and the only byproduct is water. Has important application prospect in the field of synthesizing aromatic nitro compounds, and also provides a new idea for large-scale industrialized production of nitroaromatic hydrocarbon.
(8) According to the preparation method of the nitrifying of the aromatic compound, most aromatic compounds and drug molecules can be completely reacted under mild conditions through screening of the nitrifying reagent and the reaction conditions, and the yield of synthesizing the nitrified aromatic compound in the preferred embodiment is over 90%, so that the synthesis efficiency is high.
Detailed Description
The present application will be described in further detail with reference to the following examples in order to make the objects, technical solutions and advantages of the present application more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the application.
The application provides a novel green and economic nitration method of aromatic compounds, which can also be applied to the later nitration modification of various drug molecules. The method comprises the steps of taking unactivated aromatic compounds as raw materials, taking nitrate as a nitrifying reagent, performing nitration reaction in a solvent system containing hexafluoroisopropanol, removing the solvent, purifying and separating to obtain mononitrated or polynitroated aromatic nitro compounds (aromatic compounds with nitro groups on aromatic rings), and then realizing C-H nitration on aromatic rings of the aromatic compounds.
The aromatic compound of the present application may be a substituted or unsubstituted aromatic ring of C6-C60 or a substituted or unsubstituted heterocyclic aromatic ring of C4-C60. Preferably, it is a C6-C50 substituted or unsubstituted aromatic ring, a C4-C50 substituted or unsubstituted heterocyclic aromatic ring; more preferred are a C6-C30 substituted or unsubstituted aromatic ring and a C4-C30 substituted or unsubstituted heterocyclic aromatic ring.
In some embodiments, the substituted aromatic ring and the substituted heterocyclic aromatic ring are each mono-or poly-substituted, and the substituents are each independently selected from the group consisting of hydrogen, halogen, trifluoromethyl, trifluoromethoxy, nitro, cyano, phenolic hydroxyl, aldehyde, carbonyl, carboxyl, sulfonic acid, amino, acetamido, C1-C10 alkyl, C1-C10 alkoxy, C6-C30 aryloxy, C1-C10 carbonyl-containing alkyl chain, C6-C30 arylcarbonyl, C1-C10 ester, C6-C30 aryl, and C4-C30 heterocyclic aryl.
In some embodiments, the aromatic ring is selected from benzene, biphenyl, fluorene, naphthalene, anthracene, phenanthrene, pyrene, piperonyl (1, 2-methylenedioxybenzene), and binaphthyl backbones; the heterocyclic aromatic ring is selected from furan, thiophene, pyridine and indole.
In some embodiments of the present application, the aromatic compound is an aromatic hydrocarbon of formula one, and the nitration reaction is as follows:
R is one or more substituents, each independently selected from the group consisting of hydrogen, halogen, trifluoromethyl, trifluoromethoxy, nitro, cyano, phenolic hydroxyl, aldehyde, carboxyl, carbonyl, sulfonic acid, amino, acetamido, C1-C10 alkyl (more preferably C1-C5 alkyl), C1-C10 alkoxy (more preferably C1-C5 alkoxy), C6-C30 aryloxy (more preferably C6-C18 aryloxy), C1-C10 carbonyl-containing alkyl chain (more preferably C1-C5 carbonyl-containing alkyl chain), C6-C30 arylcarbonyl (more preferably C6-C18 alkylaryl carbonyl), C1-C10 ester (more preferably C1-C5 ester), and C6-C30 aryl (more preferably C6-C18 aryl).
In some preferred embodiments, the aromatic compound is selected from electron rich aromatic compounds such as benzene, toluene, piperonyl (1, 2-methylenedioxybenzene), poly-substituted benzene with C1-C5 alkyl, poly-substituted benzene with C1-C5 alkoxy, phenol, poly-substituted phenol with C1-C5 alkyl, naphthalene, poly-substituted naphthalene with C1-C5 alkyl, anthracene, substituted anthracene with C1-C5 alkyl, phenanthrene, substituted phenanthrene with C1-C5 alkyl, pyrene, substituted pyrene with C1-C5 alkyl, and the like, and can also be chlorobenzene, bromobenzene, fluorobenzene, iodobenzene, dichlorobenzene, dibromobenzene, benzotrifluoride, nitrobenzene, p-toluenesulfonic acid, piperonic acid, benzene with a rad electron substituent, phenol with a rad electron substituent, naphthalene with a rad electron substituent, anthracene with a rad electron substituent, phenanthrene with a rad electron substituent, and the like. Wherein the electron withdrawing group is selected from halogen, trifluoromethyl, trifluoromethoxy, nitro, cyano, aldehyde, carboxyl, sulfonic acid, etc.
In other embodiments, the aromatic compound is a substituted or unsubstituted heterocyclic aromatic ring. Wherein the substituted heterocyclic aromatic ring is selected from the group consisting of furan, thiophene, pyridine and indole bearing an electron withdrawing group, wherein the electron withdrawing group includes, but is not limited to, halogen, ester, carbonyl, aldehyde, carboxyl, sulfonate, trifluoromethyl, trifluoromethoxy, nitro. For example, in some embodiments, the heterocyclic aromatic hydrocarbon is 2-acetylfuran, 5-bromoindole, or the like.
Some examples demonstrate that the nitration of the target position-aromatic ring can also be achieved by the nitration process of the present application as a substrate for aromatic compounds containing complex functional groups, such as complex drug molecules with aromatic rings, amino acids and derivatives thereof, glycosides and derivatives thereof, and the like, embodying the versatility of the nitration process of the present application. The drug molecules with aromatic rings include, but are not limited to, ibuprofen, adapalene, naproxen, nabumetone, estrone, estradiol, paracetamol (acetaminophen), chrysin, diclofenac, pyriproxyfen, clofibrate, fenofibrate, bifendate, indomethacin, arbutin, and rofecoxib. The amino acids with aromatic rings include, but are not limited to, tyrosine, phenylalanine, tyrosine derivatives, phenylalanine derivatives. The glycoside molecule derivatives with aromatic rings include, but are not limited to, arbutin and lactose glycoside derivative molecules.
In some embodiments, when the substituent on the aromatic compound is an electron donating group such as a hydroxyl group or an alkoxy group, the dinitrated aromatic hydrocarbon can be obtained by controlling the reaction time and the equivalent weight of the nitrating agent. In particular, when the reactivity of the aromatic compound substrate is high, other solvents such as DCE (dichloroethane), DCM (dichloromethane) and the like may be introduced into the reaction system in addition to the HFIP solvent to reduce the reactivity of the aromatic compound substrate to obtain a mononitro compound, and the volume ratio of HFIP to other solvents is 1: (1-20) recovering a nitrifying system which is reusable for aromatic compounds by distillation of the solvent in the system. For aromatic compounds having high reactivity, the use of HFIP as a single solvent tends to produce polynitro compounds.
In some embodiments, the nitrate is one or more of ferric nitrate, bismuth nitrate pentahydrate, ferric nitrate nonahydrate, gallium nitrate hydrate, aluminum nitrate nonahydrate, and ammonium cerium nitrate, and the nitrate in the system is reusable by dilute nitric acid treatment after the reaction is completed. In a preferred embodiment, the nitrate is bismuth nitrate pentahydrate, ferric nitrate nonahydrate, gallium nitrate hydrate.
In some embodiments, the molar ratio of aromatic compound to nitrate is 1: (0.33-1). The concentration of the aromatic compound in the reaction system is 0.25-0.5M. The reaction temperature is 0-120 ℃, preferably 25-60 ℃, and the reaction time is 1-36h, preferably 1-24h. The reaction temperature and reaction time may be adjusted according to the kind of the substrate.
The nitration reaction is a liquid phase system, the reaction operation is simple, and the method comprises the following steps: adding a nitrifying reagent and an aromatic compound according to a corresponding molar ratio (0.33-1:1), adding hexafluoroisopropanol (0.25-0.5M) serving as a solvent into a tube reactor, stirring at the temperature of 0-120 ℃ for reaction for 1-36 hours, removing the solvent through rotary evaporation after the reaction, and separating to obtain a nitrified product of the aromatic compound.
The nitration reaction of the aromatic compound can realize production with the gram-scale or above, the solvent hexafluoroisopropanol of the reaction system can be recovered by a distillation method, the nitrate used can be recycled as a nitrating agent after the reaction is finished by simply treating the nitrate with nitric acid, no waste is generated, and the only byproduct is water.
Metal nitrates or nitrites are easier to handle and have higher functional group tolerance than nitric acid, often as a source of nitro groups in the C (sp 2) -H nitration reaction with a suitable catalyst. However, in the nitration reaction of the unactivated aromatic compounds, the application directly adopts metal salts such as ferric nitrate, bismuth nitrate and the like as the nitration reagent without additional additives and catalysts, and unexpectedly achieves the purpose of green nitration synthesis.
In the traditional method, sulfuric acid is used as a catalyst, nitric acid is used as a nitration system of a nitration reagent, nitric acid is dehydrated to generate nitroxyl positive ions by utilizing the acidity of concentrated sulfuric acid, and electrophilic substitution reaction is carried out; the present application provides a nitrifying agent which uses a nitrate containing ferric nitrate, bismuth nitrate, gallium nitrate, etc. which is inexpensive and contains crystal water as a nitrifying reaction of an aromatic compound, and the nitrifying ability of the nitrate is enhanced mainly by utilizing strong hydrogen bonding action of hexafluoroisopropanol as a solvent. Compared with the traditional concentrated acid reaction system, the nitration reaction system has the advantages of no use of a strong acid system, no use of an additional catalyst, mild reaction condition, high reaction speed, simple and safe reaction operation, wide universality of substrates, water as the only byproduct and environment friendliness.
The application provides a novel green and economic preparation method of aromatic hydrocarbon nitration, which can realize direct nitration of nitrate such as ferric nitrate, bismuth nitrate and the like serving as nitration reagents on unactivated aromatic compounds in hexafluoroisopropanol solvent and in later nitration modification of various drug molecules. The preparation method has the advantages of high reaction efficiency, mild reaction conditions, low-cost and easily available raw materials, simple and safe operation, wide universality of substrates, easy separation of products, high economy of atoms and steps of the reaction and the like. The method avoids the use of corrosive acid and an additional catalyst, realizes the green nitration of unactivated aromatic compounds by directly taking nitrate which is cheap and easy to obtain as a nitration reagent, has important application prospect in the field of nitroarene synthesis, and provides a new method for large-scale industrialized production of nitroarene. In some embodiments, the specific experiment includes the steps of: in a 10ml reaction tube, a magnetic stirrer is added, aromatic compound, nitrate of nitrifying reagent and hexafluoroisopropanol as solvent are added according to corresponding proportion, and a plug seals the tube orifice. The reaction mixture is stirred at 0-120 ℃. The progress of the reaction was monitored by Thin Layer Chromatography (TLC), and when no starting material remained in the system, the reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The crude mixture was then purified by flash column chromatography to provide the nitrated product. The eluent used in the column chromatography separation and purification step is a mixture of petroleum ether and ethyl acetate or dichloromethane and methanol, the volume ratio of petroleum ether to ethyl acetate is 20:1 to 1:1, and the volume ratio of dichloromethane to methanol is 20:1 to 1:4.
The following are examples:
Example 1
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, substrate 1a (79 mg,0.5mmol,1.0 eq), HFIP (1.0 mL), and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq) with a plug closing the orifice, and reacted at 100℃for 12 hours, the reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure, and the crude mixture was purified by flash column chromatography to afford nitrified product 2a (white solid, 95mg, yield 94％).1H NMR(600MHz,CDCl3)δ8.13-8.07(m,2.2H),7.84(dd,J＝1.9,7.8Hz,1H),7.74(dd,J＝1.7,7.7Hz,1H),7.71-7.66(m,2.2H),7.49-7.40(m,2H).13C NMR(101MHz,CDCl3)δ146.40,135.21,133.32,132.76,130.11,128.38,125.72,125.13,114.59.
Examples 2 to 12
Examples 2 to 12 are similar to example 1, and the preparation method of aromatic hydrocarbon nitration is different only in that nitrate as the nitration reagent and the reaction temperature are adopted, and the obtained products have different nuclear magnetic yield, and specific conditions and reaction yields are shown in the following table 1:
TABLE 1 screening of nitration reagents
| Examples | Nitrifying reagent | Equivalent of nitrifying reagent | Solvent(s) | Time (h) | Temperature (. Degree. C.) | Yield (%) |
| 2 | Ferric nitrate nonahydrate | 1.0 | HFIP | 12 | 100 | 99 |
| 3 | Bismuth nitrate pentahydrate | 1.0 | HFIP | 12 | 100 | 93 |
| 4 | Hydrated gallium nitrate | 1.0 | HFIP | 12 | 100 | 82 |
| 5 | Aluminum nitrate nonahydrate | 1.0 | HFIP | 12 | 100 | 33 |
| 6 | Copper nitrate trihydrate | 1.5 | HFIP | 12 | 100 | 39 |
| 7 | Ammonium cerium nitrate | 0.5 | HFIP | 12 | 100 | 22 |
| 8 | Silver nitrate | 3.0 | HFIP | 12 | 100 | trace |
| 9 | Sodium nitrate | 3.0 | HFIP | 12 | 100 | trace |
| 10 | Potassium nitrate | 3.0 | HFIP | 12 | 100 | trace |
| 11 | Sodium nitrite | 3.0 | HFIP | 12 | 100 | trace |
| 12 | Tert-butyl nitrous acid | 3.0 | HFIP | 12 | 100 | trace |
As can be seen from comparison with example 1, the same nitrate was used as the nitrifying agent, and the different nitrates gave a larger difference in the yield of nitroaromatics in the solvent Hexafluoroisopropanol (HFIP). Nitrate such as ferric nitrate nonahydrate, bismuth nitrate pentahydrate, gallium nitrate hydrate and the like is adopted as a nitrifying reagent, a better yield is achieved in a hexafluoroisopropanol solvent, nitrate such as aluminum nitrate nonahydrate, copper nitrate trihydrate, ammonium cerium nitrate and the like is adopted as a nitrifying reagent, a moderate yield is achieved in the hexafluoroisopropanol solvent, and nitrate such as silver nitrate, sodium nitrate, potassium nitrate, sodium nitrite, tert-butyl nitrous acid and the like is adopted as the nitrifying reagent, so that few nitrified products are obtained in the hexafluoroisopropanol solvent.
As can be seen from examples 2 to 4, a good yield can be obtained by using nitrate such as ferric nitrate nonahydrate, bismuth nitrate pentahydrate, gallium nitrate hydrate and the like as the nitrifying agent, and ferric nitrate nonahydrate is selected as the nitrifying agent in the following examples.
Examples 13 to 19
Examples 13 to 19 are similar to example 1, and the preparation method of aromatic hydrocarbon nitration is different only in the equivalent amount of the nitrating agent used, the reaction time and the reaction temperature, and the yields of the obtained products are different, and specific conditions and reaction yields are shown in the following table 2:
TABLE 2 screening of nitration reagent equivalents
| Examples | Nitrifying reagent | Equivalent of nitrifying reagent | Solvent(s) | Time (h) | Temperature (. Degree. C.) | Yield (%) |
| 13 | Ferric nitrate nonahydrate | 1.0 | HFIP | 12 | 60 | 54 |
| 14 | Ferric nitrate nonahydrate | 1.0 | HFIP | 24 | 60 | 77 |
| 15 | Ferric nitrate nonahydrate | 1.0 | HFIP | 36 | 60 | 94 |
| 16 | Ferric nitrate nonahydrate | 1.0 | HFIP | 12 | 80 | 79 |
| 17 | Ferric nitrate nonahydrate | 0.5 | HFIP | 12 | 100 | 79 |
| 18 | Ferric nitrate nonahydrate | 0.5 | HFIP | 24 | 100 | 94 |
| 19 | Ferric nitrate nonahydrate | 0.75 | HFIP | 12 | 100 | 91 |
Examples 20 to 31
Examples 20 to 31 are similar to example 1, and the preparation method of aromatic hydrocarbon nitration is different only in the solvent used, and the yields of the obtained products are different, and specific conditions and reaction yields are shown in the following table 3:
TABLE 3 screening of nitration solvents
As can be seen from comparison with example 1, when ferric nitrate nonahydrate is also used as the nitrifying agent, HFIP is used as the solvent, and the yield is greatly different from other solvents such as methylene chloride, toluene, ethyl acetate, 1, 4-dioxane, DMF, acetonitrile, methanol and the like.
Example 32
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, substrate 1b (56 mg,0.5mmol,1.0 eq), HFIP (1.0 mL), and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq), a plug was closed off the orifice, and reacted at 100℃for 12 hours. The reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure. The crude mixture was then purified by flash column chromatography to afford nitrated product 2b (colorless liquid, 69mg, yield 87％).1H NMR(600MHz,CDCl3)δ8.18(d,J＝8.5Hz,2.4H),7.87(d,J＝8.1Hz,1H),7.63-7.47(m,4.4H),7.42(t,J＝7.7Hz,1H).13C NMR(101MHz,CDCl3)δ146.65,141.51,133.30,132.02,129.71,127.72,127.18,125.70,125.06.
Example 33
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, substrate 1c (49 mg,0.5mmol,1.0 eq), HFIP (1.0 mL), and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq), a plug was closed off the orifice, and reacted at 100℃for 12 hours. The reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure. The crude mixture was then purified by flash column chromatography to afford nitrified product 2c (colorless liquid, 69mg, yield) 94％).1H NMR(600MHz,CDCl3)δ8.33-8.19(m,6.2H),8.10-8.04(m,1H),7.67-7.62(m,1H),7.33-7.28(m,2H),7.24-7.18(m,6.2H).13C NMR(151MHz,CDCl3)δ166.42(d,1JCF＝258.0Hz),135.69(d,3JCF＝8.3Hz),126.47(d,3JCF＝10.0Hz),126.31(d,4JCF＝2.8Hz),124.69(d,4JCF＝4.5Hz),118.60(d,2JCF＝20.7Hz),116.56(d,2JCF＝23.6Hz).19F NMR(565MHz,CDCl3)δ-102.00.
Example 34
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, substrate 1d (102 mg,0.5mmol,1.0 eq), HFIP (1.0 mL), and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq), a plug was closed off the orifice, and reacted at 100℃for 12 hours. The reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure. The crude mixture was then purified by flash column chromatography to afford the nitrated product 2d (white solid, 123mg, yield 99％).1H NMR(600MHz,CDCl3)δ8.03(dd,J＝1.3,7.9Hz,1H),7.95-7.88(m,6.4H),7.84(dd,J＝1.6,8.1Hz,1H),7.51-7.46(m,1H),7.28-7.24(m,1H).13C NMR(151MHz,CDCl3)δ153.1,147.8,141.99,138.76,133.49,129.16,125.52,124.94,102.82,86.31.
Example 35
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, substrate 1e (118 mg,0.5mmol,1.0 eq), HFIP (1.0 mL), and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq) with a plug closing the orifice, and reacted at 100℃for 36 hours, the reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure, the crude mixture was then purified by flash column chromatography to afford nitrated product 2e (white solid, 131mg, yield 93％).1H NMR(600MHz,CDCl3)δ7.95(dd,J＝1.0,1.9Hz,1H),7.79(d,J＝8.6Hz,1H),7.65-7.61(m,1H).13C NMR(151MHz,CDCl3)δ137.73,131.63,127.51,126.91,115.89.
Example 36
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, substrate 1f (73 mg,0.5mmol,1.0 eq), HFIP (1.0 mL), and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq), a plug was closed off the orifice, and reacted at 100℃for 24 hours, the reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure, and the crude mixture was purified by flash column chromatography to give nitrified product 2f (colorless liquid, 77mg, yield) 78％).1H NMR(600MHz,CDCl3)δ7.88(d,J＝8.8Hz,1H),7.58(d,J＝2.2Hz,1H),7.40(dd,J＝2.2,8.7Hz,1H).13C NMR(101MHz,CDCl3)δ139.46,131.92,128.66,128.06,126.89.
Example 37
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, 1g of substrate (57 mg,0.5mmol,1.0 eq), HFIP (1.0 mL) and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq) with a plug closing the orifice, reacted at 100℃for 24 hours, the reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure, and the crude mixture was purified by flash column chromatography to give 2g of nitrated product (colorless liquid, 69mg, yield) 87％).1H NMR(600MHz,CDCl3)δ8.16(td,J＝5.7,9.1Hz,1H),7.07-7.01(m,2H).13C NMR(151MHz,CDCl3)δ165.85(d,1J＝259.7Hz,3J＝11.1Hz),156.93(d,1J＝255.2Hz,3J＝13.2Hz),128.39(d,3J＝8.7Hz,4J＝2.2Hz),112.32(d,2J＝18.8Hz,4J＝4.3Hz),106.68(d,2J＝24.3Hz,4J＝4.2Hz).19F NMR(565MHz,CDCl3)δ-97.64,-110.99.
Example 38
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, substrate 1h (165 mg,0.5mmol,1.0 eq), HFIP (1.0 mL) and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq) with a plug closing the orifice and reacted at 100℃for 24 hours, the reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure, the crude mixture was then purified by flash column chromatography to afford the nitrated product 2h (white solid, 163mg, yield) 87％).1H NMR(600MHz,CDCl3)δ8.41(d,J＝1.8Hz,1H),7.81(dd,J＝1.8,8.5Hz,1H),7.58(d,J＝8.5Hz,1H).13C NMR(151MHz,CDCl3)δ149.74,138.30,126.51,100.39,87.77.
Example 39
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, substrate 1i (40 mg,0.5mmol,1.0 eq), HFIP (1.0 mL), and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq) with a plug closing the orifice, and reacted at 60℃for 12 hours, the reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure, and the crude mixture was purified by flash column chromatography to afford nitrated product 2i (colorless liquid, 60mg, yield 98％).1H NMR(600MHz,CDCl3)δ8.19(d,J＝8.7Hz,2H),7.68(t,J＝7.4Hz,1H),7.52(t,J＝8.0Hz,2H).13C NMR(151MHz,CDCl3)δ148.19,134.66,129.35,123.46.
Example 40
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, substrate 1j (46 mg,0.5mmol,1.0 eq), HFIP (1.0 mL), and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq), a plug was closed off the orifice, and reacted at 60℃for 12 hours, the reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure, and the crude mixture was purified by flash column chromatography to give nitrified product 2j (colorless liquid, 71mg, yield) 99％).1H NMR(600MHz,CDCl3)δ8.09(d,J＝8.7Hz,2H),7.94(d,J＝8.3Hz,1.2H),7.49(t,J＝8.2Hz,1.2H),7.33(d,J＝5.0Hz,2H),7.30(d,J＝8.6Hz,2.4H).13C NMR(151MHz,CDCl3)δ146.07,133.62,133.09,132.84,129.89,126.96,124.69,123.57,21.67,20.47.
Example 41
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, substrate 1k (53 mg,0.5mmol,1.0 eq), HFIP (1.0 mL), and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq), a plug was closed off the orifice, and reacted at 60℃for 12 hours. The reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure. The crude mixture was then purified by flash column chromatography to afford nitrified product 2k (colorless liquid, 59mg, yield) 76％).Colorless liquid.1H NMR(600MHz,CDCl3)δ8.16-8.11(m,2.6H),7.86(dd,J＝1.4,8.1Hz,1H),7.52(td,J＝1.4,7.5Hz,1H),7.36(dd,J＝1.4,7.7Hz,1H),7.34-7.31(m,3.6H),2.91(q,J＝7.5Hz,2H),2.76(q,J＝7.6Hz,2.6H),1.28(td,J＝5.0,7.6Hz,7H).13C NMR(151MHz,CDCl3)δ152.15,139.05,133.05,131.28,128.77,126.90,124.62,123.76,28.98,26.25,15.17,15.03.
Example 42
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, 1l of substrate (67 mg,0.5mmol,1.0 eq), HFIP (1.0 mL) and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq) with a plug closing the orifice and reacted at 60℃for 12 hours, the reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure, the crude mixture was then purified by flash column chromatography to give 2l of nitrated product (colorless liquid, 79mg, yield) 88％).1H NMR(600MHz,CDCl3)δ8.20-8.14(m,7.2H),7.59-7.53(m,8.2H),7.49-7.44(m,1H),7.35-7.29(m,2H),1.43(s,9H),1.39(s,32.4H).13C NMR(151MHz,CDCl3)δ158.99,146.13,130.88,128.73,126.97,126.37,124.00,123.48,35.53,31.18,30.80.
Example 43
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, substrate 1m (54 mg,0.5mmol,1.0 eq), HFIP (1.0 mL), and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq) with a plug closing the orifice, reacted at room temperature (25 ℃ C.) for 18 hours, the reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure, and the crude mixture was purified by flash column chromatography to give the nitrified product 2m (colorless liquid, 64mg, yield) 85％).1H NMR(400MHz,CDCl3)δ7.74(s,1H),7.31-7.23(d,J＝7.8Hz,1H),7.18(d,J＝7.8Hz,1H),2.51(s,3H).13C NMR(101MHz,CDCl3)δ149.10,137.14,133.89,132.60,130.50,124.92,20.69,20.01.
Example 44
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, substrate 1n (60 mg,0.5mmol,1.0 eq), HFIP (1.0 mL), and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq) with a plug closing the orifice, reacted at room temperature (25 ℃ C.) for 18 hours, the reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure, and the crude mixture was purified by flash column chromatography to afford nitrated product 2n (colorless liquid, 79mg, yield) 63％).1H NMR(600MHz,CDCl3)δ6.92(s,2H),2.31(s,3H),2.28(s,6H).13C NMR(151MHz,CDCl3)δ149.92,140.43,129.74,129.57,21.18,17.68.
Example 45
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, substrate 1O (67 mg,0.5mmol,1.0 eq), HFIP (1.0 mL), and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq) with a plug closing the orifice, and reacted at room temperature (25 ℃ C.) for 18 hours the reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure, and the crude mixture was purified by flash column chromatography to afford the nitrated product 2O (white solid, 69mg, yield) 77％).1H NMR(600MHz,CDCl3)δ7.04(s,1H),2.25(s,6H),2.12(s,6H).13C NMR(151MHz,CDCl3)δ153.32,135.44,132.56,124.50,19.74,14.02.
Example 46
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, substrate 1p (74 mg,0.5mmol,1.0 eq), HFIP (1.0 mL), and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq) with a plug closing the orifice, reacted at room temperature (25 ℃ C.) for 18 hours the reaction mixture was removed the solvent under reduced pressure, then the crude mixture was purified by flash column chromatography to afford nitrified product 2p (white solid, 69mg, yield 71％).1H NMR(600MHz,CDCl3)δ2.24(s,3H),2.22(s,6H),2.15(s,6H).13C NMR(151MHz,CDCl3)δ151.79,137.03,134.06,123.71,17.02,16.55,15.09.
Example 47
A reaction tube of 10mL of transparent glass was charged with a magnetic stirrer, substrate 1q (47 mg,0.5mmol,1.0 eq), HFIP/DCE=1:19 (1.0 mL) and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq) with a plug closing the orifice and reacted at room temperature (25 ℃ C.) for 18 hours, the reaction mixture was freed of the solvent under reduced pressure, and the crude mixture was purified by flash column chromatography to give nitrified product 2q (yellow solid, 50mg, yield) 72％).1H NMR(600MHz,CDCl3)δ8.23-8.10(m,2H),6.98-6.86(m,2H),6.30(s,1H).13C NMR(151MHz,CDCl3)δ161.66,141.71,126.42,115.84.
Example 48
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, substrate 1q (47 mg,0.5mmol,1.0 eq), HFIP (1.0 mL), and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq) with a plug closing the orifice, and reacted at room temperature (25 ℃ C.) for 18 hours the reaction mixture was removed of the solvent under reduced pressure, and the crude mixture was purified by flash column chromatography to give nitrified product 2q' (white solid, 78mg, yield 85％).1H NMR(600MHz,CDCl3)δ11.02(s,1H),9.07(d,J＝2.8Hz,1H),8.46(dd,J＝2.7,9.3Hz,1H),7.34(d,J＝9.2Hz,1H).13C NMR(151MHz,CDCl3)δ159.19,131.78,122.03,121.39.
Example 49
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, substrate 2q (70 mg,0.5mmol,1.0 eq), HFIP (1.0 mL), and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq) with a plug closing the orifice, and reacted at room temperature (25 ℃ C.) for 12 hours the reaction mixture was freed of solvent under reduced pressure, and the crude mixture was purified by flash column chromatography to give nitrified product 2q' (white solid, 91mg, yield 99％).1H NMR(600MHz,CDCl3)δ11.02(s,1H),9.07(d,J＝2.8Hz,1H),8.46(dd,J＝2.7,9.3Hz,1H),7.34(d,J＝9.2Hz,1H).13C NMR(151MHz,CDCl3)δ159.19,131.78,122.03,121.39.
Example 50
A reaction tube of 10mL of transparent glass was charged with a magnetic stirrer, substrate 1r (54 mg,0.5mmol,1.0 eq), HFIP/DCE=1:19 (1.0 mL), and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq), a plug was closed off the orifice, and the reaction was allowed to react at room temperature (25 ℃ C.) for 3 hours 86％).1H NMR(600MHz,CDCl3)δ10.42(s,1H),7.87(s,1H),7.38(d,J＝7.7Hz,1H),7.04(d,J＝8.6Hz,1H),2.33(s,3H).13C NMR(101MHz,CDCl3)δ153.22,138.87,133.26,130.20,124.45,119.73,20.35.
Example 51
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, substrate 1r '(54 mg,0.5mmol,1.0 eq), HFIP (1.0 mL), and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq) with a plug closing the orifice, and reacted at room temperature (25 ℃ C.) for 12 hours, the reaction mixture was freed of the solvent under reduced pressure, and the crude mixture was purified by flash column chromatography to give nitrified product 2r' (yellow solid, 94mg, yield 95％).1H NMR(600MHz,CDCl3)δ11.27(s,1H),8.14(s,2H),2.45(s,3H).13C NMR(151MHz,CDCl3)δ147.57,137.39,131.85,129.55,20.41.
Example 52
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, substrate 1s (62 mg,0.5mmol,1.0 eq), HFIP (1.0 mL), and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq) with a plug closing the orifice, and reacted at room temperature (25 ℃ C.) for 6 hours the reaction mixture was removed of the solvent under reduced pressure, and the crude mixture was purified by flash column chromatography to afford nitrified product 2s (white solid, 83mg, yield 99％).1H NMR(600MHz,CDCl3)δ11.01(s,1H),9.94(s,1H),8.63(s,1H),8.13(d,J＝8.8Hz,1H),7.31(d,J＝8.7Hz,1H).13C NMR(151MHz,CDCl3)δ188.68,159.38,136.46,129.42,128.68,121.40.
Example 53
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, substrate 1t (81 mg,0.5mmol,1.0 eq), HFIP (1.0 mL) and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq) with a plug closing the orifice and reacted at room temperature (25 ℃ C.) for 12 hours the reaction mixture was freed of solvent under reduced pressure, the crude mixture was then purified by flash column chromatography to afford the nitrated product 2t (pale yellow solid, 88mg, yield 85％).1H NMR(600MHz,CDCl3)δ10.79(s,1H),8.43(d,J＝1.1Hz,1H),7.82(dd,J＝2.3,8.8Hz,1H),7.31(d,J＝8.8Hz,1H).13C NMR(151MHz,CDCl3)δ157.30,133.87(q,3J＝3.3Hz),133.24,123.26(q,3J＝4.5Hz),122.20(q,2J＝34.6Hz).123.05(q,1J＝271.7Hz),121.36.19F NMR(565MHz,CDCl3)δ-62.35.
Example 54
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, substrate 1u (60 mg,0.5mmol,1.0 eq), HFIP (1.0 mL) and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq) and a plug closed the orifice and reacted at room temperature (25 ℃ C.) for 12 hours the reaction mixture was freed of solvent under reduced pressure, the crude mixture was then purified by flash column chromatography to give nitrified product 2u (yellow solid, 81mg, yield 99％).1H NMR(600MHz,CDCl3)δ10.89(s,1H),8.47(d,J＝2.6Hz,1H),7.82(d,J＝8.6Hz,1H),7.30(d,J＝8.9Hz,1H).13C NMR(151MHz,CDCl3)δ157.91,139.70,130.23,121.88,116.73,104.62.
Example 55
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, substrate 1v (69 mg,0.5mmol,1.0 eq), HFIP (1.0 mL), and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq) with a plug closing the orifice, and reacted at room temperature (25 ℃ C.) for 12 hours the reaction mixture was removed of the solvent under reduced pressure, then the crude mixture was purified by flash column chromatography to afford nitrified product 2v (yellow solid, 85mg, yield 93％).1H NMR(600MHz,CD3OD)δ8.80(d,J＝3.1Hz,7H),8.02(dd,J＝3.1,9.6Hz,9H),6.68(d,J＝9.6Hz,9H).13C NMR(151MHz,CD3OD)δ172.22,137.85,132.53,129.40,126.90,125.47.
Example 56
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, substrate 1w (54 mg,0.5mmol,1.0 eq), HFIP (1.0 mL) and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq) with a plug closing the orifice and reacted at room temperature (25 ℃ C.) for 12 hours the reaction mixture was freed of solvent under reduced pressure, then the crude mixture was purified by flash column chromatography to give nitrified product 2w (colorless liquid, 60mg, yield 77％).1H NMR(400MHz,CDCl3)δ8.30-8.12(m,2H),7.01-6.84(m,2H),3.91(s,3H).13C NMR(151MHz,CDCl3)δ164.72,141.67,126.03,114.13,56.09.
Example 57
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, substrate 1X (69 mg,0.5mmol,1.0 eq), HFIP (1.0 mL), and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq) with a plug closing the orifice and reacted at room temperature (25 ℃ C.) for 12 hours the reaction mixture was freed of solvent under reduced pressure, then the crude mixture was purified by flash column chromatography to afford nitrified product 2X (yellow solid, 83mg, yield 91％).1H NMR(600MHz,CDCl3)δ7.39(d,J＝3.2Hz,1H),7.11(dd,J＝3.1,9.1Hz,1H),7.03(d,J＝9.1Hz,1H),3.92(s,3H),3.81(s,3H).13C NMR(151MHz,CDCl3)δ153.02,147.53,121.07,115.28,110.11,57.25,56.19.
Example 58
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, substrate 1y (63 mg,0.5mmol,1.0 eq), HFIP (1.0 mL), and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq), a plug was closed off the orifice, and reacted at 60℃for 12 hours the reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure, and the crude mixture was purified by flash column chromatography to afford nitrified product 2y (colorless liquid, 68mg, yield) 79％).1H NMR(600MHz,CDCl3)δ8.01(d,J＝2.3Hz,1.2H),7.71(dd,J＝0.9,2.1Hz,1H),7.50(dd,J＝2.3,8.2Hz,1.2H),7.44(d,J＝8.2Hz,1H),7.34(ddt,J＝0.7,2.1,7.5Hz,1H),7.32(d,J＝8.2Hz,1.2H),2.60(s,3.6H),2.44(d,J＝0.8Hz,3H).13C NMR(151MHz,CDCl3)δ138.43,134.11,133.99,133.21,132.60,132.21,131.65,126.04,124.89,124.08,20.86,20.16.
Example 59
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, substrate 1z (131 mg,0.5mmol,1.0 eq), HFIP (1.0 mL), and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq) with a plug closing the orifice, and reacted at room temperature (25 ℃ C.) for 24 hours the reaction mixture was removed of the solvent under reduced pressure, and the crude mixture was purified by flash column chromatography to afford nitrified product 2z (yellow solid, 113mg, yield 74％).1H NMR(600MHz,CDCl3)δ9.62(s,1H),7.87(dd,J＝0.9,2.0Hz,1H),7.73(d,J＝8.5Hz,1H),7.70-7.64(m,2H),7.39(dd,J＝2.1,8.5Hz,1H),7.23(d,J＝7.9Hz,2H),2.37(s,3H),2.33(s,3H).13C NMR(151MHz,CDCl3)δ144.78,137.40,136.86,135.79,134.62,131.40,130.07,127.32,126.04,121.74,21.71,20.60.HRMS m/z(ESI):calcd.for C14H15N2O4S[M+H]+:307.0747,found:307.07471.
Example 60
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, substrate 1aa (120 mg,0.5mmol,1.0 eq), HFIP (1.0 mL) and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq), the plug was closed off the orifice and reacted at 120℃for 24 hours the reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure, and the crude mixture was purified by flash column chromatography to afford nitrated product 2aa (colorless liquid, 82mg, yield 57％).1H NMR(600MHz,CDCl3)δ8.56(d,J＝2.7Hz,2.8H),8.25(dd,J＝2.7,9.1Hz,2.8H),8.18(dq,J＝1.3,2.6Hz,1H),8.07(dd,J＝2.5,8.8Hz,1H),7.87(d,J＝8.8Hz,1H),7.48(dq,J＝1.5,9.0Hz,2.8H).13C NMR(151MHz,CDCl3)δ152.35,134.96,129.80,124.23,122.76,121.54,121.16,117.43,116.66.19F NMR(565MHz,CDCl3)δ-57.36,-57.68.HRMS m/z(ESI):calcd.for C7H4BrF3NO3[M+H]+:285.9321,found:285.93206.
Example 61
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, substrate 1bb (70 mg,0.5mmol,1.0 eq), HFIP (1.0 mL) and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq) and a plug closed the orifice and reacted at room temperature (25 ℃ C.) for 18 hours the reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure and the crude mixture was purified by flash column chromatography to afford nitrated product 2bb (colorless liquid, 91mg, yield) 99％).1H NMR(600MHz,CDCl3)δ7.87(d,J＝11.1Hz,1H),6.82(d,J＝8.2Hz,1H),3.96(s,3H),2.62(s,3H).13C NMR(151MHz,CDCl3)δ151.80(d,3J＝10.5Hz),149.52(d,1J＝248.7Hz),140.66(d,3J＝7.0Hz),132.50(d,4J＝3.7Hz),115.92(d,4J＝1.9Hz),113.61(d,2J＝22.6Hz),56.64,21.50.19F NMR(565MHz,CDCl3)δ-135.44.HRMS m/z(ESI):calcd.for C8H9FNO3[M+H]+:186.0561,found:186.05613.
Example 62
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, 1cc (135 mg,0.5mmol,1.0 eq), HFIP (1.0 mL), and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq) with a plug closing the orifice, and reacted at room temperature (25 ℃ C.) for 12 hours, the reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure, and the crude mixture was purified by flash column chromatography to give 2cc (white solid, 127mg, yield) of the nitrified product 81％).1H NMR(600MHz,CDCl3)δ7.50(d,J＝1.9Hz,1H),7.49(d,J＝1.9Hz,1H),1.38(s,9H),1.32(s,9H).13C NMR(151MHz,CDCl3)δ153.98,142.16,128.78,124.68,114.47,36.56,35.33,31.18,30.97.
Example 63
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, substrate 1dd (103 mg,0.5mmol,1.0 eq), HFIP (1.0 mL) and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq), a plug was closed off the orifice, and reacted at 100℃for 18 hours the reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure, and the crude mixture was purified by flash column chromatography to give nitrified product 2dd (colorless liquid, 114mg, yield) 91％).1H NMR(600MHz,CDCl3)δ7.79(s,1H),7.74(s,1H),2.41(s,3H).13C NMR(151MHz,CDCl3)δ139.57,137.32,134.97,127.60,112.27,19.89.
Example 64
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, substrate 1ee (102 mg,0.5mmol,1.0 eq), HFIP (1.0 mL), and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq) with a plug closing the orifice and reacted at 120℃for 24 hours, the reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure, and the crude mixture was purified by flash column chromatography to give nitrified product 2ee (colorless liquid, 82mg, yield 66％).1H NMR(600MHz,CDCl3)δ7.57(dd,J＝3.1,7.2Hz,1H),7.53(dd,J＝3.1,7.4Hz,1H),4.00(s,3H).13C NMR(151MHz,CDCl3)δ157.29(d,1J＝252.4Hz),147.78(d,4J＝3.8Hz),125.41,125.32,120.63(d,3J＝9.8Hz),112.00(d,2J＝27.0Hz),63.01.19F NMR(565MHz,CDCl3)δ-113.27.HRMS m/z(ESI):calcd.for C7H6BrFNO3[M+H]+:249.9510,found:249.95102.
Example 65
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, substrate 1ff (82 mg,0.5mmol,1.0 eq), HFIP (1.0 mL), and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq) with a plug closing the orifice, and reacted at room temperature (25 ℃ C.) for 12 hours the reaction mixture was removed of the solvent under reduced pressure, then the crude mixture was purified by flash column chromatography to afford nitrified product 2ff (pale yellow solid, 96mg, yield 92％).1H NMR(600MHz,CDCl3)δ7.49(s,1H),6.72(s,1H),6.16(s,2H),2.46(s,3H).13C NMR(151MHz,CDCl3)δ199.30,152.81,148.95,140.16,135.16,106.24,104.84,103.78,30.26.
Example 66
A10 ml reaction tube of transparent glass was charged with a magnetic stirrer, substrate 1gg (136 mg,1mmol,1.0 eq), tfOH (45 mg,3.0 mmol) and Fe (NO 3)3·9H2 O (162 mg,0.4mmol,0.4 eq) and a plug closed the tube orifice and reacted at room temperature (25 ℃ C.) for 1 hour the reaction mixture was freed from the solvent under reduced pressure and the crude mixture was purified by flash column chromatography to give nitrified product 2gg (white solid, 163mg, yield) 92％).1H NMR(400MHz,CDCl3)δ8.80(s,3H),8.37(ddd,J＝1.1,2.4,8.2Hz,3H),8.32(dt,J＝1.4,7.7Hz,3H),7.87(dd,J＝1.5,7.8Hz,1H),7.72-7.67(m,1H),7.65-7.61(m,4H),3.95(s,9H),3.88(s,3H).13C NMR(101MHz,CDCl3)δ165.83,164.95,148.29,135.28,132.97,131.89,131.85,129.88,129.71,127.39,124.55,123.93,53.25,52.80.
Example 67
A reaction tube of 10ml of transparent glass was charged with a magnetic stirrer, substrate 1hh (146 mg,1mmol,1.0 eq), tfOH (45 mg,3.0mmol,3.0 eq) and Fe (NO 3)3·9H2 O (162 mg,0.4mmol,0.4 eq), a plug was closed off the orifice, and the reaction was allowed to react at room temperature (25 ℃ C.) for 1 hour 99％).1H NMR(600MHz,CDCl3)δ8.50(s,1H),8.44(d,J＝8.3Hz,1H),7.98(d,J＝7.8Hz,1H),7.74(t,J＝8.1Hz,1H).13C NMR(151MHz,CDCl3)δ148.42,132.45(q,2J＝34.2Hz),131.27(q,J＝3.6Hz),130.50,126.81,122.99(d,1J＝272.8Hz),120.98(q,3J＝3.9Hz).
Example 68
A reaction tube of 10ml of transparent glass was charged with a magnetic stirrer, substrate 1ii (225 mg,1mmol,1.0 eq), tfOH (45 mg,3.0mmol,3.0 eq) and Fe (NO 3)3·9H2 O (162 mg,0.4mmol,0.4 eq) and a plug closed the orifice and reacted at room temperature (25 ℃ C.) for 12 hours 97％).1H NMR(600MHz,CDCl3)δ8.11(s,1H),7.92(d,J＝8.4Hz,1H),7.69(d,J＝8.4Hz,1H).13C NMR(151MHz,CDCl3)δ150.16,136.28,131.31(q,2J＝34.7Hz),129.74(q,3J＝3.5Hz),123.00(q,3J＝3.9Hz),122.65(q,4J＝273.0Hz),118.90.19F NMR(565MHz,CDCl3)δ-63.06.
Example 69
A reaction tube of 10ml of transparent glass was charged with a magnetic stirrer, substrate 1jj (86 mg,1mmol,1.0 eq), tfOH (45 mg,3.0mmol,3.0 eq) and Fe (NO 3)3·9H2 O (162 mg,0.4mmol,0.4 eq) and a plug closed the orifice, and reacted at room temperature (25 ℃ C.) for 12 hours 96％).1H NMR(600MHz,CD3OD)δ8.30(s,1H),7.92(d,J＝7.9Hz,1H),7.51(d,J＝7.7Hz,1H),2.56(s,3H).13C NMR(151MHz,CD3OD)δ150.05,136.65,134.26,131.04,122.91,19.97.
Example 70
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, substrate 1kk (100 mg,0.5mmol,1.0 eq), HFIP (1.0 mL), and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq) with a plug closing the orifice, and reacted at room temperature (25 ℃ C.) for 12 hours 67％).1H NMR(600MHz,CDCl3)δ7.74(d,J＝2.3Hz,1H),7.28(dd,J＝2.3,8.6Hz,1H),7.15(d,J＝8.3Hz,2H),6.93-6.89(m,3H),2.38(s,3H),2.34(s,3H).13C NMR(151MHz,CDCl3)δ153.99,148.81,141.00,134.89,133.94,133.28,130.51,125.73,120.49,118.89,20.78,20.48.
Example 71
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, substrate 1ll (105 mg,0.5mmol,1.0 eq), HFIP (1.0 mL), and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq), a plug was closed off the orifice, and reacted at 120℃for 24 hours. The reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure. The crude mixture was then purified by flash column chromatography to afford nitrified product 2ll (white solid, 97mg, yield) 74％).1H NMR(600MHz,CDCl3)δ8.35(d,J＝1.8Hz,1H),7.94(dd,J＝1.8,7.9Hz,1H),7.73-7.67(m,2H),7.48(d,J＝7.9Hz,1H),7.32(d,J＝7.9Hz,2H),2.69(s,3H),2.46(s,3H).13C NMR(151MHz,CDCl3)δ193.93,149.09,144.28,137.76,137.06,133.98,133.84,133.13,130.30,129.49,126.25,21.87,20.74.HRMS m/z(ESI):calcd.for C15H14NO3[M+H]+:256.0968,found:256.09673.
Example 72
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, 1mm of substrate (77 mg,0.5mmol,1.0 eq), HFIP (1.0 mL) and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq) with a plug closing the orifice and reacted at 60℃for 12 hours, the reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure, the crude mixture was then purified by flash column chromatography to give a nitrified product 2mm (white solid, 98mg, yield) 98％).1H NMR(600MHz,CDCl3)δ8.35-8.28(m,3.2H),7.88(dd,J＝1.3,8.1Hz,1H),7.78-7.74(m,3.2H),7.66(dt,J＝1.3,6.1Hz,3.2H),7.64(dd,J＝1.3,7.6Hz,1H),7.56-7.51(m,4H),7.50-7.43(m,5.8H),7.37-7.35(m,2H).13C NMR(151MHz,CDCl3)δ149.80,148.10,147.56,139.22,136.81,132.79,132.45,129.67,129.44,129.18,128.72,128.67,128.39,128.28,127.88,124.59,124.56.
Example 73
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, substrate 1nn (156 mg,0.5mmol,1.0 eq), HFIP (1.0 mL), and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq), a plug was closed off the orifice, and reacted at 120℃for 24 hours. The reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure. The crude mixture was then purified by flash column chromatography to give nitrified product 2nn (white solid, 176mg, yield) 99％).1H NMR(600MHz,CDCl3)δ8.03(d,J＝2.0Hz,1H),7.76(dd,J＝2.0,8.2Hz,1H),7.58-7.53(m,2H),7.29(d,J＝8.2Hz,1H),7.18-7.11(m,2H).13C NMR(151MHz,CDCl3)δ149.38,135.71,135.43,134.27,133.17,132.17,129.55,127.42,123.21,121.98.HRMS m/z(ESI):calcd.for C12H8Br2NO2[M+H]+:355.8916,found:355.89158.
Example 74
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, substrate 1oo (64 mg,0.5mmol,1.0 eq), HFIP (1.0 mL), and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq), the plug was closed off the orifice, and reacted at room temperature (25 ℃ C.) for 18 hours the reaction mixture was removed the solvent under reduced pressure, then the crude mixture was purified by flash column chromatography to afford the nitrated product 2oo (yellow solid, 86mg, yield 99％).1H NMR(600MHz,CDCl3)δ8.56(d,J＝8.7Hz,1H),8.22(dd,J＝1.2,7.6Hz,1H),8.11(d,J＝8.0Hz,1H),7.95(d,J＝9.5Hz,1H),7.71(ddd,J＝1.3,6.9,8.6Hz,1H),7.62(ddd,J＝1.1,6.8,8.1Hz,1H),7.53(t,J＝7.9Hz,1H).13C NMR(151MHz,CDCl3)δ134.78,134.45,129.56,128.72,127.46,125.23,124.24,124.12,123.22.
Example 75
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, substrate 1pp (71 mg,0.5mmol,1.0 eq), HFIP (1.0 mL) and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq) with a plug closing the orifice and reacted at room temperature (25 ℃ C.) for 12 hours the reaction mixture was removed the solvent under reduced pressure then the crude mixture was purified by flash column chromatography to give the nitrated product 2pp (pale yellow solid, 73mg, yield 78％).1H NMR(600MHz,CDCl3)δ8.60(d,J＝8.7Hz,1H),8.12(d,J＝7.8Hz,1H),8.08(d,J＝8.5Hz,1H),7.71(ddd,J＝1.3,6.9,8.5Hz,1H),7.64(ddd,J＝1.3,6.9,8.3Hz,1H),7.37(d,J＝7.9Hz,1H),2.77(s,3H).13C NMR(151MHz,CDCl3)δ142.37,133.13,128.96,127.17,125.18,125.02,124.72,123.86,123.68,20.25.
Example 76
A reaction tube of 10mL of transparent glass was charged with a magnetic stirrer, substrate 1qq (79 mg,0.5mmol,1.0 eq), (HFIP: DCE=1:9) (1.0 mL) and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq) with a plug closing the orifice, and reacted at room temperature (25 ℃ C.) for 12 hours, the reaction mixture was freed of the solvent under reduced pressure, and the crude mixture was purified by flash column chromatography to give nitrified product 2qq (pale yellow solid, 95mg, yield) 94％).1H NMR(600MHz,CDCl3)δ8.77(d,J＝8.8Hz,1H),8.38(d,J＝8.7Hz,1H),8.35(d,J＝8.5Hz,1H),7.75-7.70(m,1H),7.58(t,J＝7.7Hz,1H),6.79(d,J＝8.7Hz,1H),4.09(s,3H).13C NMR(101MHz,CDCl3)δ160.69,139.25,130.15,127.33,126.93,126.64,125.66,123.54,122.86,101.98,56.38.
Example 77
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, substrate 1qq '(79 mg,0.5mmol,1.0 eq), HFIP (1.0 mL), and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq), a plug was closed off the orifice, and the reaction was carried out at room temperature (25 ℃ C.) for 12 hours the reaction mixture was removed of solvent under reduced pressure, then the crude mixture was purified by flash column chromatography to afford nitrified product 2qq' (yellow solid, 102mg, yield 82％).1H NMR(600MHz,CDCl3)δ8.81(s,1H),8.71(d,J＝8.7Hz,1H),8.48(d,J＝8.5Hz,1H),7.93(ddd,J＝1.3,6.9,8.6Hz,1H),7.84-7.75(m,1H),4.22(s,3H).13C NMR(151MHz,CDCl3)δ156.23,132.93,129.81,129.12,128.15,125.08,124.18,120.91,64.45.HRMS m/z(ESI):calcd.for C11H9N2O5[M+H]+:249.0506,found:249.05060.
Example 78
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, substrate 1rr (104 mg,0.5mmol,1.0 eq), HFIP (1.0 mL), and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq), a plug was closed off the orifice, and the reaction was allowed to react at room temperature (25 ℃ C.) for 24 hours the reaction mixture was removed of solvent under reduced pressure, then the crude mixture was purified by flash column chromatography to give nitrified product 2rr (pale yellow solid, 101mg, yield 80％).1H NMR(600MHz,CDCl3)δ8.61(d,J＝8.6Hz,1H),8.55(d,J＝8.0Hz,5.5H),8.47(d,J＝8.8Hz,1H),8.40(d,J＝7.5Hz,5.5H),8.23(d,J＝7.5Hz,1H),8.05(d,J＝8.2Hz,5.5H),7.94(dd,J＝1.0,7.5Hz,1H),7.89(d,J＝8.2Hz,5.5H),7.81-7.71(m,11H),7.69-7.63(m,1H),7.54(dd,J＝7.5,8.8Hz,1H).13C NMR(151MHz,CDCl3)δ146.6,133.69,132.76,131.81,130.26,130.06,129.55,128.93,128.59,128.23,126.15,124.48,123.90,123.71.
Example 79
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, substrate 1ss (143 mg,0.5mmol,1.0 eq), HFIP (1.0 mL), and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq) with a plug closing the orifice, and reacted at room temperature (25 ℃ C.) for 18 hours the reaction mixture was freed of solvent under reduced pressure, then the crude mixture was purified by flash column chromatography to afford nitrified product 2ss (yellow solid, 152mg, yield 92％).1H NMR(600MHz,CDCl3)δ8.34(dd,J＝1.2,8.7Hz,1H),8.11(dd,J＝1.2,7.5Hz,1H),8.04(d,J＝8.2Hz,1H),7.82(d,J＝8.2Hz,1H),7.48(dd,J＝7.5,8.7Hz,1H).13C NMR(151MHz,CDCl3)δ137.18,133.85,129.81,129.32,128.48,126.21,123.61,122.95,121.02.HRMS m/z(ESI):calcd.for C10H6Br2NO2[M+H]+:329.8760,found:329.87607.
Example 80
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, substrate 1tt (78 mg,0.5mmol,1.0 eq), HFIP (1.0 mL) and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq) and a plug closed the orifice and reacted at room temperature (25 ℃ C.) for 12 hours the reaction mixture was freed of solvent under reduced pressure after which the crude mixture was purified by flash column chromatography to afford the nitrated product 2tt (pale yellow solid, 89mg, yield 89％).2tt 1H NMR(600MHz,CDCl3)δ10.16(s,1H),8.17(d,J＝8.1Hz,3H),8.14(d,J＝7.2Hz,1H),7.76(s,1H),7.67(t,J＝7.9Hz,1H).13C NMR(151MHz,CDCl3)δ190.06,148.07,135.06,135.05,134.26,134.04,132.97,126.76,126.06,125.68,120.90.
Example 81
A reaction tube of 10mL of transparent glass was charged with a magnetic stirrer, substrate 1uu (89 mg,0.5mmol,1.0 eq), (HFIP: DCE=1:9) (1.0 mL) and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq) with a plug closing the orifice, and reacted at room temperature (25 ℃ C.) for 12 hours, the reaction mixture was freed of the solvent under reduced pressure, and the crude mixture was purified by flash column chromatography to give nitrified product 2uu (pale yellow solid, 89mg, yield) 80％).1H NMR(600MHz,CDCl3)δ8.60(s,1H),8.05(d,J＝8.5Hz,2H),7.94(d,J＝8.9Hz,2H),7.67-7.61(m,2H),7.55(t,J＝7.6Hz,2H).13C NMR(151MHz,CDCl3)δ130.94,130.51,129.02,128.52,126.35,122.80,121.53.
Example 82
A reaction tube of 10mL of transparent glass was charged with a magnetic stirrer, substrate 1vv (89 mg,0.5mmol,1.0 eq), (HFIP: DCE=1:9) (1.0 mL) and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq) with a plug closing the orifice, and reacted at room temperature (25 ℃ C.) for 12 hours, the reaction mixture was freed of the solvent under reduced pressure, and the crude mixture was purified by flash column chromatography to give nitrified product 2vv (pale yellow solid, 80mg, yield) 71％).1H NMR(600MHz,CDCl3)δ9.51(d,J＝1.9Hz,1H),8.91(J＝4.2Hz,1H),8.73-8.69(m,7.6H),8.65(d,J＝8.4Hz,7.6H),8.51-8.47(m,7.6H),8.43(s,7.6H),8.34(dd,J＝2.2,8.7Hz,1H),8.27(d,J＝9.3Hz,1H),8.19-8.16(m,1H),7.97(d,J＝7.9Hz,7.6H),7.95-7.89(m,3H),7.83-7.79(m,7.6H),7.78-7.72(m,15.2H),7.72-7.66(m,8.6H).
Example 83
A reaction tube of 10mL of transparent glass was charged with a magnetic stirrer, substrate 1ww (137 mg,0.5mmol,1.0 eq), (HFIP: DCE=1:9) (1.0 mL) and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq) with a plug closing the orifice, and reacted at 60℃for 12 hours, the reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure, and the crude mixture was purified by flash column chromatography to give the nitrated product 2ww (pale yellow solid, 137mg, yield) 86％).1H NMR(600MHz,CDCl3)δ8.31-8.24(m,2H),7.79(d,J＝8.2Hz,1H),7.66(d,J＝8.1Hz,1H),7.63(d,J＝1.8Hz,1H),7.54(dd,J＝1.8,8.1Hz,1H),1.53(s,6H).13C NMR(151MHz,CDCl3)δ157.08,154.39,147.58,144.74,135.96,131.02,126.74,123.80,123.69,122.88,120.41,118.51,47.71,26.78.HRMS m/z(ESI):calcd.for C15H13BrNO2[M+H]+:318.0124,found:318.01245.
Example 84
A reaction tube of 10mL of transparent glass was charged with a magnetic stirrer, substrate 1xx (101 mg,0.5mmol,1.0 eq), (HFIP: DCE=1:9) (1.0 mL) and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq) with a plug closing the orifice, and reacted at room temperature (25 ℃ C.) for 12 hours, the reaction mixture was freed of the solvent under reduced pressure, and the crude mixture was purified by flash column chromatography to give nitrified product 2xx (yellow solid, 101mg, yield) 82％).1H NMR(600MHz,CDCl3)δ8.71(dd,J＝3.7,9.4Hz,1H),8.52(d,J＝8.4Hz,1H),8.19(dd,J＝7.5,16.8Hz,2H),8.12(d,J＝9.5Hz,1H),8.08(d,J＝8.9Hz,1H),8.03(t,J＝7.6Hz,1H),7.97(d,J＝8.5Hz,1H),7.91(d,J＝9.0Hz,1H).13C NMR(151MHz,CDCl3)δ142.58,134.94,131.40,130.74,130.70,129.95,127.64,127.13,127.04,126.76,124.64,124.61,124.04,123.44,122.61,121.58.
Example 85
A reaction tube of 10mL of transparent glass was charged with a magnetic stirrer, substrate 1yy (157 mg,0.5mmol,1.0 eq), (HFIP: DCE=1:9) (1.0 mL) and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq) and a plug closed the orifice, and reacted at room temperature (25 ℃ C.) for 24 hours, the reaction mixture was freed of the solvent under reduced pressure, and the crude mixture was purified by flash column chromatography to give nitrified product 2yy (pale yellow solid, 127mg, yield) 71％).1H NMR(600MHz,CDCl3)δ8.85(d,J＝2.4Hz,1H),8.17(d,J＝9.1Hz,1H),8.02(d,J＝9.1Hz,1H),7.96(dd,J＝2.4,9.4Hz,1H),7.90(d,J＝8.2Hz,1H),7.60(d,J＝9.1Hz,1H),7.47(d,J＝9.1Hz,1H),7.35(ddd,J＝1.2,6.7,8.1Hz,1H),7.25-7.23(m,1H),7.21(d,J＝9.3Hz,1H),7.03(d,J＝7.6Hz,1H),3.83(s,3H),3.78(s,3H).13C NMR(101MHz,CDCl3)δ158.23,155.01,143.81,137.00,133.73,131.98,130.21,129.28,128.30,127.31,126.85,126.83,125.30,124.72,123.85,119.82,117.96,115.56,113.92,56.81,56.70.
Example 86
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, substrate 1zz (194 mg,0.5mmol,1.0 eq), HFIP (1.0 mL), and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq) with a plug closing the orifice, and reacted at room temperature (25 ℃ C.) for 12 hours the reaction mixture was removed the solvent under reduced pressure, then the crude mixture was purified by flash column chromatography to afford nitrified product 2zz (pale yellow solid, 165mg, yield 76％).2zz-1:1H NMR(600MHz,CDCl3)δ8.74(d,J＝2.3Hz,1H),8.07(d,J＝8.4Hz,1H),8.02(dd,J＝8.7,5.9Hz,2H),7.97(dd,J＝9.4,2.4Hz,1H),7.69(d,J＝8.4Hz,1H),7.58(t,J＝7.5Hz,1H),7.52(d,J＝6.8Hz,2H),7.41-7.35(m,2H),7.30(d,J＝9.1Hz,1H),7.26-7.18(m,4H),3.64(s,3H).13C NMR(151MHz,CDCl3)δ157.42,143.77,138.21,137.65,137.09,134.44,132.71,132.60,129.60,128.59,128.28,127.92,127.47,127.30,127.18,126.78,126.69,125.36,125.11,120.77,120.10,114.42,56.02.HRMS m/z(ESI):calcd.for C28H20NO4[M+H]+:434.1387,found:434.13887.2zz-2:1H NMR(600MHz,CDCl3)δ7.99-7.93(m,3H),7.90(d,J＝9.1Hz,1H),7.56(dd,J＝8.4,18.9Hz,4H),7.41(dt,J＝7.5,15.0Hz,4H),7.31(t,J＝7.8Hz,1H),7.25-7.20(m,3H),3.61(s,3H).13C NMR(151MHz,CDCl3)δ197.33,156.45,148.41,138.32,136.36,134.14,133.61,132.91,132.68,132.18,131.14,130.30,129.42,128.39,128.23,127.74,127.38,127.08,126.74,126.11,125.78,124.42,122.02,117.97,113.78,56.04.HRMS m/z(ESI):calcd.for C28H20NO4[M+H]+:434.1387,found:434.13887.
Example 87
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, substrate 1aaa (61 mg,0.5mmol,1.0 eq), HFIP (1.0 mL), and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq) with a plug closing the orifice, and reacted at room temperature (25 ℃ C.) for 12 hours the reaction mixture was removed the solvent under reduced pressure, then the crude mixture was purified by flash column chromatography to afford nitrified product 2aaa (white solid, 98mg, yield 92％).1H NMR(600MHz,CDCl3)δ7.88(d,J＝8.5Hz,1H),7.65(s,1H),6.86(d,J＝8.7Hz,1H),6.14(s,2H).13C NMR(151MHz,CDCl3)δ:153.42,148.41,120.11,107.82,104.73,103.30.
Example 88
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, substrate 1bbb (89 mg,0.5mmol,1.0 eq), HFIP (1.0 mL), and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq), a plug was closed off the orifice, and the reaction was allowed to react at room temperature (25 ℃ C.) for 12 hours the reaction mixture was removed of solvent under reduced pressure, then the crude mixture was purified by flash column chromatography to afford nitrified product 2bbb (pale yellow solid, 165mg, yield 96％).1H NMR(600MHz,CD3OD)δ7.44(s,1H),7.20(s,1H),6.24(s,2H).13C NMR(151MHz,CD3OD)δ199.10,152.71,148.85,140.27,135.11,106.24,104.84,103.78.
Example 89
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, substrate 1ccc (55 mg,0.5mmol,1.0 eq), HFIP (1.0 mL), and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq), a plug was closed off the orifice, and reacted at 120℃for 24 hours. The reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure. The crude mixture was then purified by flash column chromatography to give nitrified product 2ccc (pale yellow solid, 69mg, yield) 86％).1H NMR(400MHz,CDCl3)δ7.30(s,1H),7.20(s,1H),2.54(s,3H);13C NMR(101MHz,CDCl3)δ186.8,151.9,151.5,116.7,111.9,26.3.
Example 90
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, substrate 1ddd (60 mg,0.5mmol,1.0 eq), HFIP (1.0 mL), and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq), a plug was closed off the orifice, and reacted at 120℃for 24 hours. The reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure. The crude mixture was then purified by flash column chromatography to afford the nitrated product 2ddd (pale yellow solid, 71mg, yield) 81％).1H NMR(400MHz,CDCl3)δ7.80(s,1H),7.50(s,1H),2.51(s,3H);13C NMR(101MHz,CDCl3)δ187.1,152.4,151.9,116.9,112.5,26.8.
Example 91
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, substrate 1eee (86 mg,0.5mmol,1.0 eq), HFIP (1.0 mL), and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq) with a plug closing the orifice, and reacted at room temperature (25 ℃ C.) for 12 hours the reaction mixture was removed of the solvent under reduced pressure, and the crude mixture was purified by flash column chromatography to give nitrified product 2eee (pale yellow solid, 97mg, yield 86％).1H NMR(400MHz,CDCl3):δ8.13-8.09(m,2H),8.07(s,1H),7.52(d,J＝1.0Hz,1H),4.02(s,3H);13C NMR(100MHz,CDCl3):δ158.8,153.0,150.3,131.6,128.6,112.4,110.6,109.1,53.1.
Example 92
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, substrate 1fff (76 mg,0.5mmol,1.0 eq), HFIP (1.0 mL), and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq) with a plug closing the orifice, and reacted at room temperature (25 ℃ C.) for 12 hours, the reaction mixture was removed of the solvent under reduced pressure, and then the crude mixture was purified by flash column chromatography to give nitrified product 2fff (pale yellow solid, 65mg, yield 66％).1H NMR(400MHz,CD3CN)δ8.36(d,J＝8.4Hz,1H),7.63(d,J＝8.5Hz,1H);13C NMR(75MHz,CD3CN)δ152.4,143.5,142.1,137.3,124.3,116.9.
The preparation method can also be applied to the post-nitrification modification of various drug molecules, amino acids, amino acid derivatives, saccharides and saccharide derivatives. The universality of the substrate aims at proving that the preparation method has wider application range. The following experiment is to realize the later nitrification of complex molecules such as drug molecules, amino acids, saccharides and the like under the preparation method.
Example 93
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, substrate 3a (103 mg,0.5mmol,1.0 eq), HFIP (1.0 mL), and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq) with a plug closing the orifice, and reacted at 60℃for 6 hours, the reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure, and the crude mixture was purified by flash column chromatography to afford nitrified product 4a (colorless liquid, 112mg, yield 89％).1H NMR(600MHz,CD3OD)δ7.84(s,3H),7.74(s,1H),7.56(d,J＝7.9Hz,3H),7.36(d,J＝7.7Hz,3H),7.23(d,J＝7.6Hz,1H),7.11(d,J＝7.7Hz,1H),2.77(d,J＝7.4Hz,6H),2.59(d,J＝6.7Hz,2H),1.96-1.90(m,1H),1.89(dd,J＝6.7,13.2Hz,3H),1.57(d,J＝6.9Hz,3H),1.51(d,J＝6.8Hz,9H),1.39-1.27(m,4H),0.97-0.94(m,6H),0.94-0.90(m,18H).13C NMR(151MHz,CD3OD)δ217.37,201.45,151.28,150.41,143.47,142.64,135.44,135.02,133.92,132.81,130.24,128.25,125.81,124.43,45.24,42.08,31.22,30.74,22.50,22.69,18.33,18.94.HRMS m/z(ESI):calcd.for C13H16NO4[M-H]-:250.1085,found:250.10860.
Example 94
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, substrate 3b (58 mg,0.25mmol,1.0 eq), HFIP (1.0 mL) and Fe (NO 3)3·9H2 O (101 mg,0.25mmol,1.0 eq) with a plug closing the orifice and reacted at room temperature (25 ℃ C.) for 2 hours the reaction mixture was freed from the solvent under reduced pressure, then the crude mixture was purified by flash column chromatography to afford nitrified product 4b (pale yellow solid, 68mg, yield 99％).1H NMR(600MHz,CD3OD)δ7.90(d,J＝9.1Hz,1H),7.79(s,1H),7.59(d,J＝8.8Hz,1H),7.54(d,J＝8.8Hz,1H),7.40(d,J＝9.1Hz,1H),3.97(s,3H),3.89(t,J＝7.0Hz,1H),1.54(d,J＝7.1Hz,3H).13C NMR(151MHz,CD3OD)δ177.76,149.73,139.30,136.96,133.14,130.23,129.52,127.49,125.62,121.31,114.71,57.56,46.26,18.73.HRMS m/z(ESI):calcd.for C14H12NO5[M-H]-:274.0721,found:274.07218.
Example 95
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, substrate 3c (103 mg,0.25mmol,1.0 eq), HFIP (1.0 mL) and Fe (NO 3)3·9H2 O (101 mg,0.25mmol,1.0 eq) and a plug closed the orifice and reacted at room temperature (25 ℃ C.) for 12 hours the reaction mixture was freed of solvent under reduced pressure, then the crude mixture was purified by flash column chromatography to afford nitrified product 4c (white solid, 112mg, yield 98％).1H NMR(600MHz,CD3OD)δ8.64(s,4.5H),8.28(d,J＝8.7Hz,9H),7.97(s,1H),7.81(s,3.5H),7.74(d,J＝8.5Hz,7H),7.65(d,J＝8.8Hz,4.5H),7.63(s,4.5H),7.44(d,J＝8.3Hz,2H),4.05(s,3H),3.88(s,10.5H),2.16(s,27H),2.13(s,13.5H),1.86(s,27H).13C NMR(151MHz,CD3OD)δ178.17,145.98,138.94,134.42,133.21,132.68,132.18,131.02,130.34,128.23,126.26,124.43,121.91,62.20,42.20,39.41,37.82,30.43.HRMS m/z(ESI):calcd.for C28H26NO5[M-H]-:456.1816,found:456.18177.
Example 96
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, substrate 3d (58 mg,0.25mmol,1.0 eq), HFIP (1.0 mL) and Fe (NO 3)3·9H2 O (101 mg,0.25mmol,1.0 eq) and a plug closed the orifice and reacted at room temperature (25 ℃ C.) for 24 hours the reaction mixture was freed from the solvent under reduced pressure, then the crude mixture was purified by flash column chromatography to afford nitrified product 4d (pale yellow solid, 61mg, yield 89％).1H NMR(600MHz,CDCl3)δ7.88(d,J＝9.1Hz,1H),7.62(s,1H),7.60(d,J＝8.8Hz,1H),7.44(d,J＝8.7Hz,1H),7.31(d,J＝9.1Hz,1H),4.01(s,3H),3.04(t,J＝7.4Hz,2H),2.83(t,J＝7.4Hz,2H),2.15(s,3H).13C NMR(151MHz,CDCl3)δ207.58,148.42,138.19,136.15,131.86,130.50,128.58,126.80,124.43,120.89,113.42,57.23,44.80,30.28,29.51.HRMS m/z(ESI):calcd.for C15H16NO4[M+H]+:274.1074,found:274.10742.
Example 97
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, substrate 3e (91 mg,0.5mmol,1.0 eq), HFIP (1.0 mL), and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq) with a plug closing the orifice and reacted at room temperature (25 ℃ C.) for 2 hours the reaction mixture was freed of solvent under reduced pressure, then the crude mixture was purified by flash column chromatography to afford nitrified product 4e (yellow solid, 97mg, yield 86％).1H NMR(600MHz,CD3OD)δ7.83(s,1H),7.27(d,J＝8.7Hz,1H),6.84(d,J＝8.6Hz,1H),3.58(dd,J＝4.4,8.8Hz,1H),3.13(d,J＝14.4Hz,1H),2.79(dd,J＝8.7,14.4Hz,1H).13C NMR(151MHz,CD3OD)δ175.35,137.68,137.54,131.45,127.30,125.65,116.48,58.08,39.17.HRMS m/z(ESI):calcd.for C9H9N2O5[M-H]-:225.0517,found:225.05160.
Example 98
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, substrate 3f (112 mg,0.5mmol,1.0 eq), HFIP (1.0 mL), and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq), a plug was closed off the orifice, and the reaction was carried out at room temperature (25 ℃ C.) for 1.5 hours 81％).1H NMR(600MHz,CD3OD)δ7.94(s,1H),7.50(d,J＝8.6Hz,1H),7.04(d,J＝2.9Hz,1H),4.48(p,J＝3.5Hz,1H),3.21(dt,J＝4.2,14.0Hz,1H),2.94(dd,J＝7.5,14.5Hz,1H),1.93(s,3H).13C NMR(151MHz,CD3OD)δ172.45,154.74,139.42,135.38,131.70,129.08,126.45,120.73,57.26,38.19,22.72.HRMS m/z(ESI):calcd.for C11H11N2O6[M-H]-:267.0623,found:267.06228.
Example 99
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, substrate 3f (112 mg,0.5mmol,1.0 eq), HFIP (1.0 mL), and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq) with a plug closing the orifice, and reacted at room temperature (25 ℃ C.) for 3 hours 92％).1H NMR(600MHz,CD3OD)δ8.14(s,2H),4.75-4.61(m,1H),3.26(d,J＝14.0Hz,1H),3.05-2.93(m,1H),1.96(s,3H).13C NMR(151MHz,CD3OD)δ174.18,173.16,154.39,139.08,135.35,132.26,130.75,126.38,120.85,54.70,37.18,22.32.HRMS m/z(ESI):calcd.for C11H11N2O6[M-H]-:267.0623,found:267.06228.
Example 100
A reaction tube of 10mL of transparent glass was charged with a magnetic stirrer, 3g of substrate (135 mg,0.5mmol,1.0 eq), (HFIP: DCE=1:9) (1.0 mL) and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq) with a plug closing the orifice, and reacted at room temperature (25 ℃ C.) for 4 hours, the reaction mixture was freed of the solvent under reduced pressure, and the crude mixture was purified by flash column chromatography to give 4g of nitrified product (yellow solid, 59mg, yield) 37％).1H NMR(400MHz,CDCl3)δ10.41(s,1H),7.98(d,J＝1.5Hz,1H),6.86(s,1H),3.03-2.83(m,2H),2.58-2.46(m,1H),2.46-2.38(m,1H),2.27-1.96(m,5H),1.67-1.44(m,6H),0.91(s,3H).13C NMR(101MHz,CDCl3)δ153.03,148.93,133.23,131.88,121.66,119.10,50.48,47.94,43.57,37.84,35.89,31.39,29.74,26.01,25.81,21.66,13.89.
Example 101
A reaction tube of 10mL of transparent glass was charged with a magnetic stirrer, 3g of substrate (135 mg,0.5mmol,1.0 eq), (HFIP: DCE=1:9) (1.0 mL) and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq) with a plug closing the orifice, and reacted at room temperature (25 ℃ C.) for 24 hours 91％).1H NMR(600MHz,CDCl3)δ10.62(s,1H),8.16(s,1H),2.89(dd,J＝3.5,8.0Hz,2H),2.56-2.49(m,1H),2.48-2.41(m,1H),2.28(td,J＝4.4,11.1Hz,1H),2.17(dd,J＝9.6,18.7Hz,1H),2.14-2.01(m,3H),1.67-1.55(m,3H),1.55-1.45(m,3H),0.91(s,3H).13C NMR(151MHz,CDCl3)δ144.95,141.77,139.21,133.64,132.24,122.79,50.13,47.77,43.55,37.11,35.81,31.24,25.87,24.96,24.86,21.55,13.82.HRMS m/z(ESI):calcd.for C18H19N2O6[M-H]-:359.1249,found:359.12490.
Example 102
A reaction tube of 10mL of transparent glass was charged with a magnetic stirrer, a substrate 3h (135 mg,0.5mmol,1.0 eq), (HFIP: DCE=1:9) (1.0 mL) and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq) with a plug closing the orifice, and reacted at room temperature (25 ℃ C.) for 12 hours, the reaction mixture was freed of the solvent under reduced pressure, and the crude mixture was purified by flash column chromatography to afford the nitrated product 4h (yellow solid, 65mg, yield) 41％).1H NMR(600MHz,CD3OD)δ7.91(s,1H),6.78(s,1H),3.68(t,J＝8.8Hz,1H),2.99-2.77(m,2H),2.31(d,J＝13.3Hz,1H),2.13(d,J＝9.9Hz,1H),2.10-2.03(m,1H),2.00(d,J＝13.0Hz,1H),1.94-1.87(m,1H),1.71(q,J＝8.4Hz,1H),1.58-1.46(m,2H),1.39-1.30(m,4H),1.19(q,J＝11.4Hz,1H),0.79(s,3H).13C NMR(151MHz,CD3OD)δ155.78,149.23,134.07,133.23,122.55,121.02,82.34,51.28,44.75,44.28,39.83,37.71,30.67,30.58,27.89,27.27,23.95,11.60.HRMS m/z(ESI):calcd.for C18H22NO4[M-H]-:316.1554,found:316.15523.
Example 103
A reaction tube of 10mL of transparent glass was charged with a magnetic stirrer, substrate 3h (135 mg,0.5mmol,1.0 eq), (HFIP: DCE=1:9) (1.0 mL) and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq) with a plug closing the orifice and reacted at room temperature (25 ℃ C.) for 24 hours, the reaction mixture was freed of solvent under reduced pressure, and the crude mixture was purified by flash column chromatography to afford the nitrated product 4h' (yellow solid, 143mg, yield) 79％).1H NMR(600MHz,CD3OD)δ7.91(s,1H),3.68(t,J＝8.8Hz,1H),2.73-2.62(m,2H),2.31(d,J＝15.9Hz,1H),2.11(d,J＝9.9Hz,1H),2.10-2.02(m,1H),2.00(d,J＝12.8Hz,1H),1.91(d,J＝8.7Hz,1H),1.71(q,J＝9.7Hz,1H),1.52(q,J＝14.6,16.6Hz,2H),1.44-1.34(m,2H),1.35-1.26(m,2H),1.24-1.15(m,1H),0.80(s,3H).13C NMR(151MHz,CD3OD)δ149.70,135.98,124.42,124.29,82.35,51.06,44.63,44.29,39.69,37.69,30.67,27.49,27.36,25.62,23.89,11.60.HRMS m/z(ESI):calcd.for C18H21N2O6[M-H]-:361.1405,found:361.14018.
Example 104
A reaction tube of 10mL of transparent glass was charged with a magnetic stirrer, substrate 3i (76 mg,0.5mmol,1.0 eq), (HFIP: DCE=1:9) (1.0 mL) and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq) with a plug closing the orifice, and reacted at room temperature (25 ℃ C.) for 1 hour, the reaction mixture was freed of the solvent under reduced pressure, and the crude mixture was purified by flash column chromatography to give nitrified product 4i (yellow solid, 39mg, yield) 40％).1H NMR(600MHz,CD3OD)δ8.37(d,J＝2.7Hz,1H),7.60(dd,J＝2.6,9.1Hz,1H),7.04(d,J＝9.0Hz,1H),2.13(s,3H).13C NMR(151MHz,CD3OD)δ171.66,154.34,135.43,131.04,130.37,122.03,116.99,23.60.HRMS m/z(ESI):calcd.for C8H7N2O4[M-H]-:195.0411,found:195.04110.
Example 105
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, substrate 3i (76 mg,0.5mmol,1.0 eq), HFIP (1.0 mL), and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq) with a plug closing the orifice, and reacted at room temperature (25 ℃ C.) for 12 hours the reaction mixture was freed of solvent under reduced pressure, and the crude mixture was purified by flash column chromatography to afford nitrified product 4i' (yellow solid, 96mg, yield 80％).1H NMR(600MHz,DMSO)δ10.38(s,1H),8.40(s,2H),2.06(s,3H).13C NMR(151MHz,DMSO)δ171.40,168.77,139.77,139.71,120.37,120.31,23.77.HRMS m/z(ESI):calcd.for C8H6N3O6[M-H]-:240.0262,found:240.02613.
Example 106
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, substrate 3j (127 mg,0.5mmol,1.0 eq), HFIP (1.0 mL), and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq) with a plug closing the orifice and reacted at room temperature (25 ℃ C.) for 2 hours the reaction mixture was freed of solvent under reduced pressure, then the crude mixture was purified by flash column chromatography to afford nitrified product 4j (yellow solid, 136mg, yield 91％).1H NMR(600MHz,CDCl3)δ14.10(s,1H),12.02(s,1H),8.10(d,J＝7.4Hz,2H),7.65-7.53(m,3H),6.92(s,1H),6.48(s,1H).13C NMR(151MHz,CDCl3)δ181.83,167.60,165.15,153.44,133.08,129.86,129.61,126.97,118.29,106.80,100.87.HRMS m/z(ESI):calcd.for C15H8NO6[M-H]-:298.0357,found:298.03579.
Example 107
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, substrate 3k (148 mg,0.5mmol,1.0 eq), HFIP (1.0 mL) and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq) with a plug closing the orifice and reacted at room temperature (25 ℃ C.) for 3 hours the reaction mixture was freed of solvent under reduced pressure, the crude mixture was then purified by flash column chromatography to afford the nitrated product 4k (yellow orange solid, 145mg, yield 85％).1H NMR(600MHz,CD3OD)δ8.17(s,1H),7.97-7.91(m,1H),7.50(d,J＝8.1Hz,2H),7.22(t,J＝8.1Hz,1H),6.35(d,J＝8.9Hz,1H),3.69(s,2H).13C NMR(151MHz,CD3OD)δ189.02,151.49,141.40,137.40,133.29,130.19,127.77,127.38,124.21,115.07,44.23.HRMS m/z(ESI):calcd.for C14H9Cl2N2O4[M-H]-:338.9945,found:338.99450.
Example 108
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, 3l of substrate (161 mg,0.5mmol,1.0 eq), HFIP (1.0 mL) and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq) with a plug closing the orifice and reacted at room temperature (25 ℃ C.) for 12 hours the reaction mixture was freed from the solvent under reduced pressure, and the crude mixture was purified by flash column chromatography to give 4l of nitrated product (pale yellow solid, 180mg, yield 99％).1H NMR(600MHz,CDCl3)δ8.17(s,1.3H),8.13(s,1H),7.66(s,1.3H),7.56(q,J＝7.7Hz,2.3H),7.47(s,1H),7.32(dd,J＝7.9,16.0Hz,4.6H),7.21-7.07(m,5.6H),7.01(d,J＝8.9Hz,1.3H),6.96(dd,J＝8.0,14.5Hz,4.6H),6.86(d,J＝6.1Hz,2.3H),6.73(t,J＝9.3Hz,2.3H),5.69-5.52(m,2.3H),4.34(d,J＝11.3Hz,1H),4.28(d,J＝7.5Hz,1.3H),4.20(d,J＝17.5Hz,1H),4.12(d,J＝12.2Hz,1.3H),1.51(d,J＝6.6Hz,3H),1.49(d,J＝6.3Hz,4H).13C NMR(151MHz,CDCl3)δ162.94,157.23,154.75,146.84,146.75,142.02,138.86,138.81,130.04,129.86,124.65,123.93,123.60,123.34,121.82,118.59,117.72,117.01,116.96,116.78,115.76,111.55,110.63,72.52,71.38,68.86,68.74,17.00,16.98.HRMS m/z(ESI):calcd.for C20H19N2O5[M+H]+:367.1288,found:367.12896.
Example 109
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, substrate 3m (122 mg,0.5mmol,1.0 eq), HFIP (1.0 mL) and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq) with a plug closing the orifice and reacted at room temperature (25 ℃ C.) for 18 hours the reaction mixture was freed of solvent under reduced pressure, then the crude mixture was purified by flash column chromatography to afford the nitrated product 4m (colorless liquid, 143mg, yield 99％).1H NMR(600MHz,CDCl3)δ7.73(s,1H),7.38(d,J＝9.1Hz,1H),6.95(d,J＝8.8Hz,1H),4.24(q,J＝7.1Hz,2H),1.63(s,6H),1.25(t,J＝6.2Hz,3H).13C NMR(151MHz,CDCl3)δ173.31,147.65,143.32,132.92,127.22,125.24,121.51,82.17,62.03,25.16,14.16.
Example 110
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, substrate 3n (181 mg,0.5mmol,1.0 eq), HFIP (1.0 mL) and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq) with a plug closing the orifice, reacted at 80℃for 24 hours, the reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure, and the crude mixture was purified by flash column chromatography to give nitrified product 4n (colorless liquid, 187mg, yield 92％).1H NMR(600MHz,CDCl3)δ8.18(s,1H),7.90(d,J＝9.0Hz,1H),7.70(d,J＝8.2Hz,2H),7.48(d,J＝8.1Hz,2H),6.98(d,J＝8.7Hz,1H),5.08(d,J＝6.2Hz,1H),1.70(s,6H),1.22(d,J＝6.2Hz,6H).13C NMR(101MHz,CDCl3)δ192.23,172.24,152.48,141.81,139.47,135.14,134.25,131.21,130.20,129.08,127.40,118.38,82.25,69.98,25.28,21.61.
Example 111
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, substrate 3O (209 mg,0.5mmol,1.0 eq), HFIP (1.0 mL), and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq), a plug was closed off the orifice, and reacted at 60℃for 12 hours. The reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure. The crude mixture was then purified by flash column chromatography to afford the nitrated product 4O (white solid, 251mg, yield 99％).1H NMR(600MHz,DMSO)δ6.23(s,4H),4.07(s,6H),3.58(s,6H).13C NMR(151MHz,DMSO)δ162.90,149.18,138.65,135.52,119.62,107.39,104.25,61.07,53.14.HRMS m/z(ESI):calcd.for C20H17N2O14[M+H]+:509.0674,found:509.06768.
Example 112
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, substrate 3p (178 mg,0.5mmol,1.0 eq), HFIP (1.0 mL), and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq) with a plug closing the orifice, reacted at room temperature (25 ℃ C.) for 1 hour the reaction mixture was removed the solvent under reduced pressure, then the crude mixture was purified by flash column chromatography to afford nitrified product 4p (yellow solid, 108mg, yield 54％).1H NMR(600MHz,CDCl3)δ7.67(s,1H),7.66(d,J＝8.1Hz,2H),7.51(d,J＝8.1Hz,2H),7.08(s,1H),3.98(s,3H),3.72(s,2H),2.38(s,3H).13C NMR(151MHz,CDCl3)δ175.25,167.82,150.08,141.17,140.60,136.72,133.73,132.68,131.37,129.67,128.80,112.36,111.67,101.78,57.12,29.93,13.83.HRMS m/z(ESI):calcd.for C19H14ClN2O6[M-H]-:401.0546,found:401.05471.
Example 113
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, substrate 3q (136 mg,0.5mmol,1.0 eq), HFIP (1.0 mL), and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq) with a plug closing the orifice, and reacted at room temperature (25 ℃ C.) for 1 hour the reaction mixture was removed the solvent under reduced pressure, then the crude mixture was purified by flash column chromatography to afford nitrified product 4q (pale yellow solid, 111mg, yield) 70％).1H NMR(600MHz,CDCl3).δ7.83(d,J＝3.0Hz,1H),7.46(dd,J＝2.9,9.2Hz,1H),7.12(d,J＝9.1Hz,1H),4.70-4.54(m,1H),3.92(d,J＝9.9Hz,1H),3.73(dd,J＝5.7,12.1Hz,1H),3.51-3.45(m,3H),3.43-3.36(m,1H).13C NMR(151MHz,CDCl3)δ151.60,151.12,135.19,128.63,121.54,113.13,103.28,78.28,77.85,74.79,71.28,62.44.HRMS m/z(ESI):calcd.for C12H16NO9[M+H]+:318.0820,found:318.08219.
Example 114
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, substrate 3q (136 mg,0.5mmol,1.0 eq), HFIP (1.0 mL), and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq) with a plug closing the orifice and reacted at room temperature (25 ℃ C.) for 12 hours the reaction mixture was freed of solvent under reduced pressure, then the crude mixture was purified by flash column chromatography to afford the nitrated product 4q' (yellow orange solid, 156mg, yield) 86％).1H NMR(600MHz,CD3OD)δ8.02(s,2H),3.92(d,J＝12.0Hz,1H),3.76-3.68(m,1H),3.47(q,J＝10.4,10.8Hz,3H),3.41(t,J＝8.9Hz,1H),3.34-3.28(m,1H).13C NMR(151MHz,CD3OD)δ141.07,140.98,137.66,121.65,103.73,98.03,93.90,78.29,77.72,74.69,71.21,62.38.HRMS m/z(ESI):calcd.for C12H13N2O11[M-H]-:361.0525,found:361.05236.
Example 115
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, substrate 3r (227 mg,0.5mmol,1.0 eq), HFIP (1.0 mL), and Fe (NO 3)3·9H2 O (202 mg,0.5mmol,1.0 eq), a plug was closed off the orifice, and the reaction was carried out at room temperature (25 ℃ C.) for 12 hours, the solvent was removed from the reaction mixture under reduced pressure, and then the crude mixture was purified by flash column chromatography to give nitrified product 4r (pale yellow liquid, 247mg, yield 99％).1H NMR(600MHz,CDCl3)δ7.57-7.52(m,1H),7.21-7.16(m,1H),7.00(d,J＝9.1Hz,1H),5.46-5.39(m,2H),5.07(d,J＝8.1Hz,1H),4.99(d,J＝7.9Hz,1H),4.15(d,J＝6.0Hz,2H),4.07(t,J＝6.1Hz,1H),3.89(s,3H),2.14(s,3H),2.05(s,3H),2.03(s,3H),1.97(s,3H).13C NMR(101MHz,CDCl3)δ170.56,170.19,170.04,169.37,149.61,149.24,139.37,124.02,114.81,114.12,100.10,77.36,71.51,70.71,68.50,67.04,61.76,57.02,20.74,20.64,20.58,20.56.HRMS m/z(ESI):calcd.for C21H26NO13[M+H]+:500.1399,found:500.13996.
The preparation method can be used for preparing the reaction with the scale being larger than gram, and experiments of gram-scale reaction aim to prove that the preparation method can realize large-scale production, can recover the solvent used by a nitration system and can recover nitrate of the nitration reagent by simple post-treatment of dilute nitric acid. The following experiment is to realize the large-scale synthesis of part of nitroaromatic hydrocarbon by using part of substrate under the preparation method.
Example 116
A50 ml round bottom flask was charged with magnetic stirrer, substrate 1a(2.34g,15.0mmol,1.0equiv.)、Fe(NO3)3·9H2O(2.43g,6.0mmol,0.4equiv.)、HFIP(15mL)., and the round bottom flask was connected to a reflux condenser and refluxed at 100℃for 72 hours, after completion of the reaction (monitored by thin layer chromatography) the mixture was cooled to room temperature. The reaction mixture was distilled to recover the solvent HFIP. The crude mixture was then purified by a short silica gel column to afford the nitrated product 2a (2.90 g, 98%).
Example 117
A50 mL round bottom flask was charged with magnetic stirrer, substrate 1u (3.639 g,30.5mmol,1.0 equiv.), fe (NO 3)3·9H2 O (4.937 g,12.2mmol,0.4 equiv.) and HFIP (20 mL.) the round bottom flask was stirred at room temperature for 24 hours after completion of the reaction (monitored by thin layer chromatography), the mixture was cooled to room temperature the solvent HFIP was recovered by distillation and the crude mixture was purified by a short silica column to afford nitrified product 2u (4.705 g, 94%).
Comparative example 1
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, a substrate 3k (148 mg,0.5mmol,1.0 eq.), HFIP (1.0 mL) and concentrated HNO 3 (35 mg,0.5mmol,1.0 eq.) and a stopper was closed to the mouth of the tube and reacted at room temperature (25 ℃ C.) for 3 hours. The reaction mixture was freed from the solvent under reduced pressure. The crude mixture was then purified by flash column chromatography to afford the nitration product 4k (yellow orange solid, 71mg, 42% yield).
Comparative example 2
A10 mL reaction tube of transparent glass was charged with a magnetic stirrer, 3l of substrate (161 mg,0.5mmol,1.0 eq.), HFIP (1.0 mL) and concentrated HNO 3 (35 mg,0.5mmol,1.0 eq.) and a plug was closed to the tube orifice and reacted at room temperature (25 ℃ C.) for 12 hours. The reaction mixture was freed from the solvent under reduced pressure. Purification of the crude mixture by flash column chromatography then provided only a small 4l (less than 20% yield) of nitrated product.
The structural formulas of the products 2a-2fff and 4a-4r in the specific examples 1-115 of the present application are as follows:
It will be readily appreciated by those skilled in the art that the foregoing description is merely a preferred embodiment of the application and is not intended to limit the application, but any modifications, equivalents, improvements or alternatives falling within the spirit and principles of the application are intended to be included within the scope of the application.
Claims (10)
1. The nitrifying process of aromatic compound features that aromatic compound as material and nitrate as nitrifying reagent are nitrified in solvent system containing hexafluoroisopropanol to obtain aromatic nitro compound; the aromatic compound is a C6-C60 substituted or unsubstituted aromatic ring or a C4-C60 substituted or unsubstituted heterocyclic aromatic ring.
2. The nitration process of claim 1, wherein the aromatic compound is a substituted aromatic ring or a substituted heterocyclic aromatic ring, each of which is mono-or poly-substituted, and each of the substituents is independently selected from the group consisting of hydrogen, halogen, trifluoromethyl, trifluoromethoxy, nitro, cyano, phenolic hydroxyl, aldehyde, carbonyl, carboxyl, sulfonic acid, amino, acetamido, C1-C10 alkyl, C1-C10 alkoxy, C6-C30 aryloxy, C1-C10 carbonyl-containing alkyl chain, C6-C30 arylcarbonyl, C1-C10 ester, C6-C30 aryl, and C4-C30 heterocyclic aryl.
3. The nitration process of claim 1, wherein the aromatic ring is selected from the group consisting of benzene, biphenyl, fluorene, naphthalene, anthracene, phenanthrene, pyrene, piperonyl (1, 2-methylenedioxybenzene), and binaphthyl backbones;
the heterocyclic aromatic ring is selected from furan, thiophene, pyridine and indole.
4. The nitration process according to claim 1, characterized in that the substituted heterocyclic aromatic ring is selected from the group consisting of furan, thiophene, pyridine and indole bearing an electron withdrawing group, wherein the electron withdrawing group is preferably halogen, ester, carbonyl, aldehyde, carboxyl, sulfonic acid, trifluoromethyl, trifluoromethoxy, nitro.
5. The nitration process according to claim 1, wherein the aromatic compound is a drug molecule having an aromatic ring, an amino acid having an aromatic ring or a glycoside derivative having an aromatic ring, wherein
The drug molecule with aromatic ring is selected from ibuprofen, adapalene, naproxen, nabumetone, estrone, estradiol, acetaminophen, chrysin, diclofenac, pyriproxyfen, clofibrate, fenofibrate, bifendate, indomethacin, arbutin and rofecoxib;
The amino acid with an aromatic ring is selected from tyrosine and phenylalanine.
The glycoside with an aromatic ring is selected from arbutin and lactoside.
6. The nitration process of claim 1, wherein the nitrate salt is one or more of ferric nitrate, bismuth nitrate pentahydrate, ferric nitrate nonahydrate, gallium nitrate hydrate, aluminum nitrate nonahydrate, and ammonium cerium nitrate.
7. The nitration process of claim 1, wherein the solvent for the nitration reaction is hexafluoroisopropanol; or (b)
The solvent for the nitration reaction is a mixed solvent of hexafluoroisopropanol and other organic solvents, the other solvents are methylene dichloride and/or dichloroethane, and the volume ratio of the hexafluoroisopropanol to the other solvents is 1: (1-20).
8. The nitration process of claim 1, wherein the aromatic compound is fed in a molar ratio to nitrate of 1: (0.33-1).
9. The nitration process of claim 1, wherein the aromatic compound is present in the reaction system in a concentration of from 0.25 to 0.5M.
10. The nitration process according to claim 1, characterized in that the reaction temperature is between 0 ℃ and 120 ℃, preferably between 25 ℃ and 60 ℃; the reaction time is 1-36h.
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