CN108675923B - 一种由环酮化合物与2-芳基丙烯及二甲亚砜共同构建螺环化合物的方法 - Google Patents
一种由环酮化合物与2-芳基丙烯及二甲亚砜共同构建螺环化合物的方法 Download PDFInfo
- Publication number
- CN108675923B CN108675923B CN201810678427.5A CN201810678427A CN108675923B CN 108675923 B CN108675923 B CN 108675923B CN 201810678427 A CN201810678427 A CN 201810678427A CN 108675923 B CN108675923 B CN 108675923B
- Authority
- CN
- China
- Prior art keywords
- compound
- cyclic ketone
- spiro
- reaction
- ketone compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 title claims abstract description 121
- -1 cyclic ketone compound Chemical class 0.000 title claims abstract description 36
- 150000003413 spiro compounds Chemical class 0.000 title claims abstract description 26
- 238000000034 method Methods 0.000 title claims abstract description 24
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 title claims abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims abstract description 71
- USHAGKDGDHPEEY-UHFFFAOYSA-L potassium persulfate Chemical compound [K+].[K+].[O-]S(=O)(=O)OOS([O-])(=O)=O USHAGKDGDHPEEY-UHFFFAOYSA-L 0.000 claims abstract description 10
- 238000005580 one pot reaction Methods 0.000 claims abstract description 6
- 125000001424 substituent group Chemical group 0.000 claims description 27
- 125000000217 alkyl group Chemical group 0.000 claims description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
- 229910052799 carbon Inorganic materials 0.000 claims description 11
- 125000001624 naphthyl group Chemical group 0.000 claims description 11
- 150000002367 halogens Chemical class 0.000 claims description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 9
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- 239000012298 atmosphere Substances 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- LCPVQAHEFVXVKT-UHFFFAOYSA-N 2-(2,4-difluorophenoxy)pyridin-3-amine Chemical compound NC1=CC=CN=C1OC1=CC=C(F)C=C1F LCPVQAHEFVXVKT-UHFFFAOYSA-N 0.000 claims description 6
- CHQMHPLRPQMAMX-UHFFFAOYSA-L sodium persulfate Substances [Na+].[Na+].[O-]S(=O)(=O)OOS([O-])(=O)=O CHQMHPLRPQMAMX-UHFFFAOYSA-L 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 125000000623 heterocyclic group Chemical group 0.000 claims description 5
- 230000001681 protective effect Effects 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 239000011593 sulfur Substances 0.000 claims description 2
- 229930192474 thiophene Natural products 0.000 claims description 2
- 238000001308 synthesis method Methods 0.000 abstract description 5
- 230000009286 beneficial effect Effects 0.000 abstract description 4
- 239000003054 catalyst Substances 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 3
- PFUVRDFDKPNGAV-UHFFFAOYSA-N sodium peroxide Chemical compound [Na+].[Na+].[O-][O-] PFUVRDFDKPNGAV-UHFFFAOYSA-N 0.000 abstract description 2
- QNXSIUBBGPHDDE-UHFFFAOYSA-N indan-1-one Chemical compound C1=CC=C2C(=O)CCC2=C1 QNXSIUBBGPHDDE-UHFFFAOYSA-N 0.000 description 41
- HEDRZPFGACZZDS-MICDWDOJSA-N deuterated chloroform Substances [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 39
- 125000003003 spiro group Chemical group 0.000 description 36
- XYLMUPLGERFSHI-UHFFFAOYSA-N alpha-Methylstyrene Chemical group CC(=C)C1=CC=CC=C1 XYLMUPLGERFSHI-UHFFFAOYSA-N 0.000 description 20
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 19
- 239000007800 oxidant agent Substances 0.000 description 15
- 125000003118 aryl group Chemical group 0.000 description 14
- 150000001875 compounds Chemical class 0.000 description 12
- 239000002994 raw material Substances 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 8
- 239000000654 additive Substances 0.000 description 8
- 238000001228 spectrum Methods 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 7
- 230000001590 oxidative effect Effects 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 150000002500 ions Chemical class 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 5
- 239000000758 substrate Substances 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 230000000996 additive effect Effects 0.000 description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 150000002576 ketones Chemical class 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 4
- XHLHPRDBBAGVEG-UHFFFAOYSA-N 1-tetralone Chemical compound C1=CC=C2C(=O)CCCC2=C1 XHLHPRDBBAGVEG-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- 125000003342 alkenyl group Chemical group 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 3
- 125000006575 electron-withdrawing group Chemical group 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 2
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 2
- 229910002567 K2S2O8 Inorganic materials 0.000 description 2
- 239000007832 Na2SO4 Substances 0.000 description 2
- 125000005605 benzo group Chemical group 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 230000021615 conjugation Effects 0.000 description 2
- 150000003997 cyclic ketones Chemical class 0.000 description 2
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 229910052805 deuterium Inorganic materials 0.000 description 2
- 229910001873 dinitrogen Inorganic materials 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- JRKICGRDRMAZLK-UHFFFAOYSA-L peroxydisulfate Chemical compound [O-]S(=O)(=O)OOS([O-])(=O)=O JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 description 2
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 238000004293 19F NMR spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- XRKMPSLIYBXQEA-UHFFFAOYSA-N 2,3-dihydroinden-1-one;pyridine Chemical group C1=CC=NC=C1.C1=CC=C2C(=O)CCC2=C1 XRKMPSLIYBXQEA-UHFFFAOYSA-N 0.000 description 1
- NHQLDWMIASRERU-UHFFFAOYSA-N 3-phenylspiro[5.5]undec-3-en-11-one Chemical compound C1(=CC=CC=C1)C1=CCC2(CCCCC2=O)CC1 NHQLDWMIASRERU-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- 102000007471 Adenosine A2A receptor Human genes 0.000 description 1
- 108010085277 Adenosine A2A receptor Proteins 0.000 description 1
- 235000005274 Annona squamosa Nutrition 0.000 description 1
- 244000028821 Annona squamosa Species 0.000 description 1
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- 238000005698 Diels-Alder reaction Methods 0.000 description 1
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 238000006845 Michael addition reaction Methods 0.000 description 1
- 241000658707 Oxandra Species 0.000 description 1
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 1
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 238000005882 aldol condensation reaction Methods 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 239000003575 carbonaceous material Substances 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000007806 chemical reaction intermediate Substances 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 229930007927 cymene Natural products 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000010520 demethylation reaction Methods 0.000 description 1
- LSXWFXONGKSEMY-UHFFFAOYSA-N di-tert-butyl peroxide Chemical compound CC(C)(C)OOC(C)(C)C LSXWFXONGKSEMY-UHFFFAOYSA-N 0.000 description 1
- 239000012969 di-tertiary-butyl peroxide Substances 0.000 description 1
- 239000012973 diazabicyclooctane Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- LSDPWZHWYPCBBB-UHFFFAOYSA-N methyl mercaptane Natural products SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000000626 neurodegenerative effect Effects 0.000 description 1
- 238000012803 optimization experiment Methods 0.000 description 1
- 150000001451 organic peroxides Chemical class 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 230000003335 steric effect Effects 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
- C07C45/69—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by addition to carbon-to-carbon double or triple bonds
-
- 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
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/20—Spiro-condensed ring systems
-
- 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
- C07D333/06—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/22—Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom
-
- 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
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/93—Spiro compounds
- C07C2603/94—Spiro compounds containing "free" spiro atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明公开了一种由环酮化合物与2‑芳基丙烯及二甲亚砜共同构建螺环化合物的方法，该方法是环酮化合物与2‑芳基丙烯在含过硫酸钾和/或过氧化钠的二甲亚砜溶液体系中通过一锅反应，即得螺环化合物；该合成方法通过一锅法实现，且反应条件温和、无需外加催化剂、选择性好、收率高，有利于工业化生产。
Description
技术领域
本发明涉及一种螺环化合物的合成方法，特别涉及一种由环酮化合物与2-芳基丙烯及二甲亚砜共同构建螺环结构的方法，属于有机合成领域。
背景技术
螺环化合物在天然产物、药物、农药等生物活性分子中亦广泛存在(Chem.Soc.Rev.2012,41,1060-1074；Eur.J.Org.Chem.2012,1935-1944；Org.Chem. Front.2015,2849-2858；ACS Catal.2013,3,540-553)，且很多螺环化合物表现出抗肿瘤、抗高血压、抗过敏等突出的生理活性，在临床应用上被广泛应用(J.Med. Chem.1996,39,4044-4057；Med.Chem.Lett.2007,17,266-271；Synthesis-Stuttgart. 2013,45,1909-1930；J.Med.Chem.2009,52,6936-6940)。
螺茚酮化合物由于其特殊的螺环骨架表现出多种生物活性和药理活性，而被广泛关注。早期的螺茚酮化合物从天然植物中被发现，如有报道从番荔枝中分离出来的生物碱具有茚酮吡啶骨架，其衍生物被发现具有磷酸二酯酶活性和抑制腺苷A2a受体结合能力，用于治疗神经退行性疾病和炎症相关的疾病(Aran go,G.J.； Cortes,D.；et al.,Azafluorenones from Oxandra cf.major and biogenetic considerations[J].Phytochemistry,1987,26,2093-2098)。到目前为止，现有技术中已有报道合成螺茚酮化合物的方法，如比较典型的是1-茚酮和甲醛先进行缩合反应、继而和乙酰基丙二烯反应，可得到含1-茚酮骨架螺环类化合物(Tetrahedron Lett.2013,54,4425-4428)。又如从1-茚酮出发，与丙烯酸酯经过迈克尔缩合、迪克曼缩合，也可以合成含1-茚酮骨架螺环类化合物(Helv Chim Acta 1995,78, 857-865)。但这些方法均存在流程长、原料不易得、总收率低、后处理复杂等缺点。中国专利(CN108047007A)公开了一种含1-茚酮骨架螺环类化合物的合成方法，其以芳香羧酸和α,β-不饱和酮为原料，采用伞花烃二氯化钌二聚体等催化剂以及锰、锌等重金属添加剂，通过一步法经历了芳香羧酸邻位C-H键和α,β- 不饱和酮的共轭加成反应、分子内脱水环化、与第二分子α,β-不饱和酮的迈克尔加成、分子内羟醛缩合等四步反应合成了1-茚酮骨架螺环类化合物(反应路线如下)，虽然该方法通过一步反应合成1-茚酮骨架螺环类化合物，但是需要采用昂贵的催化剂，且用到重金属添加剂，不利于环保，成本较高。
发明内容
针对现有的构建螺环结构的方法存在步骤复杂，成本高，对环境不友好等缺陷，本发明的目的是在于提供一种由环酮化合物提供α-碳、DMSO提供甲基以及2-芳基丙烯提供丙烯共同构建螺环结构的方法，该合成方法通过一锅法实现，且反应条件温和、无需外加催化剂、选择性好、收率高，有利于工业化生产。
为了实现上述技术目的，本发明提供了一种由环酮化合物与2-芳基丙烯及二甲亚砜共同构建螺环化合物的方法，该方法是环酮化合物与2-芳基丙烯在含过硫酸钾和/或过氧化钠的二甲亚砜溶液体系中通过一锅反应，即得螺环化合物；
所述螺环化合物具有式1结构：
所述环酮化合物具有式2结构：
所述2-芳基丙烯具有式3结构：
其中，
Ar1为芳环或芳杂环，且芳环或芳杂环上含有取代基或不含取代基；
Ar2为芳基；
n为1～3。
优选的方案，环酮化合物参与反应的是α碳，其包含的取代基团对环化反应的电子效应和空间位阻效应影响明显，Ar1为芳环或芳杂环时，由于芳环可以与羰基参与共轭，能够明显增加α碳的活性。Ar1为芳杂环时，芳杂环可以为五元环或是六元环，最好是五元环。杂环上的杂环数可以为1～2个，最好是含一个杂原子。杂原子一般为氧、氮、硫等，如呋喃、吡咯或噻吩等。杂环上也可以含一些常规的取代基，如卤素(氟、氯、溴或碘等)或短链烷基(一般碳原子数少于 5)等。Ar1为芳环时，芳环可以是苯环或萘环，同时，苯环或萘环上可以含一些常规的取代基，如卤素(氟、氯、溴或碘)或短链烷基(一般碳原子数少于5)、烷氧基(C1～C5的烷氧基)等。苯环或萘环上的取代基的个数为1～2个。
本发明的2-芳基丙烯中，Ar2较优选为苯基、取代苯基、萘基或取代萘基。 Ar2选自取代苯基时，所述取代苯基包含的取代基个数为1～2个，取代基选自卤素取代基、烷基中至少一种。卤素取代基如氟、氯、溴、碘等。烷基为C1～C10的烷基；更优选为C1～C5的短链烷基，如甲基、乙基、丙基等，也可以为含支链的烷基，如异丙基、异丁基等。取代基的个数最好为1个，且取代基位置最好为对位(相对烯基)。2-芳基丙烯的选择范围局限在选择芳基取代基，芳基取代基提供大共轭体系，能使烯基上的甲基具有足够的活性参与环化。芳基取代基不能随意由其它取代基团替换，如芳杂环、烷基等替换芳基均不能获得目标产物。当 Ar1选择取代苯基时，取代基的位置最好是烯基的对位，且取代基可以为弱推电子基团，如烷基，也可以为弱拉电子基团，如卤素。而强推电子基团，如胺基、烷氧基，强拉电子基团，如硝基，难以获得理想的收率。
优选的方案，过硫酸钾和过硫酸钠总摩尔量与环酮化合物的摩尔量比为 1～2:1。较优选为1.3～1.8:1。
优选的方案，环酮化合物与2-芳基丙烯的摩尔比为1:1.5～2.5。
优选的方案，环酮化合物在二甲亚砜溶液体系中的浓度为0.1～0.5mol/L。二甲基亚砜主要起到两方面的作用，一方面起到良性溶剂的作用，另一方面作为反应底物，由两个二甲亚砜提供两个甲基作为螺环结构中环己烯环中的两个碳原子。
较优选的方案，所述反应的条件为：在保护气氛下，于120～150℃温度下，反应20～28h。较优选的方案，所述反应的条件为：在保护气氛下，于135～145℃温度下，反应22～26h。保护气氛一般指氮气或惰性气氛或两者的混合气氛。
本发明以1-茚酮与二甲亚砜及2-苯基丙烯共同构建螺环结构来对反应机理进行说明。经过查阅和参考相关文献，设计了一系列的机理研究实验，如下反应方程式(1)～(6)所示。为了证明该反应是否经过自由基的反应历程，设计了反应(1)，在标准反应条件下加入2.0当量(相对1-茚酮)的2,6-二叔丁基对甲酚(BHT)，反应12h，结果通过GC-MS仍然能顺利检测到螺环结构目标产物的生成，说明反应并没有被抑制，反应没有经历一个自由基的反应历程。为了证明该反应是否存在反应中间体，将1-茚酮与二甲亚砜及2-苯基丙烯在标准反应条件下反应12小时，通过在GC-MS检测，除了检测到目标产物螺环化合物，同时也检测到化合物B和化合物C的存在。为了证明化合物B和C是否为螺环结构构建过程中的中间体，设计了反应(2)和反应(3)，以化合物B为原料替换 2-苯基丙烯，在标准条件下反应，同时还以化合物C为原料替换化合物1-茚酮，惊喜地发现，通过GC-MS均成功检测到螺环结构，说明化合物B和C为螺环结构合成过程中可能存在的中间体。为了进一步弄清化合物B的来源，进一步设计了反应(4)，将2-苯基丙烯与二甲亚砜直接在标准条件下进行反应，通过在GC-MS检测发现了化合物B的存在，同时还获得了化合物A。为了进一步弄清化合物C的来源，进一步设计了反应(5)，将2-苯基丙烯与二甲亚砜直接在标准条件下进行反应，通过在GC-MS检测发现了化合物C的存在，同时还获得了化合物D。为了获得更准确的验证二甲亚砜是否参与螺环结构中环己烯环的生成，设计了反应(6)，采用同位素标记的氘代二甲亚砜替换常规的二甲基亚砜在标准条件下反应，成功地在螺环结构的环己烯环中检测到氘的存在，并且在两个碳原子上检测到氘的存在，说明由二甲基亚砜提供了两个甲基。标准反应条件：在 N2下，将1-茚酮(0.5mmol)，α-甲基苯乙烯(0.75mmol)和DMSO(2mL)，140℃，反应24h。
反应式(1):
反应式(2):
反应式(3)：
反应式(4):
反应式(5)：
反应式(6):
根据上述实验，本发明提出了由1-茚酮与二甲亚砜及2-苯基丙烯共同构建螺环结构的合理机理：如下反应方程式所示。首先，采用K2S2O8活化DMSO，得到使DMSO转化成二甲基硫正离子，同时2-苯基丙烯释放氢质子，转化成2- 苯基丙烯负离子，1-茚酮也释放氢质子，变成1-茚酮负离子，2-苯基丙烯负离子和1-茚酮负离子均很容易偶联二甲基硫正离子生成硫甲醚类化合物A和D，硫甲醚类化合物A和D在K2S2O8氧化作用下，经过去甲基化反应脱除小分子甲基硫醇化合物，得到化合物B和C，化合物B与化合物C发生迪尔斯阿尔德反应，最终得到目标产物。
相对现有技术，本发明的技术方案带来的有益技术效果：
1)本发明的螺环结构由环酮和环己烯构成，且可以包含丰富的取代基，及可修饰基团，为以螺环结构为母体的药物等合成提供有效的中间体。
2)本发明首次由环酮化合物提供α碳、2-芳基丙烯提供丙烯基以及二甲基亚砜提供甲基成功构建螺环结构，为螺环结构的构建提供了一种全新的合成思路。
3)本发明的螺环结构的合成过程中无需使用催化剂，相对现有的合成方法，避免了使用昂贵及具有污染性质的催化剂和添加剂，有利于降低成本和环保。
4)本发明的螺环合成过程中采用环酮化合物、2-芳基丙烯以及二甲基亚砜作为基本原料，都为现有的常规化工原料，成本低廉，有利于工业化生产。
5)本发明的螺环结构的合成过程中采用一锅法反应，且反应条件温和，操作简单，满足工业生产要求。
6)本发明的螺环结构合成过程中原料利用率高，产物收率可以达到80％以上。
7)本发明的螺环结构合成过程中对底物原料的适应范围较广，可以构建多种取代基团的螺环化合物，且取代基位置选择性强。
附图说明
【图1】为1'-phenyl-6,7-dihydro-4H-spiro[benzo[b]thiophene-5,4'-cyclohex[6]en]- 4-one的核磁碳谱图。
【图2】为1'-phenyl-6,7-dihydro-4H-spiro[benzo[b]thiophene-5,4'-cyclohex[6]en]- 4-one的核磁氢谱图。
【图3】为1-(4-fluorophenyl)spiro[cyclohex[6]ene-4,2'-inden]-1'(3'H)-one的核磁碳谱图。
【图4】为1-(4-fluorophenyl)spiro[cyclohex[6]ene-4,2'-inden]-1'(3'H)-one的核磁氢谱图。
【图5】为1-phenylspiro[cyclohex[6]ene-4,2'-inden]-1'(3'H)-one的核磁碳谱图。
【图6】为1-phenylspiro[cyclohex[6]ene-4,2'-inden]-1'(3'H)-one的核磁氢谱图。
【图7】为6'-methoxy-1-phenylspiro[cyclohex[6]ene-4,2'-inden]-1'(3'H)-one的核磁碳谱图。
【图8】为6'-methoxy-1-phenylspiro[cyclohex[6]ene-4,2'-inden]-1'(3'H)-one的核磁氢谱图。
具体实施方式
以下实施例旨在进一步说明本发明内容，而不是限制本发明权利要求的保护范围。
除另有说明外，所有反应均在Schlenk试管中进行。
所有反应原料溶剂从商业来源获得，并且不经进一步纯化而使用。
产品分离采用硅胶色谱柱，硅胶(粒度300目-400目)。
1H NMR(400MHz)、13C NMR(100MHz)和19F NMR(376MHz)检测采用Bruker ADVANCEIII光谱仪，以CDCl3为溶剂，以TMS为内标，化学位移以百万分率(ppm)计，以四甲基硅烷的0.0ppm为参考位移。使用以下缩写(或其组合)来解释多重性：s＝单峰，d＝双峰，t＝三重峰，q＝四重峰，m＝多重峰， br＝宽峰。偶合常数J的单位为赫兹(Hz)。化学位移以ppm表示，参考氘代氯仿在77.0ppm三重态的中心线或参考氘代DMSO在39.52ppm七重态的中心线。
GC-MS采用GC-MS QP2010设备检测，HRMS采用电子电离(EI)方法测量，质量分析仪类型为TOF，EI采用Esquire 3000plus仪器检测。
1.条件优化实验:
由1-茚酮与二甲亚砜及2-苯基丙烯共同构建螺环结构为例，对氧化剂及其用量、反应温度、反应溶剂及添加剂等多个影响因素进行了探讨，以寻求最佳的反应条件。
具体反应过程：将1-茚酮、α-甲基苯乙烯、氧化剂、添加剂和DMSO，在N2气氛下，反应24h。
反应路线如下：
表1：不同反应条件下目标产物螺环结构的收率
1)添加剂的选择
从表1中看出，添加剂的使用对反应有很大的影响，大量实验表明，如表1 中项目1～6和11，在1-茚酮与二甲亚砜及2-苯基丙烯构建螺环结构的反应过程中，还没有发现有利于提高反应效率，增加收率的良性添加剂，如DABCO、DBU、 K2CO3、Cs2CO3、Et3N或NaOAc等碱性物质作为添加剂使用时，明显抑制反应，基本得不到目标产物螺环化合物。
3)氧化剂的选择
本发明尝试了本领域几种常见的氧化剂，如表1中项目9～15，氧化剂如过硫酸盐、有机过氧化物、无机双氧水等，发现仅在过硫酸钾或过硫酸钠作为氧化剂时具有较好的反应效果，当使用叔丁基过氧化氢(TBHP)、DTBP或双氧水 (H2O2)作为氧化剂时几乎没有得到目标产物，因此，选择过过硫酸钾或过硫酸钠作为最优的氧化剂。
4)氧化剂用量的选择
在确定过硫酸钾及过硫酸钠等为最佳氧化剂后，探索不同用量的氧化剂对反应的影响。如表1中项目11、16和17。当氧化剂的用量在0.5～0.75当量之间时，随着氧化剂量的增大，其原料的转化率及产物的产率也随之增大。而当氧化剂的用量大于0.75当量时，其产率下降明显。因此，0.75当量的过硫酸盐为反应的最佳用量。
5)反应温度的选择
反应温度是影响化学反应过程的一个重要因素，为了得到最佳反应温度，研究了在不同温度下该反应的产率，如表1中项目7～11。在小于100℃温度，基本上得不到目标产物，温度达到120℃以上时，反应产率明显提高，升高温度到140℃，反应产率达到最高，而高于140℃，反应副反应明显。因此，140℃为该反应的最适温度。
6)反应溶剂的选择
由于DMSO在合成二氢吡喃过程中是同时作为反应底物和溶剂，是其他溶剂不可替换的。本发明的溶剂可以采用DMSO，同时也可以采用DMSO与其它溶剂的混合溶剂。
2.反应底物的选择范围：
在确定了螺环结构最优合成条件后，对反应的底物范围及适用性进行了探究，实验结果如表2和表3所示。表2为不同的环酮化合物与2-苯基丙烯及DMSO 的反应结果。从表2中可以看出，茚酮类及芳杂环并环酮类等均可以与2-苯基丙烯及DMSO在标准的反应条件下有效地合成对应的螺环结构，且目标产物的产率在70％左右，最高可达80％以上，收率是比较理想的。并且，大量实验表明环酮化合物中羰基最好是连接在共轭体系上，如苯环、萘环、芳杂环等上，由于羰基可以参与共轭可以明显提高羰基α碳的活性，易于失去氢质子，使其能顺利与2-苯基丙烯及DMSO构建螺环结构，产率在80％左右。如环酮羰基如果连接其他非共轭基团，如烷基等，环酮与2-苯基丙烯及DMSO构建螺环的收率明显降低。表3为不同2-芳基丙烯与1-茚酮或苯并环己酮及DMSO的反应结果，实验结果表明，丙烯上2位取代基必须是具有大共轭体系的基团，如芳基，其他的芳杂环、烷基等均无法满足要求，大共轭体系的芳基有利于提高α-甲基的活性。而芳基上的取代基的选择也是由要求的，不能为推电子或拉电子能力较强的取代基团，如硝基、烷氧基等，而推电子或拉电子能力较若的取代基团，如卤素、烷基等均满足要求。取代基的位置最好是对位。
(1)不同的环酮化合物与2-苯基丙烯及DMSO的反应方程式如下：
称取过二硫酸钾(K2S2O8)(202.5mg，0.75mmol)，环酮化合物(0.5mmol) 置于25ml的施伦克反应管中，再向其中加入二甲亚砜(DMSO，2ml)，2-苯基丙烯(118mg，1mmol)，充入氮气。140℃下，搅拌24小时。反应完成后，冷却至室温，加水(4ml)，乙酸乙酯萃取(3*5ml)，无水Na2SO4干燥，减压蒸馏掉溶剂后，硅胶柱(200-300目)分离，得到目标产物螺环结构。
表2.不同的环酮化合物与2-苯基丙烯及DMSO反应结果
(2)不同2-芳基丙烯与1-茚酮或苯并环己酮及DMSO的反应方程式如下：
称取过二硫酸钾(K2S2O8)(202.5mg,0.75mmol)，1-茚酮或苯并环己酮(0.5 mmol)置于25ml的施伦克反应管中，再向其中加入二甲亚砜(DMSO，2ml)， 2-芳基丙烯(1mmol)，充入氮气。140℃下，搅拌24小时。反应完成后，冷却至室温，加水(4ml)，乙酸乙酯萃取(3*5ml)，无水Na2SO4干燥，减压蒸馏掉溶剂后，硅胶柱(200-300目)分离，得到目标产物螺环化合物。
表3不同2-芳基丙烯与1-茚酮或苯并环己酮及DMSO的反应结果
部分螺环化合物的分子结构表征：
1-phenylspiro[cyclohex[6]ene-4,2'-inden]-1'(3'H)-one；
13C NMR(101MHz,CDCl3)δ211.07,152.80,141.52,136.05,135.90,134.95,128.36,127.52, 127.02,126.74,125.06,124.36,122.55,48.17,39.10,35.08,29.30,24.86.
5'-fluoro-1-phenylspiro[cyclohex[6]ene-4,2'-inden]-1'(3'H)-one；
13C NMR(101MHz,CDCl3)δ209.12,168.70,155.66(d,J＝10.0Hz),141.40,136.08,132.25, 128.38,127.09,126.64(d,J＝10.5Hz),125.05,122.32,115.86(d,J＝23.8Hz),113.32(d,J＝22.1 Hz),48.54,39.00,35.04,29.27,24.76
5'-chloro-1-phenylspiro[cyclohex[6]ene-4,2'-inden]-1'(3'H)-one；
13C NMR(101MHz,CDCl3)δ209.53,154.25,141.43,141.35,136.08,134.34,128.40,128.37, 127.11,126.93,125.48,125.05,122.26,48.46,38.82,35.03,29.28,24.75.
6'-bromo-1-phenylspiro[cyclohex[6]ene-4,2'-inden]-1'(3'H)-one；
13C NMR(101MHz,CDCl3)δ209.53,151.26,141.35,137.77,137.65,136.10,128.39,128.32, 127.27,127.11,125.05,122.23,121.67,48.80,38.72,35.02,29.26,24.77.
4'-methyl-1-phenylspiro[cyclohex[6]ene-4,2'-inden]-1'(3'H)-one；
13C NMR(101MHz,CDCl3)δ211.40,151.78,141.45,136.00,135.90,135.67,135.39,128.38, 127.75,127.05,125.03,122.63,121.74,48.03,37.97,35.22,29.34,24.87,17.91.
6'-methyl-1-phenylspiro[cyclohex[6]ene-4,2'-inden]-1'(3'H)-one；
13C NMR(101 MHz,CDCl3)δ211.17,150.14,141.55,137.44,136.23,136.04,136.01,128.36, 127.00,126.43,125.05,124.26,122.63,48.50,38.75,35.14,29.33,24.88,21.15.
5'-methoxy-1-phenylspiro[cyclohex[6]ene-4,2'-inden]-1'(3'H)-one；
13C NMR(101 MHz,CDCl3)δ209.15,165.56,155.66,141.58,135.99,129.07,128.34,126.96, 126.02,125.03,122.70,115.45,109.86,55.65,48.31,39.17,35.16,29.38,24.87.
6'-methoxy-1-phenylspiro[cyclohex[6]ene-4,2'-inden]-1'(3'H)-one；
13C NMR(101 MHz,CDCl3)δ211.07,159.53,145.59,141.53,137.00,136.01,128.37,127.46, 127.02,125.05,124.37,122.60,105.43,55.63,49.04,38.44,35.19,29.37,24.91.
1-phenyl-3',4'-dihydro-1'H-spiro[cyclohex[6]ene-4,2'-naphthalen]-1'-one；
13C NMR(101 MHz,CDCl3)δ202.43,143.23,141.52,134.74,133.16,131.81,128.73,128.33, 128.11,126.87,126.71,124.98,122.39,43.07,32.50,30.34,28.00,25.24,24.45.
7'-bromo-1-phenyl-3',4'-dihydro-1'H-spiro[cyclohex[6]ene-4,2'-naphthalen]-1'-one；
13C NMR(101 MHz,CDCl3)δ201.05,141.86,141.39,135.88,134.80,133.35,130.86,130.55, 128.33,126.92,124.97,122.08,120.72,42.95,32.37,30.10,27.89,24.76,24.38.
1'-phenyl-6,7-dihydro-4H-spiro[benzo[b]thiophene-5,4'-cyclohex[6]en]-4-one；
13C NMR(101 MHz,CDCl3)δ197.46,153.96,141.49,136.15,134.67,128.31,126.87,125.68, 124.97,123.48,122.40,42.86,31.96,31.77,27.94,24.56,22.07.
9-phenylspiro[5.5]undec-8-en-1-one；
13C NMR(101 MHz,CDCl3)δ215.34,141.55,135.04,128.22,126.75,124.94,122.10,47.01, 38.55,36.62,33.23,29.66,27.91,24.05,20.96.
1'-phenyl-8,9-dihydrospiro[benzo[7]annulene-6,4'-cyclohex[6]en]-5(7H)-one；
13C NMR(101 MHz,CDCl3)δ213.68,141.56,141.43,137.17,135.76,130.30,128.72,128.28, 126.98,126.88,126.44,125.00,122.19,48.47,35.68,34.66,34.10,30.24,24.58,23.23.
1-(p-tolyl)spiro[cyclohex[6]ene-4,2'-inden]-1'(3'H)-one；
13C NMR(101 MHz,CDCl3)δ211.14,152.84,138.67,136.70,135.93,135.82,134.92,129.04, 127.49,126.73,124.91,124.35,121.68,48.22,39.08,35.07,29.30,24.86,21.09.
1-(4-chlorophenyl)spiro[cyclohex[6]ene-4,2'-inden]-1'(3'H)-one；
13C NMR(101 MHz,CDCl3)δ210.83,152.69,139.92,135.83,135.00,132.69,128.44,127.57, 126.74,126.33,124.38,123.18,48.01,39.13,35.02,29.23,24.80.
1-(4-fluorophenyl)spiro[cyclohex[6]ene-4,2'-inden]-1'(3'H)-one；
13C NMR(101 MHz,CDCl3)δ210.92,162.04(d,J＝245.9 Hz),152.72,137.63,135.86,135.14, 134.97,127.55,126.72,126.57(d,J＝7.8 Hz),124.38,122.45,115.10(d,J＝21.3 Hz),48.05,39.12, 35.00,29.26,25.02.
4-(naphthalen-2-yl)spiro[cyclohex[3]ene-1,2'-inden]-1'(3'H)-one；
13C NMR(101 MHz,CDCl3)δ211.05,152.83,138.64,135.92,135.80,135.00,133.54,132.64, 128.14,127.85,127.57,126.78,126.18,125.68,124.40,123.70,123.44,123.28,48.24,39.15, 35.24,29.36,24.87.
1-(4-fluorophenyl)-3',4'-dihydro-1'H-spiro[cyclohex[6]ene-4,2'-naphthalen]-1'-one；
13C NMR(101 MHz,CDCl3)δ202.32,160.73,143.16,137.67,133.86,133.17,131.77,128.71, 128.09,126.71,126.47(d,J＝7.8 Hz),122.27,115.03(d,J＝21.2 Hz),42.97,32.48,30.51,27.98, 25.20,24.6。
Claims (5)
1.一种由环酮化合物与2-芳基丙烯及二甲亚砜共同构建螺环化合物的方法，其特征在于：环酮化合物与2-芳基丙烯在含过硫酸钾和/或过硫酸钠的二甲亚砜溶液体系中通过一锅反应，即得螺环化合物；
所述螺环化合物具有式1结构：
式1
所述环酮化合物具有式2结构：
式2
所述2-芳基丙烯具有式3结构：
式3
其中，
Ar1为苯环、萘环或芳杂环，且苯环或萘环不含取代基或包含卤素、碳原子数少于5的烷基、C1~C5烷氧基中至少一种取代基，芳杂环不含取代基或包含碳原子数少于5的烷基、卤素中至少一种取代基；所述芳杂环为含氧、氮或硫中至少一种的五元杂环；
Ar2为苯基、取代苯基、萘基或取代萘基；所述取代苯基包含卤素或C1~C5烷基中至少一种取代基；所述取代萘基包含卤素或C1~C5烷基中至少一种取代基；
n为1~3；
过硫酸钾和过硫酸钠的总摩尔量与环酮化合物的摩尔量比为1~2:1；
所述反应的条件为：在保护气氛下，于120~150℃温度下，反应20~28h。
2.根据权利要求1所述的一种由环酮化合物与2-芳基丙烯及二甲亚砜共同构建螺环化合物的方法，其特征在于：所述芳杂环为噻吩、呋喃或吡咯。
3.根据权利要求1所述的一种由环酮化合物与2-芳基丙烯及二甲亚砜共同构建螺环化合物的方法，其特征在于：环酮化合物与2-芳基丙烯的摩尔比为1:1.5~2.5。
4.根据权利要求1所述的一种由环酮化合物与2-芳基丙烯及二甲亚砜共同构建螺环化合物的方法，其特征在于：环酮化合物在二甲亚砜溶液体系中的浓度为0.1~0.5mol/L。
5.根据权利要求1所述的一种由环酮化合物与2-芳基丙烯及二甲亚砜共同构建螺环化合物的方法，其特征在于：所述反应的条件为：在保护气氛下，于135~145℃温度下，反应22~26h。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810678427.5A CN108675923B (zh) | 2018-06-27 | 2018-06-27 | 一种由环酮化合物与2-芳基丙烯及二甲亚砜共同构建螺环化合物的方法 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810678427.5A CN108675923B (zh) | 2018-06-27 | 2018-06-27 | 一种由环酮化合物与2-芳基丙烯及二甲亚砜共同构建螺环化合物的方法 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108675923A CN108675923A (zh) | 2018-10-19 |
| CN108675923B true CN108675923B (zh) | 2021-04-27 |
Family
ID=63812292
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810678427.5A Active CN108675923B (zh) | 2018-06-27 | 2018-06-27 | 一种由环酮化合物与2-芳基丙烯及二甲亚砜共同构建螺环化合物的方法 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108675923B (zh) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102348698A (zh) * | 2009-03-13 | 2012-02-08 | 生命医药公司 | β-分泌酶的抑制剂 |
| CN108047007A (zh) * | 2018-01-09 | 2018-05-18 | 陕西师范大学 | 一种含1-茚酮骨架螺环类化合物的合成方法 |
-
2018
- 2018-06-27 CN CN201810678427.5A patent/CN108675923B/zh active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102348698A (zh) * | 2009-03-13 | 2012-02-08 | 生命医药公司 | β-分泌酶的抑制剂 |
| CN108047007A (zh) * | 2018-01-09 | 2018-05-18 | 陕西师范大学 | 一种含1-茚酮骨架螺环类化合物的合成方法 |
Non-Patent Citations (2)
| Title |
|---|
| Mizoroki-Heck Cyclizations of Amide Derivatives for the Introduction of Quaternary Centers;Medina,Jose M等;《ANGEWANDTE CHEMIE-INTERNATIONAL EDITION》;20170601;第56卷(第23期);第6567-6571页 * |
| Synthesis of Spiro[cyclohexane-l,2"-[2H]indene] Derivatives as Inhibitors of Steroid 5α-Reductase;Shu-Kun Lin等;《HELVETICA CHIMICA ACTA》;19951231;第78卷(第4期);第857-865页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN108675923A (zh) | 2018-10-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Han et al. | Total synthesis, stereochemical assignment, and biological activity of all known (−)-trigonoliimines | |
| Sá et al. | Fast and efficient preparation of Baylis–Hillman-derived (E)-allylic azides and related compounds in aqueous medium | |
| Liu et al. | Oxidative radical ring-opening/cyclization of cyclopropane derivatives | |
| Fang et al. | gem-Dialkylthio vinylallenes: Alkylthio-regulated reactivity and application in the divergent synthesis of pyrroles and thiophenes | |
| Tiefenbacher et al. | An expeditious asymmetric formal synthesis of the antibiotic platensimycin | |
| Reddy et al. | Sc (OTf) 3-catalyzed intramolecular aza-Prins cyclization for the synthesis of heterobicycles | |
| Boruah et al. | KF/Al2O3 mediated 1, 3-dipolar cycloaddition of azomethine ylides: a novel and convenient procedure for the synthesis of highly substituted pyrrolidines | |
| Liu et al. | Regioselective biomimetic oxidation of halogenated resveratrol for the synthesis of (±)-ε-viniferin and its analogues | |
| Huang et al. | Cp∗ Rh/Ag catalyzed C–H activation/cyclization sequences of NH-sulfoximines to fused aza-polyheterocycles under gentle conditions | |
| CN108675922B (zh) | 一种螺环化合物及其合成方法 | |
| Wang et al. | Copper (I)-catalyzed direct oxidative annulation of 1, 3-dicarbonyl compounds with maleimides: Access to polysubstituted dihydrofuran derivatives | |
| Mali et al. | Development and applications of double Diels‐Alder reaction in organic synthesis | |
| CN108675923B (zh) | 一种由环酮化合物与2-芳基丙烯及二甲亚砜共同构建螺环化合物的方法 | |
| CN108148021B (zh) | 2-亚胺(3h)多取代呋喃或噻吩衍生物及其合成 | |
| Wynberg et al. | The Synthesis of 1H, 3H-Thieno [3, 4-c] thiophene1, 2 | |
| Guha et al. | A facile synthesis of 2-(2-phenyl-4H-chromen-4-ylidene)-2H-indene-1, 3-diones and related compounds involving an interesting aerial oxidation | |
| Li-Zhulanov et al. | Cascade transformation of 4-hydroxymethyl-2-carene into novel cage methanopyrano [4, 3-b] thieno [3, 2-g] benzofuran derivative | |
| Chang et al. | Trifluoroacetic Anhydride Mediated One-Pot Synthesis of 1-Aryl Isochroman-3-ones via the Carboxy-Pictet–Spengler Reaction | |
| Kondo et al. | Synthetic utility of tert-butyl azidoacetate on the Hemetsberger-Knittel reaction (synthetic studies of indoles and related compounds part 47) | |
| CN108675921B (zh) | 一种螺茚酮化合物的合成方法 | |
| Raiman et al. | A convenient approach to the synthesis of 2-(2-aminoethyl) pyrroles and their heterocyclization into hydrogenated pyrrolopyridines and related pyrroloindolizines | |
| CN108863739B (zh) | 一种由芳基乙酮与2-芳基丙烯及二甲基亚砜构建环己烯衍生物的方法 | |
| Robert et al. | Neat total synthesis of six monoterpenic alkaloids of the actinidine series | |
| Yu et al. | Catalyst-free and atom-economic synthesis of substituted 1-acetyl and 1-hydroxyl carbazoles | |
| Lee et al. | Rh~ 2 (Opiv)~ 4-Catalyzed Reactions of Diazo Compound Derived from Meldrum's Acid and Styrenes. Efficient Synthesis of Cyclopropanes |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20240822 Address after: No. 87, Suzhong Avenue, Shangku Comprehensive Industrial Park, Korla City, Bazhou, Xinjiang Uygur Autonomous Region, 841000 Patentee after: Xinjiang Puhesu New Environmental Protection Materials Co.,Ltd. Country or region after: China Address before: No.1 shijihu Chuangye Road, Yuanjiang City, Yiyang City, Hunan Province 413100 Patentee before: YUANJIANG HUALONG CATALYST TECHNOLOGY Co.,Ltd. Country or region before: China |