CN106966889A - 一种(E)‑β,γ‑烯基羧酸衍生物及其制备方法 - Google Patents
一种(E)‑β,γ‑烯基羧酸衍生物及其制备方法 Download PDFInfo
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- CN106966889A CN106966889A CN201710278535.9A CN201710278535A CN106966889A CN 106966889 A CN106966889 A CN 106966889A CN 201710278535 A CN201710278535 A CN 201710278535A CN 106966889 A CN106966889 A CN 106966889A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 31
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims abstract description 81
- 239000000758 substrate Substances 0.000 claims abstract description 75
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 claims abstract description 65
- 238000006473 carboxylation reaction Methods 0.000 claims abstract description 42
- 229910002092 carbon dioxide Inorganic materials 0.000 claims abstract description 41
- 239000001569 carbon dioxide Substances 0.000 claims abstract description 40
- 239000003638 chemical reducing agent Substances 0.000 claims abstract description 26
- 239000007868 Raney catalyst Substances 0.000 claims abstract description 23
- 229910000564 Raney nickel Inorganic materials 0.000 claims abstract description 23
- 239000000654 additive Substances 0.000 claims abstract description 23
- 230000000996 additive effect Effects 0.000 claims abstract description 22
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 19
- 239000003960 organic solvent Substances 0.000 claims abstract description 12
- 239000000126 substance Substances 0.000 claims abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims description 67
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 66
- 239000002585 base Substances 0.000 claims description 39
- -1 Phenyl Chemical group 0.000 claims description 30
- 239000002904 solvent Substances 0.000 claims description 25
- 230000015572 biosynthetic process Effects 0.000 claims description 22
- 150000001875 compounds Chemical class 0.000 claims description 20
- 238000000034 method Methods 0.000 claims description 20
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 19
- 229910052759 nickel Inorganic materials 0.000 claims description 18
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 17
- TVDSBUOJIPERQY-UHFFFAOYSA-N prop-2-yn-1-ol Chemical class OCC#C TVDSBUOJIPERQY-UHFFFAOYSA-N 0.000 claims description 17
- 125000001424 substituent group Chemical group 0.000 claims description 17
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
- 125000006239 protecting group Chemical group 0.000 claims description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 14
- 239000012675 alcoholic extract Substances 0.000 claims description 14
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 14
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 13
- 239000011572 manganese Substances 0.000 claims description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 11
- 230000008859 change Effects 0.000 claims description 11
- 238000001035 drying Methods 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- 239000012074 organic phase Substances 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 238000010790 dilution Methods 0.000 claims description 9
- 239000012895 dilution Substances 0.000 claims description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 8
- 125000004185 ester group Chemical group 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 8
- 239000000376 reactant Substances 0.000 claims description 8
- 125000001544 thienyl group Chemical group 0.000 claims description 8
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 claims description 7
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 7
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 7
- 238000006467 substitution reaction Methods 0.000 claims description 7
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 238000012805 post-processing Methods 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 4
- 239000005695 Ammonium acetate Substances 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical group [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 claims description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 4
- VEQPNABPJHWNSG-UHFFFAOYSA-N Nickel(2+) Chemical compound [Ni+2] VEQPNABPJHWNSG-UHFFFAOYSA-N 0.000 claims description 4
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims description 4
- 229910052783 alkali metal Inorganic materials 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- 125000000304 alkynyl group Chemical group 0.000 claims description 4
- 235000019257 ammonium acetate Nutrition 0.000 claims description 4
- 229940043376 ammonium acetate Drugs 0.000 claims description 4
- ITCMXBVIXVDAKR-UHFFFAOYSA-M azanium tetrabutylazanium diacetate Chemical group C(C)(=O)[O-].[NH4+].C(CCC)[N+](CCCC)(CCCC)CCCC.C(C)(=O)[O-] ITCMXBVIXVDAKR-UHFFFAOYSA-M 0.000 claims description 4
- 150000001721 carbon Chemical group 0.000 claims description 4
- 150000007942 carboxylates Chemical class 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 239000012043 crude product Substances 0.000 claims description 4
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- 150000004820 halides Chemical class 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 239000011630 iodine Substances 0.000 claims description 4
- 229910052748 manganese Inorganic materials 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- 125000001453 quaternary ammonium group Chemical group 0.000 claims description 4
- 150000003568 thioethers Chemical class 0.000 claims description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 3
- 229910021586 Nickel(II) chloride Inorganic materials 0.000 claims description 3
- XIXADJRWDQXREU-UHFFFAOYSA-M lithium acetate Chemical compound [Li+].CC([O-])=O XIXADJRWDQXREU-UHFFFAOYSA-M 0.000 claims description 3
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical group Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 claims description 3
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 229920006395 saturated elastomer Polymers 0.000 claims description 3
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 3
- 239000011701 zinc Substances 0.000 claims description 3
- 239000004912 1,5-cyclooctadiene Substances 0.000 claims description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 2
- 150000001298 alcohols Chemical class 0.000 claims description 2
- 150000001345 alkine derivatives Chemical class 0.000 claims description 2
- 235000019270 ammonium chloride Nutrition 0.000 claims description 2
- ZOAIGCHJWKDIPJ-UHFFFAOYSA-M caesium acetate Chemical compound [Cs+].CC([O-])=O ZOAIGCHJWKDIPJ-UHFFFAOYSA-M 0.000 claims description 2
- 150000007522 mineralic acids Chemical class 0.000 claims description 2
- BFSQJYRFLQUZKX-UHFFFAOYSA-L nickel(ii) iodide Chemical compound I[Ni]I BFSQJYRFLQUZKX-UHFFFAOYSA-L 0.000 claims description 2
- 230000009467 reduction Effects 0.000 claims description 2
- 229910052725 zinc Inorganic materials 0.000 claims description 2
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 2
- SHWZFQPXYGHRKT-FDGPNNRMSA-N (z)-4-hydroxypent-3-en-2-one;nickel Chemical group [Ni].C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O SHWZFQPXYGHRKT-FDGPNNRMSA-N 0.000 claims 2
- 125000003368 amide group Chemical group 0.000 claims 2
- 150000004657 carbamic acid derivatives Chemical class 0.000 claims 2
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 1
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims 1
- 150000001340 alkali metals Chemical group 0.000 claims 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 claims 1
- 235000011056 potassium acetate Nutrition 0.000 claims 1
- MRYQZMHVZZSQRT-UHFFFAOYSA-M tetramethylazanium;acetate Chemical compound CC([O-])=O.C[N+](C)(C)C MRYQZMHVZZSQRT-UHFFFAOYSA-M 0.000 claims 1
- 229930192474 thiophene Natural products 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 3
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 114
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 57
- 238000005160 1H NMR spectroscopy Methods 0.000 description 36
- 239000000047 product Substances 0.000 description 29
- 239000007788 liquid Substances 0.000 description 25
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 18
- 238000006555 catalytic reaction Methods 0.000 description 15
- 238000003786 synthesis reaction Methods 0.000 description 12
- 238000004440 column chromatography Methods 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 239000003153 chemical reaction reagent Substances 0.000 description 10
- 239000011734 sodium Substances 0.000 description 10
- 239000012265 solid product Substances 0.000 description 10
- IYRGXJIJGHOCFS-UHFFFAOYSA-N neocuproine Chemical compound C1=C(C)N=C2C3=NC(C)=CC=C3C=CC2=C1 IYRGXJIJGHOCFS-UHFFFAOYSA-N 0.000 description 9
- 125000003118 aryl group Chemical group 0.000 description 8
- 230000000052 comparative effect Effects 0.000 description 8
- BMGNSKKZFQMGDH-FDGPNNRMSA-L nickel(2+);(z)-4-oxopent-2-en-2-olate Chemical group [Ni+2].C\C([O-])=C\C(C)=O.C\C([O-])=C\C(C)=O BMGNSKKZFQMGDH-FDGPNNRMSA-L 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- 239000002994 raw material Substances 0.000 description 7
- 238000006722 reduction reaction Methods 0.000 description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 125000000524 functional group Chemical group 0.000 description 4
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 4
- 239000003446 ligand Substances 0.000 description 4
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 4
- 238000004293 19F NMR spectroscopy Methods 0.000 description 3
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- 230000000903 blocking effect Effects 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 125000001072 heteroaryl group Chemical group 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 238000007445 Chromatographic isolation Methods 0.000 description 2
- 235000008733 Citrus aurantifolia Nutrition 0.000 description 2
- 241000790917 Dioxys <bee> Species 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 235000011941 Tilia x europaea Nutrition 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 238000005937 allylation reaction Methods 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- 150000001502 aryl halides Chemical class 0.000 description 2
- 125000005002 aryl methyl group Chemical group 0.000 description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- 229910000085 borane Inorganic materials 0.000 description 2
- 125000001589 carboacyl group Chemical group 0.000 description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-N carbonic acid monoamide Natural products NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 2
- 239000004568 cement Substances 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- HQWPLXHWEZZGKY-UHFFFAOYSA-N diethylzinc Chemical compound CC[Zn]CC HQWPLXHWEZZGKY-UHFFFAOYSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 239000004571 lime Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- IPLJNQFXJUCRNH-UHFFFAOYSA-L nickel(2+);dibromide Chemical compound [Ni+2].[Br-].[Br-] IPLJNQFXJUCRNH-UHFFFAOYSA-L 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- WLHPCEJPGLYEJZ-UHFFFAOYSA-N prop-2-enyltin Chemical compound [Sn]CC=C WLHPCEJPGLYEJZ-UHFFFAOYSA-N 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 238000010926 purge Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- KJAMZCVTJDTESW-UHFFFAOYSA-N tiracizine Chemical compound C1CC2=CC=CC=C2N(C(=O)CN(C)C)C2=CC(NC(=O)OCC)=CC=C21 KJAMZCVTJDTESW-UHFFFAOYSA-N 0.000 description 2
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
- JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 125000006736 (C6-C20) aryl group Chemical group 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000004174 2-benzimidazolyl group Chemical group [H]N1C(*)=NC2=C([H])C([H])=C([H])C([H])=C12 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- BKOOMYPCSUNDGP-UHFFFAOYSA-N 2-methylbut-2-ene Chemical group CC=C(C)C BKOOMYPCSUNDGP-UHFFFAOYSA-N 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000474 3-butynyl group Chemical class [H]C#CC([H])([H])C([H])([H])* 0.000 description 1
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- HZYLVYNCWLAIGF-UHFFFAOYSA-N 4-[[[2-(cyclohexylamino)-2-oxoethyl]-(4-propan-2-ylbenzoyl)amino]methyl]-N-hydroxybenzamide Chemical compound CC(C)c1ccc(cc1)C(=O)N(CC(=O)NC1CCCCC1)Cc1ccc(cc1)C(=O)NO HZYLVYNCWLAIGF-UHFFFAOYSA-N 0.000 description 1
- CWDWFSXUQODZGW-UHFFFAOYSA-N 5-thiazolyl Chemical group [C]1=CN=CS1 CWDWFSXUQODZGW-UHFFFAOYSA-N 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical group N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 description 1
- YPJRYQGOKHKNKZ-UHFFFAOYSA-N CCC1(C)CCCCC1 Chemical compound CCC1(C)CCCCC1 YPJRYQGOKHKNKZ-UHFFFAOYSA-N 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229910013594 LiOAc Inorganic materials 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 229910021585 Nickel(II) bromide Inorganic materials 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- KDCGOANMDULRCW-UHFFFAOYSA-N Purine Natural products N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- 238000003723 Smelting Methods 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical group C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- XKMRRTOUMJRJIA-UHFFFAOYSA-N ammonia nh3 Chemical group N.N XKMRRTOUMJRJIA-UHFFFAOYSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000005101 aryl methoxy carbonyl group Chemical group 0.000 description 1
- 125000005110 aryl thio group Chemical group 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 238000001354 calcination Methods 0.000 description 1
- 229910002090 carbon oxide Inorganic materials 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000007805 chemical reaction reactant Substances 0.000 description 1
- 125000002603 chloroethyl group Chemical group [H]C([*])([H])C([H])([H])Cl 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000001047 cyclobutenyl group Chemical group C1(=CCC1)* 0.000 description 1
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- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 1
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
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- 230000004151 fermentation Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
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- 229910052737 gold Inorganic materials 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
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- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000012263 liquid product Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- HRDXJKGNWSUIBT-UHFFFAOYSA-N methoxybenzene Chemical group [CH2]OC1=CC=CC=C1 HRDXJKGNWSUIBT-UHFFFAOYSA-N 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- LHJARSDQUNCSJG-UHFFFAOYSA-N nickel;propan-2-one Chemical compound [Ni].CC(C)=O LHJARSDQUNCSJG-UHFFFAOYSA-N 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 238000005245 sintering Methods 0.000 description 1
- 229910000144 sodium(I) superoxide Inorganic materials 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 125000003698 tetramethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000004417 unsaturated alkyl group Chemical group 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
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Abstract
本发明公开了一种(E)‑β,γ‑烯基羧酸衍生物及其制备方法,本发明的制备方法包含以下步骤:在有机溶剂中,在镍催化剂、双氮配体、还原剂和添加剂存在的条件下,将如式(II)所示的烯丙醇类底物与二氧化碳进行羧化反应,即可。本发明的制备方法选择性高,原料试剂易得,具有高度化学选择性和区域选择性,收率高,纯度好,生成成本低,更适合工业生产。
Description
技术领域
本发明涉及一种(E)-β,γ-烯基羧酸衍生物及其制备方法。
背景技术
在催化条件下高区域选择性地固定二氧化碳合成羧酸类化合物一直是合成化学里非常重要的挑战之一。二氧化碳是通过燃烧或呼吸产生的最终产物,在工业生产中能产生大量CO2副产物,如制备氢气和氨气、粮食发酵、烧制石灰、备水泥烧制石灰、备水泥冶铁等。其中碳具有最高价态正四价,因而二氧化碳极为稳定,其活化具有相当大的挑战性。金属试剂与二氧化碳的羧基化反应提供了一条途径来制备羧酸类化合物。在过去的十几年里,过渡金属催化条件下区域选择性地固定二氧化碳合成羧酸类化合物一直是研究的热点之一,可参考下述非专利文献报道:(a)Liu,Q.;Wu,L.;Jackstell,R.;Beller,M.NatureCommun.2015,6,5933.(b)Aresta,M.;Dibenedetto,A.;Angelini,A.Chem.Rev.2014,114,1709.(c)Cokoja,M.;Bruckmeier,C.;Rieger,B.;Herrmann,W.A.;Kühn,F.E.Angew.Chem.,Int.Ed.2011,50,8510.(d)M.;Moragas,T.;Gallego,D.;Martin,R.ACSCatal.2016,6,6739.(e)Yu,D.;Teong,S.P.;Zhang,Y.Coord.Chem.Rev.2015,293,279.(f)Yeung,C.S.;Dong,V.M.Top Catal.2014,57,1342.(g)Tsuji,Y.;Fujihara,T.Chem.Commun.2012,48,9956.(h)Huang,K.;Sun,C.-L.;Shi,Z.-J.Chem.Soc.Rev.2011,40,2435.(i)Duong,H.A.;Huleatt,P.B.;Tan,Q.-W.;Shuying,E.L.Org.Lett.2013,15,4034.(j)Wu,J.;Hazari,N.Chem.Commun.2011,47,1069.(k)Hruszkewycz,D.P.;Wu,J.;Hazari,N.;Incarvito,C.D.J.Am.Chem.Soc.2011,133,3280.(l)Johansson,R.;Wendt,O.F.Dalton Trans.2007,4,488.(m)Shi,M.;Nicholas,K.M.J.Am.Chem.Soc.1997,119,5057.(n)Miao,B.;Ma,S.Org.Chem.Front.2015,2,65.(o)Miao,B.;Ma,S.Chem.Commun.2014,50,3285.(p)Medeiros,M.J.;Pintaric,C.;Olivero,S.;Dunach,E.Electrochim.Acta 2011,56,4384.(q)Torii,J.;Tanaka,H.;Hamatani,T.;Morisaki,K.;Jutand,A.;Pfluger,F.;Fauvarque,J.-F.Chem.Lett.1986,169.
这些转化方法为固定二氧化碳合成羧酸类化合物提供了新的途径,然而这些方法需要用到高活性的底物如烯丙基卤代物、烯丙基硼试剂、烯丙基锡试剂、芳基卤代物、苄基卤代物等,或者需要用到如二乙基锌、三甲基铝等高活性还原剂,成为这类转化在实际应用中的不利因素,因为制备这些底物需要额外的步骤,且在反应后会产生大量的副产物,原子经济性差,高活性还原剂价格昂贵,反应条件苛刻,官能团兼容性非常有限等。因此,在Ni(II)催化二氧化碳羧化反应体系中,发展廉价底物与还原剂的反应体系一直是化学家们致力解决的一个问题。
烯丙醇本质上是一种活性醇化合物,只要在合适催化剂的作用下,可以作为亲电试剂的前驱体,直接与亲核试剂作用生成烯丙基化产物,而且生成的副产物只有水,不产生污染环境的废弃物,很显然这是一种绿色的烯丙基化合成方法。目前,环境友好型的烯丙醇作为一种替代传统烯丙基化试剂正在逐步得到大家的重视,近年来在该领域发表了大量的相关文章,可参考如下述非专利文献报道:(a)Sundararaju,B.;Achard,M.;Bruneau,C.Chem.Soc.Rev.2012,41,4467.(b)Bandini,M.;Cera,G.;Chiarucci,M.Synthesis 2012,44,504.(c)Tamaru,Y.;Kimura,M.Pure Appl.Chem.2008,80,979.(d)Muzart,J.Eur.J.Org.Chem.2007,3077.(e)Kita,Y.;Kavthe,R.D.;Oda,H.;Mashima,K.Angew.Chem.,Int.Ed.2016,55,1098.(f)Azizi,M.S.;Edder,Y.;Karim,A.;Sauthier,M.Eur.J.Org.Chem.2016,3796.(g)Kita,Y.;Sakaguchi,H.;Hoshimoto,Y.;Nakauchi,D.;Nakahara,Y.;Carpentier,J.-F.;Ogoshi,S.;Mashima,K.Chem.Eur.J.2015,21,14571.(h)Matsubara,R.;Jamison,T.F.J.Am.Chem.Soc.2010,132,6880.(i)Bricout,H.;Carpentier,J.-F.;Mortreux,A.J.Mol.Cat.1998,136,243.(j)Alvarez,E.;Cuvigny,T;Julia,M.J.Organomet.Chem.1988,339,199.(k)Yamamoto,T.;Ishizu,J.;Yamamoto,A.J.Am.Chem.Soc.1981,103,6863.
目前,发展一种高效、环保、价格低廉的通过固定二氧化碳合成羧酸类化合物的制备方法具有重要的意义。
发明内容
本发明所要解决的技术问题是为了克服现有的固定二氧化碳合成羧酸类化合物的方法或需要用到高活性的底物如烯丙基卤代物、烯丙基硼试剂、烯丙基锡试剂、芳基卤代物、苄基卤代物等,或需要用到如二乙基锌、三甲基铝等高活性还原剂等缺陷,其中,前者反应原料的制备需要额外的步骤,且在反应后会产生大量的副产物,原子经济性差;而后者的高活性还原剂价格昂贵,反应条件苛刻,官能团兼容性非常有限,因而提供了一种(E)-β,γ-烯基羧酸衍生物及其制备方法。本发明的制备方法选择性高,原料试剂易得,具有高度化学选择性和区域选择性,收率高,纯度好,生成成本低,更适合工业生产。
本发明通过下述技术方案来解决上述技术问题。
本发明提供了一种如式(I)所示的(E)-β,γ-烯基羧酸衍生物的制备方法,其包括如下步骤:在有机溶剂中,在镍催化剂、双氮配体、还原剂和添加剂存在的条件下,将如式(II)所示的烯丙醇类底物与二氧化碳进行羧化反应,即可;
其中,所述的如式(II)所示的烯丙醇类底物中,以*标记的碳原子表示其为(R)或(S)型的单一构型手性碳或其任意比例混合物;以显示的化学键表示其连接的双键为(E)或(Z)型的单一构型或其任意比例混合物;R和R’中至少一个为H;当R不为H时,R为不以烯基或炔基直接与如式(II)所示的烯丙醇类底物结构中其他部分相连的取代基;当R’不为H时,R’为不以烯基或炔基直接与如式(II)所示的烯丙醇类底物结构中其他部分相连的取代基;所述的如式(I)所示的(E)-β,γ-烯基羧酸衍生物中,R”为R和R’中不为H的那一个,当R和R’均为H时,R”也为H。
本发明中,当R不为H时,R优选为-(CH2)n-R1;其中,n选自1-12中的任一整数,进一步优选为2-5中的任一整数,如3或4;R1选自R1A、-O(-R1B)、-S(-R1C)或-N(-R1D)(-R1E)、-C(=O)(OR1F)、-CN、卤素或-NO2;其中,R1A选自H、取代或未取代的C1-C30烷基、取代或未取代的C6-C20芳基、或取代或未取代的C2-C20杂芳基;其中,所述的卤素优选为氟、氯、溴或碘;所述的C1-C30烷基优选为C1-C6烷基,进一步优选为甲基、乙基、丙基、丁基、戊基或己基;所述的C6-C20芳基优选为C6-C10芳基,进一步优选为苯基;所述的C2-C20杂芳基优选为C2-C10杂芳基,进一步优选为噻吩基或吲哚基,更进一步优选所述的噻吩基为2-噻吩基,更进一步优选所述的吲哚基为1-吲哚基;
R1B选自H、取代或取代基的苯基、或本领域常规所用的醇羟基保护基;所述的醇羟基保护基优选为使所述的醇羟基形成醚、羧酸酯、缩醛或缩酮类衍生物的醇羟基保护基,进一步优选为-Ac、-Bz、或-TBS;
R1C选自H、取代或未取代的苯基、或本领域常规所用的巯基保护基;所述的巯基保护基优选为使所述的巯基形成硫醚、硫缩醛或硫醇酯类衍生物的巯基保护基,进一步优选为-Bn;
R1D和R1E各自独立地选自H或本领域常规所用的氨基保护基、或二者共同构成本领域常规所用的氨基保护基,所述的氨基保护基优选为使所述的氨基形成酰胺类、氨基甲酸酯类或烃基类衍生物的氨基保护基,更进一步优选为-Cbz、-Boc、-Fmoc、-Phth、-Ts、-PMB或-Bn。
R1F选自C1-C10烷基,所述的C1-C10烷基优选C1-C6烷基,进一步优选为甲基、乙基、丙基、丁基、戊基或己基。
上述各基团中所述的取代基各自独立地选自C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基或酯基,所述的C1-C6烷基优选为C1-C3烷基,进一步优选为甲基或乙基;所述的C1-C6烷氧基优选为C1-C3烷氧基,进一步优选为甲氧基或乙氧基;所述的C1-C6卤代烷基优选为C1-C3卤代烷基,进一步优选为-CF3;所述的酯基优选为-COOMe。
本发明中,当R’不为H时,R’优选为-(CH2)n’-R2;其中,n’选自1-12中的任一整数,进一步优选为2-5中的任一整数,如3或4;R2选自R2A、-O(-R2B)、-S(-R2C)或-N(-R2D)(-R2E)、-C(=O)(OR2F)、-CN、卤素或-NO2;其中,所述的卤素优选为氟、氯、溴或碘;R2A选自H、取代或未取代的C1-C30烷基、取代或未取代的C6-C20芳基、或取代或未取代的C2-C20杂芳基;所述的C1-C30烷基优选为C1-C6烷基,进一步优选为甲基、乙基、丙基、丁基、戊基或己基;所述的C6-C20芳基优选为C6-C10芳基,进一步优选为苯基;所述的C2-C20杂芳基优选为C2-C10杂芳基,进一步优选为噻吩基或吲哚基,更进一步优选所述的噻吩基为2-噻吩基,更进一步优选所述的吲哚基为1-吲哚基;
R2B选自H、取代或取代基的苯基、或本领域常规所用的醇羟基保护基;所述的醇羟基保护基优选为使所述的醇羟基形成醚、羧酸酯、缩醛或缩酮类衍生物的醇羟基保护基,进一步优选为-Ac、-Bz、或-TBS;
R2C选自H、取代或未取代的苯基、或本领域常规所用的巯基保护基;所述的巯基保护基优选为使所述的巯基形成硫醚、硫缩醛或硫醇酯类衍生物的巯基保护基,进一步优选为-Bn;
R2D和R2E各自独立地选自H或本领域常规所用的氨基保护基、或二者共同构成本领域常规所用的氨基保护基,所述的氨基保护基优选为使所述的氨基形成酰胺类、氨基甲酸酯类或烃基类衍生物的氨基保护基,更进一步优选为-Cbz、-Boc、-Fmoc、-Phth、-Ts、-PMB或-Bn。
R2F选自C1-C10烷基,所述的C1-C10烷基优选C1-C6烷基,进一步优选甲基、乙基、丙基、丁基、戊基或己基。
上述各基团中所述的取代基各自独立地选自C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基或酯基,所述的C1-C6烷基优选为C1-C3烷基,进一步优选为甲基或乙基;所述的C1-C6烷氧基优选为C1-C3烷氧基,进一步优选为甲氧基或乙氧基;所述的C1-C6卤代烷基优选为C1-C3卤代烷基,进一步优选为-CF3;所述的酯基优选为-COOMe。
本发明中,所述的如式(II)所示的烯丙醇类底物进一步优选选自下列化合物:
本发明中,所述的镍催化的二氧化碳羧化反应可在本领域进行镍催化的二氧化碳羧化反应的常规反应环境下进行,本发明优选在无水无氧条件下进行。
本发明中,所述的有机溶剂为本领域进行镍催化的二氧化碳羧化反应常规所用的有机溶剂,本发明优选为极性非质子溶剂,进一步优选为N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺(DMA)、N-甲基吡咯烷酮(NMP)、1,3-二甲基-2-咪唑啉酮(DMI)和六甲基磷酰三胺(HMPA)中的一种或多种,更进一步优选为DMF。
本发明中,所述的有机溶剂的用量为本领域进行镍催化的二氧化碳羧化反应常规所用,本发明优选所述的如式(II)所示的烯丙醇类底物在所述的有机溶剂中摩尔浓度为0.05-1.0mol/L,进一步优选为0.125-0.250mol/L。
本发明中,所述的镍催化剂为本领域进行镍催化的二氧化碳羧化反应常规所用的镍催化剂,包括本领域中各种常见的镍(0)催化剂和/或镍(II)催化剂。其中,所述的镍(0)催化剂优选为乙酰丙酮镍(Ni(acac)2)和/或双-(1,5-环辛二烯)镍(Ni(cod)2);所述的镍(II)催化剂优选为氯化镍、溴化镍和碘化镍中的一种或多种;本发明中进一步优选为乙酰丙酮镍。
本发明中,所述的镍催化剂的用量为本领域进行镍催化的二氧化碳羧化反应常规所用,并不需要进行特别限定。本发明优选所述的镍催化剂与所述的如式(II)所示的烯丙醇类底物的摩尔比为0.005:1-0.2:1,进一步优选为0.01:1-0.1:1。
本发明中,所述的双氮配体在所述的镍催化的二氧化碳羧化反应中适配于所述的镍催化剂并辅助进行所述羧化反应,其为如下式所示的邻二氮菲类配体L1、L2、L3和联吡啶类配体L4中的一种或多种,进一步优选为L1。
本发明中,所述的双氮配体的用量为本领域进行镍催化的二氧化碳羧化反应时常规所用,本发明优选所述的双氮配体与所述的镍催化剂的摩尔比为2:1-4:1,进一步优选2.2:1-2.4:1。
本发明中,所述的还原剂为锰和/或锌,优选锰。
本发明中,所述的还原剂的用量为本领域进行镍催化的二氧化碳羧化反应时常规所用,本发明优选所述的还原剂与所述的如式(II)所示的烯丙醇类底物的摩尔比为1:1-3:1,进一步优选为2:1。
本发明中,所述的添加剂为本领域进行镍催化的二氧化碳羧化反应时常规所用的醋酸盐添加剂,包括碱金属醋酸盐和/或季铵醋酸盐;其中,所述的碱金属醋酸盐优选为醋酸钾、醋酸锂和醋酸铯中的一种或多种,所述的季铵醋酸盐优选为四丁基醋酸铵和/或四甲基醋酸铵;本发明进一步优选为四丁基醋酸铵。
本发明中,所述的添加剂的用量为本领域进行镍催化的二氧化碳羧化反应时常规所用,本发明优选所述的添加剂与所述的如式(II)所示的烯丙醇类底物的摩尔比为1:1-4:1,进一步优选为2:1-3:1。
本发明中,所述的如式(II)所示的烯丙醇底物可由本领域此类化合物常规所用的制备方法制备得到,本发明优选由其对应的炔丙醇类化合物直接通过还原反应制备得到。
本发明中,优选所述的如式(I)所示的(E)-β,γ-烯基羧酸衍生物的制备方法,其进一步还包括如下步骤:将由如式(III)所示的炔丙醇类底物进行还原反应,得到所述的如式(II)所示的烯丙醇底物,即可;
其中,所述的如式(III)所示的炔丙醇类底物中,R和R’的限定均如上所述;所述的还原反应可采用本领域中能够将炔丙醇类化合物还原为其对应的烯丙醇类化合物的常规还原反应的常规反应条件和参数进行。
本发明进一步还提供了一种如式(I)所示的(E)-β,γ-烯基羧酸衍生物的制备方法,其包括如下步骤:在有机溶剂中,在镍催化剂、双氮配体、还原剂和添加剂存在的条件下,将如式(III)所示的炔丙醇底物与二氧化碳进行羧化反应,即可;
其中,所述的取代基R、R’和R”的定义、所述的镍催化剂、所述的双氮配体、所述的还原剂和所述的添加剂以及所述的羧化反应的反应条件与参数均如前所述;特别地,所述的还原剂与所述的底物的摩尔比优选为3:1-5:1,进一步优选为4:1;所述的添加剂与所述的底物的摩尔比优选为1:1-6:1,优选为3:1-5:1。
本发明中,所述的如式(III)所示的炔丙醇底物进一步优选选自下列化合物:
本发明中,当本发明的羧化反应的反应物为如式(II)所示的烯丙醇类底物时,所述的如式(II)所示的烯丙醇类底物、所述的镍催化剂、所述的配体、所述的还原剂和所述的添加剂的加料量摩尔比优选为1:0.1:0.2:2.0:3.0;当本发明的羧化反应的反应物为如式(III)所示的炔丙醇类底物时,所述的如式(III)所示的炔丙醇类底物、所述的镍催化剂、所述的配体、所述的还原剂和所述的添加剂的加料量摩尔比优选为1:0.1:0.2:4.0:5.0。
本发明中,所述的如式(I)所示的(E)-β,γ-烯基羧酸衍生物的制备方法可采用本领域进行镍催化的二氧化碳羧化反应时常规所用的加料顺序,本发明优选:先将所述的镍催化剂、所述的配体、所述的还原剂和所述的添加剂加入反应体系中,加入顺序不做特别限定,再冲入二氧化碳气体,最后加入所述的如式(II)所示的烯丙醇类底物或如式(III)所示的炔丙醇类底物和所述的有机溶剂。
本发明中,所述的二氧化碳作为反应物之一,可采用本领域进行镍催化的二氧化碳羧化反应时常规所用的二氧化碳源引入反应体系中,本发明优选直接将二氧化碳气体通入,更优选在所述的反应体系为真空状态下直接将二氧化碳气体通入,上述通入操作为更彻底地对反应体系的空气进行置换可重复1-4次,如3次。
本发明中,所述的羧化反应的反应温度为本领域进行镍催化的二氧化碳羧化反应时常规所用,本发明优选所述的反应温度为10-60℃,进一步优选为20-25℃。
本发明中,所述的羧化反应的反应进程可采用本领域常规测试方法(例如TLC、GC、HPLC或NMR)进行监测,一般以反应底物不再参与反应时为反应终点。当以GC或HPLC进行反应终点监测时,进一步以反应体系中如式(II)所示的烯丙醇类底物或如式(III)所示的炔丙醇底物的含量(GC%或HPLC%)<0.5%时作为反应的终点。
本发明中,所述的羧化反应的反应时间优选为10-24h,进一步优选为12-15h。
本发明中,所述的如式(I)所示的(E)-β,γ-烯基羧酸衍生物的制备方法进一步还包括后处理步骤,本发明优选所述的后处理步骤为:在所述的羧化反应反应结束后,加入有机溶剂如乙酸乙酯稀释,并加入无机酸如1M氯化氢水溶液进行酸化;用有机溶剂如乙酸乙酯萃取,所得的有机相用饱和氯化铵水溶液洗涤,无水硫酸钠干燥,过滤,浓缩,即可得粗产品。
本发明中,所述的如式(I)所示的(E)-β,γ-烯基羧酸衍生物的制备方法在所述的后处理步骤结束后,优选还包括所述的粗产品纯化过程,所述的粗产品纯化过程可采用本领域常规分离纯化方法进行分离纯化,具体手段包括重结晶、薄层层析、柱层析等。本发明优选柱层析纯化,进一步优选在极性较大的展开剂条件下快速通过硅胶柱层析,以获得纯的如式(I)所示的(E)-β,γ-烯基羧酸衍生物。其中,所述的展开剂优选为甲醇与二氯甲烷的混合溶剂,并加入少量乙酸。
本发明中,所述的羧化反应具有高度优异的化学选择性和区域选择性,当本发明的羧化反应的反应物为如式(II)所示的烯丙醇类底物时,在反应结束后得到以E构型为主的产物,E/Z选择性介于10:1-20:1甚至高于20:1,如13:1、14:1、16:1、17:1、18:1、19:1等;当本发明的羧化反应的反应物为如式(III)所示的炔丙醇底物时,在反应结束后得到以直链(linear,l)的E构型为主的产物,E/Z选择性介于10:1-20:1甚至高于20:1,如11:1、13:1、14:1、17:1等;l/b选择性介于7:1-20:1甚至高于20:1,如7:1、8:1、14:1、15:1等。
本发明进一步还提供了一种如式(I)所示的(E)-β,γ-烯基羧酸衍生物、如式(II)所示的烯丙醇类底物或如式(III)所示的炔丙醇类底物:
其中,R、R’和R”的限定均如前所述。
在符合本领域常识的基础上,上述各优选条件,可任意组合,即得本发明各较佳实例。
本发明的积极进步效果在于:
1)本发明发展了一种二氧化碳羧化方法,首次发现镍催化的烯丙醇以及炔丙醇的羧化反应,制备了一系列具有高区域选择性的β,γ-不饱和羧酸;
2)本发明的制备方法原料简单易得、制备方便、反应温和、操作简单、产物易分离纯化;
3)本发明的制备方法底物普适性广、官能团兼容性好;
4)在炔丙醇的还原羧化反应中,我们通过机理研究发现,水提供还原反应中的质子,可以非常高效地进行还原反应,也为后续的反应探索提供了许多可能。
除非另有说明,在本发明说明书和权利要求书中出现的以下术语具有下述含义:
除非另有规定,术语“烷基”表示直链的或支链或环状的原子团或它们的组合,可以是完全饱和的、单元或多元不饱和的,可以包括二价和多价原子团。饱和烃原子团的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、异丁基、环己基、(环己基)甲基、环丙基甲基,以及正戊基、正己基、正庚基、正辛基等原子团的同系物或异构体。不饱和烷基具有一个或多个双键或三键,其实例包括但不限于乙烯基、2-丙烯基、丁烯基、巴豆基、2-异戊烯基、2-(丁二烯基)、2,4-戊二烯基、3-(1,4-戊二烯基)、乙炔基、1-和3-丙炔基,3-丁炔基,以及更高级的同系物和异构体。
除非另有规定,术语“芳基”表示多不饱和的芳族烃取代基,可以是单取代、二取代或多取代的,它可以是单环或多环(优选1至3个环),它们稠合在一起或共价连接。术语“杂芳基”是指含有一至四个杂原子的芳基(或环)。在一个示范性实例中,杂原子选自B、N、O和S,其中氮和硫原子任选地被氧化,氮原子任选地被季铵化。杂芳基可通过杂原子连接到分子的其余部分。芳基或杂芳基的非限制性实施例包括苯基、1-萘基、2-萘基、4-联苯基、1-吡咯基、2-吡咯基、3-吡咯基、3-吡唑基、2-咪唑基、4-咪唑基、吡嗪基、2-噁唑基、4-噁唑基、2-苯基-4-噁唑基、5-噁唑基、3-异噁唑基、4-异噁唑基、5-异噁唑基、2-噻唑基、4-噻唑基、5-噻唑基、2-呋喃基、3-呋喃基、2-噻吩基、3-噻吩基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-苯并噻唑基、嘌呤基、2-苯并咪唑基、5-吲哚基、1-异喹啉基、5-异喹啉基、2-喹喔啉基、5-喹喔啉基、3-喹啉基和6-喹啉基。上述任意一个芳基和杂芳基环系的取代基选自下文所述的可接受的取代基。
除非另有规定,为简便起见,芳基在与其他术语联合使用时(例如芳氧基、芳硫基、芳烷基)包括如上定义的芳基和杂芳基环。因此,术语“芳烷基”意在包括芳基附着于烷基的那些原子团(例如苄基、苯乙基、吡啶基甲基等),包括其中碳原子(如亚甲基)已经被例如氧原子代替的那些烷基,例如苯氧基甲基、2-吡啶氧甲基3-(1-萘氧基)丙基等。
术语“氨基保护基”是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于:甲酰基;酰基,例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基);烷氧基羰基,如叔丁氧基羰基(Boc);芳基甲氧羰基,如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc);芳基甲基,如苄基(Bn)、三苯甲基(Tr)、1,1-二-(4'-甲氧基苯基)甲基;甲硅烷基,如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。
术语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于:烷基,如甲基、乙基和叔丁基;酰基,例如链烷酰基(如乙酰基);芳基甲基,如苄基(Bn),对甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基,DPM);甲硅烷基,如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。
除非另有规定,卤代烷基的实例包括但不仅限于:三氟甲基、三氯甲基、五氟乙基,和五氯乙基。“烷氧基”代表通过氧桥连接的具有特定数目碳原子的上述烷基。C1-6烷氧基包括C1、C2、C3、C4、C5和C6的烷氧基。烷氧基的例子包括但不限于:甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基和S-戊氧基。
除非另有规定,本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备,包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式,优选的实施方式包括但不限于本发明的实施例。
除非另有规定,对于每个单个步骤最佳的反应条件和反应时间可以根据所采用的具体反应物和所用的反应物中存在的取代基而变化。除非另有说明,溶剂、温度和其它反应条件可以由本领域技术人员容易地选择。具体方法提供在合成实施例部分。反应可以以常规的方式进行后处理,例如通过从残余物中除去溶剂并根据本领域已知的方法学进一步纯化,所述方法学例如,但不限于,结晶、蒸馏、萃取、研制和色谱。除非另有说明,所述原料和试剂可商购获得或可以由本领域技术人员使用化学文献中描述的方法由可商购获得的材料制备。
除非另有规定,常规实验,包括反应条件、试剂和合成路线顺序的适当操作,与反应条件不能相容的任何化学官能团的保护,和在该方法的反应顺序中在适当的点的脱保护都包括在本发明的范围内。合适的保护基团和使用这些合适的保护基团用于保护和脱保护不同取代基的方法,是本领域技术人员熟知的,其实例可见于T.Greene和P.Wuts,Protecting Groups in Organic Synthesis(3rd ed.),John Wiley&Sons,NY(1999),其通过引用方式以其整体并入本文。本发明化合物的合成可以通过类似于在上文中描述的合成反应路线和具体实施例中所述方法来完成。
除非另有规定,原料如果不能商购,可通过选自标准有机化学技术,类似于合成已知的、结构类似的化合物的技术,或类似于上述反应路线或在合成实施例部分中所述的方法来制备。
除非另有规定,当需要化合物的旋光形式时,它可以通过进行本文所述的方法之一使用光学活性的原料(例如通过不对称诱导合适的反应步骤来制备)来获得,或通过使用标准方法(如色谱分离、重结晶或酶拆分)拆分化合物或中间体的立体异构体混合物来获得。
除非另有规定,当需要化合物的纯几何异构体时,它可以通过进行上述方法之一,使用纯几何异构体作为原料,或通过使用标准方法,如色谱分离来拆分化合物或中间体的几何异构体的混合物来制备。
除非另有规定,本发明所用试剂和原料均市售可得。
除非另有规定,本发明的化合物经手工或者软件命名,市售化合物采用供应商目录名称。
具体实施方式
下面通过实施例对本发明进行详细描述,但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明,其中也公开了其具体实施例方式,对本领域的技术人员而言,在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。下列实施例中未注明具体条件的实验方法,按照常规方法和条件,或按照商品说明书选择。
实施例1
50mL溶剂存储瓶加入Ni(acac)2(6.4mg,0.025mmol)、neocuproine(10.4mg,0.05mmol)、Mn(27.5mg,0.5mmol)、nBu4NOAc(226mg,0.75mmol),在油泵抽真空状态下,充入二氧化碳气体,如此反复三次,随后加入底物1a和DMF(2mL),盖上盖子,将溶剂存储瓶置于油浴25度加热并搅拌,15小时后,反应基本完全,慢慢加入乙酸乙酯稀释,并加入1M HCl酸化,用乙酸乙酯萃取,有机相用饱和氯化铵洗,无水硫酸钠干燥,过滤,浓缩,快速柱层析得液体产物2a,86%产率(来自于1a),>20:1E/Z。1H NMR(400MHz,CDCl3)δ7.32-7.26(m,2H),7.22-7.14(m,3H),5.74-5.48(m,2H),3.08(dd,J=6.6,0.9Hz,2H),2.76-2.66(m,2H),2.38(dd,J=14.8,7.0Hz,2H).
实施例2
操作参考例1。
得液体产物2b,93%产率(来自于1b),12:1E/Z。1H NMR(400MHz,CDCl3)δ5.68-5.43(m,2H),3.06(dd,J=6.6,0.8Hz,2H),2.02(dt,J=7.3,3.7Hz,2H),1.41-1.33(m,2H),1.31-1.23(m,4H),0.88(t,J=6.9Hz,3H).
实施例3
操作参考例1。
得液体产物2c,80%产率(来自于1c),17:1E/Z。1H NMR(400MHz,CDCl3)δ5.62-5.47(m,2H),3.64(t,J=6.5Hz,2H),3.06(d,J=5.8Hz,2H),2.07(dd,J=13.4,6.8Hz,2H),1.66-1.51(m,2H),1.51-1.36(m,2H).13C NMR(101MHz,CDCl3)δ177.40,134.84,121.35,62.69,37.70,32.06,31.94,25.09.IR(neat):3434,2933,1706,968cm-1.HRMS(ESI-TOF)calcd for C8H14NaO3[M+Na]+:181.0835,found:181.0832.
实施例4
操作参考例1。
得固体产物2d,m.p.=40-41℃,85%产率(来自于1d),14:1E/Z。1H NMR(400MHz,CDCl3)δ8.04(ddd,J=7.3,2.9,1.6Hz,2H),7.57-7.51(m,1H),7.47-7.40(m,2H),5.66-5.48(m,2H),4.32(t,J=6.6Hz,2H),3.10-3.03(m,2H),2.18-2.07(m,2H),1.82-1.73(m,2H),1.60-1.49(m,2H).13C NMR(101MHz,CDCl3)δ178.35,166.70,134.71,132.85,130.37,129.53,128.32,121.42,64.87,37.73,32.04,28.18,25.53.IR(neat):2936,1690,1276,1224,1115,969,917,709cm-1.HRMS(ESI-TOF)calcd for C15H18NaO4[M+Na]+:285.1097,found:285.1098.
实施例5
操作参考例1。
得液体产物2e,52%产率(来自于1e),16:1E/Z。1H NMR(400MHz,CDCl3)δ5.65-5.44(m,2H),3.60(t,J=6.4Hz,2H),3.06(d,J=6.3Hz,2H),2.05(q,J=6.8Hz,2H),1.56-1.46(m,2H),1.41(ddd,J=16.5,9.4,6.1Hz,2H),0.89(s,9H),0.04(s,6H).13C NMR(101MHz,CDCl3)δ178.39,135.20,120.97,63.05,37.80,32.21,32.19,25.96,25.30,18.36,-5.29.IR(neat):2929,2857,1711,1098,833,773cm-1.HRMS(ESI-TOF)calcd for C14H29O3Si[M+H]+:273.1880,found:273.1881.
实施例6
操作参考例1。
得固体产物2f,m.p.=49-50℃,94%产率(来自于1f),>20:1E/Z。1H NMR(400MHz,CDCl3)δ7.15-7.06(m,2H),6.88-6.79(m,2H),5.72-5.48(m,2H),3.80(s,3H),3.08(d,J=6.5Hz,2H),2.71-2.61(m,2H),2.35(dd,J=14.9,7.2Hz,2H).13C NMR(101MHz,CDCl3)δ178.52,157.73,134.52,133.77,129.32,121.43,113.71,55.24,37.80,34.61,34.52.IR(neat):2934,2843,1709,1511,1238,1175,1026,970,907,811cm-1.HRMS(ESI-TOF)calcdfor C13H16NaO3[M+Na]+:243.0992,found:243.0982.
实施例7
操作参考例1。
得固体产物2g,m.p.=36-37℃,66%产率(来自于1g),17:1E/Z。1H NMR(400MHz,CDCl3)δ5.85(dt,J=3.0,1.9Hz,2H),5.71-5.51(m,2H),3.09(d,J=5.9Hz,2H),2.66(t,J=7.6Hz,2H),2.38(dd,J=14.2,7.1Hz,2H),2.25(s,3H).13C NMR(101MHz,CDCl3)δ178.67,153.50,150.29,134.07,121.66,105.77,105.59,37.77,31.02,27.73,13.48.IR(neat):2924,1698,1218,965,930,783cm-1.HRMS(ESI-TOF)calcd for C11H15O3[M+H]+:195.1016,found:195.1015.
实施例8
操作参考例1。
得液体产物2h,86%产率(来自于1h),20:1E/Z。1H NMR(400MHz,CDCl3)δ7.70(d,J=7.7Hz,1H),7.63(d,J=7.8Hz,1H),7.55(t,J=7.6Hz,1H),7.36(t,J=7.6Hz,1H),5.66-5.47(m,2H),4.68(s,2H),3.53(t,J=6.5Hz,2H),3.07(d,J=6.3Hz,2H),2.08(dd,J=13.9,6.8Hz,2H),1.72-1.58(m,2H),1.49(dt,J=9.9,7.5Hz,2H).13C NMR(101MHz,CDCl3)δ178.49,137.45(q,J=1.5Hz),135.01,131.90,128.68,127.54,127.18,125.61(q,J=11.8,6.0Hz),124.34(q,J=273Hz),121.14,70.75,68.62(q,J=2.8Hz),37.78,32.21,29.13,25.64.19F NMR(376MHz,CDCl3)δ-60.20.IR(neat):2935,2861,1709,1312,1160,1114,1098,1037,768cm-1.HRMS(ESI-TOF)calcd for C16H23F3NO3[M+NH4]+:334.1625,found:334.1623.
实施例9
操作参考例1。得固体产物2i,m.p.=86-87℃,61%产率(来自于1i),19:1E/Z。1HNMR(400MHz,CDCl3)δ7.79(dt,J=6.9,3.5Hz,2H),7.73-7.61(m,2H),5.60-5.40(m,2H),3.64(t,J=7.2Hz,2H),3.02(d,J=5.4Hz,2H),2.05(dd,J=13.2,6.5Hz,2H),1.64(dt,J=15.1,7.4Hz,2H),1.45-1.31(m,2H).13C NMR(101MHz,CDCl3)δ178.03,168.44,134.52,133.85,132.05,123.15,121.44,37.77,37.67,31.92,27.99,26.24.IR(neat):2927,2853,1693,1396,716cm-1.HRMS(ESI-TOF)calcd for C16H17NNaO4[M+Na]+:310.1050,found:310.1047.
实施例10
操作参考例1。
得液体产物2j,88%产率(来自于1j),>20:1E/Z。1H NMR(400MHz,CDCl3)δ7.64(d,J=7.9Hz,1H),7.42-7.30(m,1H),7.25-7.19(m,1H),7.14-7.09(m,1H),7.09(d,J=3.2Hz,1H),6.49(dd,J=3.1,0.6Hz,1H),5.66-5.50(m,2H),4.18(t,J=7.2Hz,2H),3.06(d,J=5.2Hz,2H),2.59(dd,J=12.7,6.7Hz,2H).13C NMR(101MHz,CDCl3)δ177.77,135.82,131.02,128.59,127.70,123.91,121.42,120.98,119.28,109.31,101.11,46.05,37.62,33.32.IR(neat):2923,1704,1311,967,737cm-1.HRMS(ESI-TOF)calcd for C14H16NO2[M+H]+:230.1176,found:230.1173.
实施例11
操作参考例1。
得液体产物2a,88%产率(来自于1k),>20:1E/Z。1H NMR(400MHz,CDCl3)δ7.32-7.26(m,2H),7.22-7.14(m,3H),5.74-5.48(m,2H),3.08(dd,J=6.6,0.9Hz,2H),2.76-2.66(m,2H),2.38(dd,J=14.8,7.0Hz,2H).
实施例12
操作参考例1。
得固体产物2l,m.p.=70-71℃,89%产率(来自于1l),>20:1E/Z。1H NMR(400MHz,CDCl3)δ7.18(t,J=8.2Hz,1H),6.54-6.49(m,2H),6.47(t,J=2.3Hz,1H),5.76-5.63(m,2H),3.99(t,J=6.7Hz,2H),3.79(s,3H),3.18-3.08(m,2H),2.61-2.48(m,2H).13C NMR(101MHz,CDCl3)δ178.29,160.76,160.03,130.79,129.84,123.54,106.66,106.37,100.98,67.15,55.22,37.77,32.37.IR(neat):2940,1703,1600,1581,1281,1195,1150,973,863,755,687cm-1.HRMS(ESI-TOF)calcd for C13H17O4[M+H]+:237.1121,found:237.1122.
实施例13
操作参考例1。
得固体产物2m,m.p.=52-53℃,61%产率(来自于1m),>20:1E/Z。1H NMR(400MHz,CDCl3)δ7.23(d,J=6.3Hz,2H),7.08(d,J=7.7Hz,2H),5.70-5.46(m,2H),3.07(d,J=5.4Hz,2H),2.89(t,J=7.3Hz,2H),2.37-2.31(m,2H),2.30(s,3H).13C NMR(101MHz,CDCl3)δ177.53,136.27,132.85,132.27,130.34,129.66,122.71,37.57,33.96,32.23,21.01.IR(neat):2919,2848,1694,1493,1423,1400,1291,1226,1189,1091,968,927,795cm-1.HRMS(ESI-TOF)calcd for C13H16NaO2S[M+Na]+:259.0763,found:259.0763.
实施例14
操作参考例1。
得液体产物2n,56%产率(来自于1n),>20:1E/Z。1H NMR(400MHz,CDCl3)δ5.66(ddd,J=32.8,18.4,11.1Hz,2H),3.11(d,J=6.5Hz,2H),2.40(s,4H).13C NMR(101MHz,CDCl3)δ177.51,130.43,124.61,119.03,37.41,28.19,17.24.IR(neat):2922,2247,1707,1192,970cm-1.HRMS(ESI-TOF)calcd for C7H9NNaO2[M+Na]+:162.0525,found:162.0525.
实施例15
操作参考例1。
得液体产物2o,70%产率(来自于1o),13:1E/Z。1H NMR(400MHz,CDCl3)δ5.69-5.50(m,2H),4.08(t,J=6.7Hz,2H),3.08(d,J=6.3Hz,2H),2.36(q,J=6.4Hz,2H),2.03(s,3H).13C NMR(101MHz,CDCl3)δ177.14,171.13,130.26,123.84,63.46,37.54,31.79,20.91.IR(neat):2920,1726,1385,1238,1167,1040,972,645cm-1.HRMS(ESI-TOF)calcdforC8H12NaO4[M+Na]+:195.0628,found:195.0628.
实施例16
操作参考例1。
得液体产物2p,94%产率(来自于1p),18:1E/Z。1H NMR(400MHz,CDCl3)δ5.65-5.45(m,2H),3.07(d,J=6.5Hz,2H),2.01(q,J=6.8Hz,2H),1.44-1.34(m,2H),0.89(t,J=7.4Hz,3H).
实施例17
操作参考例1。
得液体产物2p,78%产率(来自于1q),10:1E/Z。1H NMR(400MHz,CDCl3)δ5.65-5.45(m,2H),3.07(d,J=6.5Hz,2H),2.01(q,J=6.8Hz,2H),1.44-1.34(m,2H),0.89(t,J=7.4Hz,3H).
实施例18
操作参考例1。
得液体产物2p,91%产率(来自于1r),14:1E/Z。1H NMR(400MHz,CDCl3)δ5.65-5.45(m,2H),3.07(d,J=6.5Hz,2H),2.01(q,J=6.8Hz,2H),1.44-1.34(m,2H),0.89(t,J=7.4Hz,3H).
实施例19
操作参考例1。
得固体产物2s,15%产率(来自于1s),>20:1E/Z。1H NMR(400MHz,CDCl3)δ7.39(d,J=8.0Hz,2H),7.35-7.29(m,2H),7.28-7.21(m,1H),6.53(d,J=15.9Hz,1H),6.36-6.23(m,1H),3.32(dd,J=7.1,1.2Hz,2H).
实施例20
操作参考例1。
得固体产物2t,25%产率(来自于1t),>20:1E/Z。1H NMR(400MHz,CDCl3)δ7.55(d,J=8.0Hz,2H),7.45(d,J=8.0Hz,2H),6.54(d,J=16.0Hz,1H),6.44-6.32(m,1H),3.32(d,J=6.9Hz,2H).19F NMR(376MHz,CDCl3)δ-62.58.
实施例21
50mL溶剂存储瓶加入Ni(acac)2(6.4mg,0.025mmol)、neocuproine(10.4mg,0.05mmol)、Mn(55mg,1mmol)、nBu4NOAc(377mg,1.25mmol),在油泵抽真空状态下,充入二氧化碳气体,如此反复三次,随后加入底物3a和DMF(2mL),盖上盖子,将溶剂存储瓶置于油浴25度加热并搅拌,15小时后,反应基本完全,慢慢加入乙酸乙酯稀释,并加入1M HCl酸化,用乙酸乙酯萃取,有机相用饱和氯化铵洗,无水硫酸钠干燥,过滤,浓缩,快速柱层析得液体产物2a,80%产率(来自于3a),14:1E/Z,8:1l/b。1H NMR(400MHz,CDCl3)δ7.32-7.26(m,2H),7.22-7.14(m,3H),5.74-5.48(m,2H),3.08(dd,J=6.6,0.9Hz,2H),2.76-2.66(m,2H),2.38(dd,J=14.8,7.0Hz,2H).
实施例22
操作参考例21。
得液体产物2a,58%产率(来自于3b),10:1E/Z,>20:1l/b。1H NMR(400MHz,CDCl3)δ7.32-7.26(m,2H),7.22-7.14(m,3H),5.74-5.48(m,2H),3.08(dd,J=6.6,0.9Hz,2H),2.76-2.66(m,2H),2.38(dd,J=14.8,7.0Hz,2H).
实施例23
操作参考例21。
得液体产物2p,63%产率(来自于3c),17:1E/Z,8:1l/b。1H NMR(400MHz,CDCl3)δ5.65-5.45(m,2H),3.07(d,J=6.5Hz,2H),2.01(q,J=6.8Hz,2H),1.44-1.34(m,2H),0.89(t,J=7.4Hz,3H).
实施例24
操作参考例21。
得液体产物2c,66%产率(来自于3d),13:1E/Z,>20:1l/b。1H NMR(400MHz,CDCl3)δ5.62-5.47(m,2H),3.64(t,J=6.5Hz,2H),3.06(d,J=5.8Hz,2H),2.07(dd,J=13.4,6.8Hz,2H),1.66-1.51(m,2H),1.51-1.36(m,2H).13C NMR(101MHz,CDCl3)δ177.40,134.84,121.35,62.69,37.70,32.06,31.94,25.09.IR(neat):3434,2933,1706,968cm-1.HRMS(ESI-TOF)calcd forC8H14NaO3[M+Na]+:181.0835,found:181.0832.
实施例25
操作参考例21。
得液体产物2o,61%产率(来自于3e),13:1E/Z,10:1l/b。1H NMR(400MHz,CDCl3)δ5.69-5.50(m,2H),4.08(t,J=6.7Hz,2H),3.08(d,J=6.3Hz,2H),2.36(q,J=6.4Hz,2H),2.03(s,3H).13C NMR(101MHz,CDCl3)δ177.14,171.13,130.26,123.84,63.46,37.54,31.79,20.91.IR(neat):2920,1726,1385,1238,1167,1040,972,645cm-1.HRMS(ESI-TOF)calcd forC8H12NaO4[M+Na]+:195.0628,found:195.0628.
实施例26
操作参考例21。
得液体产物2e,54%产率(来自于3f),11:1E/Z,15:1l/b。1H NMR(400MHz,CDCl3)δ5.65-5.44(m,2H),3.60(t,J=6.4Hz,2H),3.06(d,J=6.3Hz,2H),2.05(q,J=6.8Hz,2H),1.56-1.46(m,2H),1.41(ddd,J=16.5,9.4,6.1Hz,2H),0.89(s,9H),0.04(s,6H).13C NMR(101MHz,CDCl3)δ178.39,135.20,120.97,63.05,37.80,32.21,32.19,25.96,25.30,18.36,-5.29.IR(neat):2929,2857,1711,1098,833,773cm-1.HRMS(ESI-TOF)calcd forC14H29O3Si[M+H]+:273.1880,found:273.1881.
实施例27
操作参考例21。
得液体产物2h,67%产率(来自于3g),14:1E/Z,7:1l/b。1H NMR(400MHz,CDCl3)δ7.70(d,J=7.7Hz,1H),7.63(d,J=7.8Hz,1H),7.55(t,J=7.6Hz,1H),7.36(t,J=7.6Hz,1H),5.66-5.47(m,2H),4.68(s,2H),3.53(t,J=6.5Hz,2H),3.07(d,J=6.3Hz,2H),2.08(dd,J=13.9,6.8Hz,2H),1.72-1.58(m,2H),1.49(dt,J=9.9,7.5Hz,2H).13C NMR(101MHz,CDCl3)δ178.49,137.45(q,J=1.5Hz),135.01,131.90,128.68,127.54,127.18,125.61(q,J=11.8,6.0Hz),124.34(q,J=273Hz),121.14,70.75,68.62(q,J=2.8Hz),37.78,32.21,29.13,25.64.19F NMR(376MHz,CDCl3)δ-60.20.IR(neat):2935,2861,1709,1312,1160,1114,1098,1037,768cm-1.HRMS(ESI-TOF)calcd forC16H23F3NO3[M+NH4]+:334.1625,found:334.1623.
实施例28
操作参考例21。
得固体产物2g,m.p.=36-37℃,80%产率(来自于3h),11:1E/Z,8:1l/b。1H NMR(400MHz,CDCl3)δ5.85(dt,J=3.0,1.9Hz,2H),5.71-5.51(m,2H),3.09(d,J=5.9Hz,2H),2.66(t,J=7.6Hz,2H),2.38(dd,J=14.2,7.1Hz,2H),2.25(s,3H).13C NMR(101MHz,CDCl3)δ178.67,153.50,150.29,134.07,121.66,105.77,105.59,37.77,31.02,27.73,13.48.IR(neat):2924,1698,1218,965,930,783cm-1.HRMS(ESI-TOF)calcd forC11H15O3[M+H]+:195.1016,found:195.1015.
实施例29
操作参考例21。
得固体产物4i,m.p.=94-95℃,56%产率(来自于3i),>20:1E/Z,14:1l/b。1H NMR(400MHz,CDCl3)δ7.95(d,J=8.7Hz,2H),6.87(d,J=8.7Hz,2H),5.76-5.57(m,2H),4.01(t,J=6.6Hz,2H),3.85(s,3H),3.15-3.04(m,2H),2.57-2.48(m,2H).13C NMR(101MHz,CDCl3)δ177.89,166.92,162.58,131.56,130.33,123.91,122.47,114.06,67.28,51.89,37.70,32.22.IR(neat):2955,2922,2870,1703,1602,1277,1241,1225,1171,1108,980,929,855,767,695,644cm-1.HRMS(ESI-TOF)calcd for C14H16NaO5[M+Na]+:287.0890,found:287.0895.
实施例30:
50mL溶剂存储瓶加入NiCl2(6.4mg,0.025mmol)、neocuproine(10.4mg,0.05mmol)、Mn(27.5mg,0.5mmol)、nBu4NOAc(226mg,0.75mmol),在油泵抽真空状态下,充入二氧化碳气体,如此反复三次,随后加入底物1a和DMF(2mL),盖上盖子,将溶剂存储瓶置于油浴25度加热并搅拌,15小时后,反应基本完全,慢慢加入乙酸乙酯稀释,并加入1M HCl酸化,用乙酸乙酯萃取,有机相用饱和氯化铵洗,无水硫酸钠干燥,过滤,浓缩,快速柱层析得液体产物2a,82%产率(来自于1a),>20:1E/Z。1H NMR(400MHz,CDCl3)δ7.32-7.26(m,2H),7.22-7.14(m,3H),5.74-5.48(m,2H),3.08(dd,J=6.6,0.9Hz,2H),2.76-2.66(m,2H),2.38(dd,J=14.8,7.0Hz,2H).
实施例31:
50mL溶剂存储瓶加入NiBr2(6.4mg,0.025mmol)、neocuproine(10.4mg,0.05mmol)、Mn(27.5mg,0.5mmol)、nBu4NOAc(226mg,0.75mmol),在油泵抽真空状态下,充入二氧化碳气体,如此反复三次,随后加入底物1a和DMF(2mL),盖上盖子,将溶剂存储瓶置于油浴25度加热并搅拌,15小时后,反应基本完全,慢慢加入乙酸乙酯稀释,并加入1M HCl酸化,用乙酸乙酯萃取,有机相用饱和氯化铵洗,无水硫酸钠干燥,过滤,浓缩,快速柱层析得液体产物2a,83%产率(来自于1a),>20:1E/Z。1H NMR(400MHz,CDCl3)δ7.32-7.26(m,2H),7.22-7.14(m,3H),5.74-5.48(m,2H),3.08(dd,J=6.6,0.9Hz,2H),2.76-2.66(m,2H),2.38(dd,J=14.8,7.0Hz,2H).
实施例32:
50mL溶剂存储瓶加入Ni(cod)2(6.4mg,0.025mmol)、neocuproine(10.4mg,0.05mmol)、Mn(27.5mg,0.5mmol)、nBu4NOAc(226mg,0.75mmol),在油泵抽真空状态下,充入二氧化碳气体,如此反复三次,随后加入底物1a和DMF(2mL),盖上盖子,将溶剂存储瓶置于油浴25度加热并搅拌,15小时后,反应基本完全,慢慢加入乙酸乙酯稀释,并加入1M HCl酸化,用乙酸乙酯萃取,有机相用饱和氯化铵洗,无水硫酸钠干燥,过滤,浓缩,快速柱层析得液体产物2a,80%产率(来自于1a),>20:1E/Z。1H NMR(400MHz,CDCl3)δ7.32-7.26(m,2H),7.22-7.14(m,3H),5.74-5.48(m,2H),3.08(dd,J=6.6,0.9Hz,2H),2.76-2.66(m,2H),2.38(dd,J=14.8,7.0Hz,2H).
实施例33:
50mL溶剂存储瓶加入Ni(acac)2(6.4mg,0.025mmol)、neocuproine(10.4mg,0.05mmol)、Mn(27.5mg,0.5mmol)、nBu4NOAc(226mg,0.75mmol),在油泵抽真空状态下,充入二氧化碳气体,如此反复三次,随后加入底物1a和DMA(2mL),盖上盖子,将溶剂存储瓶置于油浴25度加热并搅拌,15小时后,反应基本完全,慢慢加入乙酸乙酯稀释,并加入1M HCl酸化,用乙酸乙酯萃取,有机相用饱和氯化铵洗,无水硫酸钠干燥,过滤,浓缩,快速柱层析得液体产物2a,57%产率(来自于1a),>20:1E/Z。1H NMR(400MHz,CDCl3)δ7.32-7.26(m,2H),7.22-7.14(m,3H),5.74-5.48(m,2H),3.08(dd,J=6.6,0.9Hz,2H),2.76-2.66(m,2H),2.38(dd,J=14.8,7.0Hz,2H).
实施例34:
50mL溶剂存储瓶加入Ni(acac)2(6.4mg,0.025mmol)、neocuproine(10.4mg,0.05mmol)、Zn(27.5mg,0.5mmol)、nBu4NOAc(226mg,0.75mmol),在油泵抽真空状态下,充入二氧化碳气体,如此反复三次,随后加入底物1a和DMF(2mL),盖上盖子,将溶剂存储瓶置于油浴25度加热并搅拌,15小时后,反应基本完全,慢慢加入乙酸乙酯稀释,并加入1M HCl酸化,用乙酸乙酯萃取,有机相用饱和氯化铵洗,无水硫酸钠干燥,过滤,浓缩,快速柱层析得液体产物2a,76%产率(来自于1a),>20:1E/Z。1H NMR(400MHz,CDCl3)δ7.32-7.26(m,2H),7.22-7.14(m,3H),5.74-5.48(m,2H),3.08(dd,J=6.6,0.9Hz,2H),2.76-2.66(m,2H),2.38(dd,J=14.8,7.0Hz,2H).
实施例35:
50mL溶剂存储瓶加入Ni(acac)2(6.4mg,0.025mmol)、neocuproine(10.4mg,0.05mmol)、Mn(27.5mg,0.5mmol)、LiOAc(226mg,0.75mmol),在油泵抽真空状态下,充入二氧化碳气体,如此反复三次,随后加入底物1a和DMF(2mL),盖上盖子,将溶剂存储瓶置于油浴25度加热并搅拌,15小时后,反应基本完全,慢慢加入乙酸乙酯稀释,并加入1M HCl酸化,用乙酸乙酯萃取,有机相用饱和氯化铵洗,无水硫酸钠干燥,过滤,浓缩,快速柱层析得液体产物2a,68%产率(来自于1a),>20:1E/Z。1H NMR(400MHz,CDCl3)δ7.32-7.26(m,2H),7.22-7.14(m,3H),5.74-5.48(m,2H),3.08(dd,J=6.6,0.9Hz,2H),2.76-2.66(m,2H),2.38(dd,J=14.8,7.0Hz,2H).
实施例36:
50mL溶剂存储瓶加入Ni(acac)2(6.4mg,0.025mmol)、neocuproine(10.4mg,0.05mmol)、Mn(27.5mg,0.5mmol)、KOAc(226mg,0.75mmol),在油泵抽真空状态下,充入二氧化碳气体,如此反复三次,随后加入底物1a和DMF(2mL),盖上盖子,将溶剂存储瓶置于油浴25度加热并搅拌,15小时后,反应基本完全,慢慢加入乙酸乙酯稀释,并加入1M HCl酸化,用乙酸乙酯萃取,有机相用饱和氯化铵洗,无水硫酸钠干燥,过滤,浓缩,快速柱层析得液体产物2a,63%产率(来自于1a),>20:1E/Z。1H NMR(400MHz,CDCl3)δ7.32-7.26(m,2H),7.22-7.14(m,3H),5.74-5.48(m,2H),3.08(dd,J=6.6,0.9Hz,2H),2.76-2.66(m,2H),2.38(dd,J=14.8,7.0Hz,2H).
对比例1:
将化合物1u置于与实施例1相同的反应条件下,反应不发生。
对比例2:
反应底物、反应条件参数均与实施例1相同,仅配体不同,反应不发生。配体结构如下:
对比例3:
反应底物、反应条件参数均与实施例1相同,仅配体不同,反应不发生。配体结构如下:
对比例4:
反应底物、反应条件参数均与实施例1相同,仅没有镍催化剂,反应不发生。
对比例5:
反应底物、反应条件参数均与实施例1相同,仅没有双氮配体,反应不发生。
对比例6:
反应底物、反应条件参数均与实施例1相同,仅没有添加剂,反应不发生。
对比例7:
反应底物、反应条件参数均与实施例1相同,仅没有还原剂,反应不发生。
对比例8:
反应条件参数均与实施例1相同,仅底物结构不同,反应收率为26%。底物结构如下:
最后,还需要注意的是,以上列举的仅是本发明的具体实施例子。显然,本发明不限于以上实施例子,还可以有许多变形。本领域的技术人员能从本发明公开的内容直接导出或联想到的所有变形,均应以为是本发明的保护范围。
Claims (10)
1.一种如式(I)所示的(E)-β,γ-烯基羧酸衍生物的制备方法,其包括如下步骤:在有机溶剂中,在镍催化剂、双氮配体、还原剂和添加剂存在的条件下,将如式(II)所示的烯丙醇类底物与二氧化碳进行羧化反应,即可;
其中,所述的如式(II)所示的烯丙醇类底物中,以*标记的碳原子表示其为(R)或(S)型的单一构型手性碳或其任意比例混合物;以显示的化学键表示其连接的双键为(E)或(Z)型的单一构型或其任意比例混合物;R和R’中至少一个为H;当R不为H时,R为不以烯基或炔基直接与如式(II)所示的烯丙醇类底物结构中其他部分相连的取代基;当R’不为H时,R’为不以烯基或炔基直接与如式(II)所示的烯丙醇类底物结构中其他部分相连的取代基;所述的如式(I)所示的(E)-β,γ-烯基羧酸衍生物中,R”为R和R’中不为H的那一个,当R和R’均为H时,R”也为H;所述的还原剂为锰和/或锌;所述的添加剂为碱金属醋酸盐和/或季铵醋酸盐;
其中,所述的双氮配体为L1、L2、L3和L4中的一种或多种;
2.如权利要求1所述的如式(I)所示的(E)-β,γ-烯基羧酸衍生物的制备方法,其特征在于,R为-(CH2)n-R1;其中,
n选自1-12中的任一整数,进一步优选为2-5中的任一整数;
R1选自R1A、-O(-R1B)、-S(-R1C)或-N(-R1D)(-R1E)、-C(=O)(OR1F)、-CN、卤素或-NO2;其中,
所述的卤素为氟、氯、溴或碘;
R1A选自H、取代或未取代的C1-C30烷基、取代或未取代的C6-C20芳基、或取代或未取代的C2-C20杂芳基;其中,所述的C1-C30烷基优选为C1-C6烷基,进一步优选为甲基、乙基、丙基、丁基、戊基或己基;所述的C6-C20芳基优选为C6-C10芳基,进一步优选为苯基;所述的C2-C20杂芳基优选为C2-C10杂芳基,进一步优选为噻吩基或吲哚基,更进一步优选所述的噻吩基为2-噻吩基,更进一步优选所述的吲哚基为1-吲哚基;
R1B选自H、取代或取代基的苯基、或醇羟基保护基;所述的醇羟基保护基优选为使所述的醇羟基形成醚、羧酸酯、缩醛或缩酮类衍生物的醇羟基保护基,进一步优选为-Ac、-Bz、或-TBS;
R1C选自H、取代或未取代的苯基、或巯基保护基;所述的巯基保护基优选为使所述的巯基形成硫醚、硫缩醛或硫醇酯类衍生物的巯基保护基,进一步优选为-Bn;
R1D和R1E各自独立地选自H或氨基保护基、或二者共同构成氨基保护基,所述的氨基保护基优选为使所述的氨基形成酰胺类、氨基甲酸酯类或烃基类衍生物的氨基保护基,更进一步优选为-Cbz、-Boc、-Fmoc、-Phth、-Ts、-PMB或-Bn;
R1F选自C1-C10烷基,所述的C1-C10烷基优选为C1-C6烷基,进一步优选为甲基、乙基、丙基、丁基、戊基或己基;
上述各基团中所述的取代基各自独立地选自C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基或酯基,其中,所述的C1-C6烷基优选为C1-C3烷基,进一步优选为甲基或乙基;所述的C1-C6烷氧基优选为C1-C3烷氧基,进一步优选为甲氧基或乙氧基;所述的C1-C6卤代烷基优选为C1-C3卤代烷基,进一步优选为-CF3;所述的酯基优选为-COOMe。
3.如权利要求1所述的如式(I)所示的(E)-β,γ-烯基羧酸衍生物的制备方法,其特征在于,R’优选为-(CH2)n’-R2;其中,
n’选自1-12中的任一整数,进一步优选为2-5中的任一整数;
R2选自R2A、-O(-R2B)、-S(-R2C)或-N(-R2D)(-R2E)、-C(=O)(OR2F)、-CN、卤素或-NO2;
所述的卤素为氟、氯、溴或碘;
R2A选自H、取代或未取代的C1-C30烷基、取代或未取代的C6-C20芳基、或取代或未取代的C2-C20杂芳基;所述的C1-C30烷基优选为C1-C6烷基,进一步优选为甲基、乙基、丙基、丁基、戊基或己基;所述的C6-C20芳基优选为C6-C10芳基,进一步优选为苯基;所述的C2-C20杂芳基优选为C2-C10杂芳基,进一步优选为噻吩基或吲哚基,更进一步优选所述的噻吩基为2-噻吩基,更进一步优选所述的吲哚基为1-吲哚基;
R2B选自H、取代或取代基的苯基、或醇羟基保护基;所述的醇羟基保护基优选为使所述的醇羟基形成醚、羧酸酯、缩醛或缩酮类衍生物的醇羟基保护基,进一步优选为-Ac、-Bz或-TBS;
R2C选自H、取代或未取代的苯基、或巯基保护基;所述的巯基保护基优选为使所述的巯基形成硫醚、硫缩醛或硫醇酯类衍生物的巯基保护基,进一步优选为-Bn;
R2D和R2E各自独立地选自H或氨基保护基、或二者共同构成氨基保护基,所述的氨基保护基优选为使所述的氨基形成酰胺类、氨基甲酸酯类或烃基类衍生物的氨基保护基,更进一步优选为-Cbz、-Boc、-Fmoc、-Phth、-Ts、-PMB或-Bn;
R2F选自C1-C10烷基,所述的C1-C10烷基优选为C1-C6烷基,进一步优选为甲基、乙基、丙基、丁基、戊基或己基;
上述各基团中所述的取代基各自独立地选自C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基或酯基,所述的C1-C6烷基优选为C1-C3烷基,进一步优选为甲基或乙基;所述的C1-C6烷氧基优选为C1-C3烷氧基,进一步优选为甲氧基或乙氧基;所述的C1-C6卤代烷基优选为C1-C3卤代烷基,进一步优选为-CF3;所述的酯基优选为-COOMe。
4.如权利要求1所述的如式(I)所示的(E)-β,γ-烯基羧酸衍生物的制备方法,其特征在于,所述的如式(II)所示的烯丙醇类底物选自下列化合物:
5.如权利要求1所述的如式(I)所示的(E)-β,γ-烯基羧酸衍生物的制备方法,其特征在于,其中,
所述的羧化反应在无水无氧条件下进行;
和/或,所述的有机溶剂为极性非质子溶剂,进一步优选为N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮、1,3-二甲基-2-咪唑啉酮和六甲基磷酰三胺中的一种或多种,更进一步优选为N,N-二甲基甲酰胺;
和/或,所述的如式(II)所示的烯丙醇类底物在所述的有机溶剂中摩尔浓度为0.05-1.0mol/L,优选为0.125-0.250mol/L;
和/或,所述的镍催化剂包括镍(0)催化剂和/或镍(II)催化剂;其中,所述的镍(0)催化剂优选为乙酰丙酮镍和/或双-(1,5-环辛二烯)镍;所述的镍(II)催化剂优选为氯化镍、溴化镍和碘化镍中的一种或多种;所述的镍催化剂进一步优选为乙酰丙酮镍;
和/或,所述的镍催化剂与所述的如式(II)所示的烯丙醇类底物的摩尔比为0.005:1-0.2:1,优选为0.01:1-0.1:1;
和/或,所述的双氮配体为L1;
和/或,所述的双氮配体与所述的镍催化剂的摩尔比为2:1-4:1,优选为2.2:1-2.4:1;
和/或,所述的还原剂为锰;
和/或,所述的还原剂与所述的如式(II)所示的烯丙醇类底物的摩尔比为1:1-3:1,优选为2:1;
和/或,所述的碱金属醋酸盐为醋酸钾、醋酸锂和醋酸铯中的一种或多种,所述的季铵醋酸盐为四丁基醋酸铵和/或四甲基醋酸铵;所述的添加剂优选为四丁基醋酸铵;
和/或,所述的添加剂与所述的如式(II)所示的烯丙醇类底物的摩尔比为1:1-4:1,优选为2:1-3:1。
6.如权利要求1所述的如式(I)所示的(E)-β,γ-烯基羧酸衍生物的制备方法,其特征在于,所述的制备方法进一步还包括如下步骤:将如式(III)所示的炔丙醇类底物进行还原反应,得到所述的如式(II)所示的烯丙醇底物,即可;
其中,所述的如式(III)所示的炔丙醇类底物中,R和R’的限定如权利要求1-5任一项所述。
7.一种如式(I)所示的(E)-β,γ-烯基羧酸衍生物的制备方法,其包括如下步骤:在有机溶剂中,在镍催化剂、双氮配体、还原剂和添加剂存在的条件下,将如式(III)所示的炔丙醇底物与二氧化碳进行羧化反应,即可;
其中,所述的取代基R、R’和R”的定义、所述的镍催化剂、所述的双氮配体、所述的还原剂和所述的添加剂以及所述的羧化反应的反应条件与参数如权利要求1-5任一项所述;但是,所述的还原剂与所述的底物的摩尔比优选为3:1-5:1,进一步优选为4:1;所述的添加剂与所述的底物的摩尔比优选为1:1-6:1,优选为3:1-5:1。
8.如权利要求7所述的如式(I)所示的(E)-β,γ-烯基羧酸衍生物的制备方法,其特征在于,所述的如式(III)所示的炔丙醇底物选自下列化合物:
9.一种如权利要求1-8任一项所述的如式(I)所示的(E)-β,γ-烯基羧酸衍生物的制备方法,其特征在于,其中,
当所述的羧化反应的反应物为如式(II)所示的烯丙醇类底物时,所述的如式(II)所示的烯丙醇类底物、所述的镍催化剂、所述的双氮配体、所述的还原剂和所述的添加剂的加料量摩尔比为1:0.1:0.2:2.0:3.0;
当所述的羧化反应的反应物为如式(III)所示的炔丙醇类底物时,所述的如式(III)所示的炔丙醇类底物、所述的镍催化剂、所述的双氮配体、所述的还原剂和所述的添加剂的加料量摩尔比为1:0.1:0.2:4.0:5.0。
10.一种如权利要求1-8任一项所述的如式(I)所示的(E)-β,γ-烯基羧酸衍生物的制备方法,其特征在于,其中,
所述的制备方法的加料顺序为:先将所述的镍催化剂、所述的双氮配体、所述的还原剂和所述的添加剂加入反应体系中,加入顺序不做特别限定,再冲入二氧化碳气体,最后加入所述的如式(II)所示的烯丙醇类底物或如式(III)所示的炔丙醇类底物和所述的有机溶剂;
和/或,所述的羧化反应的反应温度为10-60℃,优选为20-25℃;
和/或,所述的羧化反应的反应时间为10-24h,优选为12-15h;
和/或,所述的羧化反应的后处理步骤为:在所述的羧化反应反应结束后,加入有机溶剂稀释,并加入无机酸进行酸化;用有机溶剂萃取,所得的有机相用饱和氯化铵水溶液洗涤,无水硫酸钠干燥,过滤,浓缩,即可得粗产品;所述的后处理步骤结束后,优选还包括所述的粗产品分离纯化过程。
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