CN106543065A - 一种4‑三氟甲基‑2,4‑二取代‑2,5‑二氢吡咯衍生物及其制备方法和应用 - Google Patents
一种4‑三氟甲基‑2,4‑二取代‑2,5‑二氢吡咯衍生物及其制备方法和应用 Download PDFInfo
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- CN106543065A CN106543065A CN201610894495.6A CN201610894495A CN106543065A CN 106543065 A CN106543065 A CN 106543065A CN 201610894495 A CN201610894495 A CN 201610894495A CN 106543065 A CN106543065 A CN 106543065A
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- CN
- China
- Prior art keywords
- trifluoromethyl
- dihydro
- pyrroles
- phenyl
- replacement
- Prior art date
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- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 title claims abstract description 84
- 238000002360 preparation method Methods 0.000 title claims abstract description 30
- JVQIKJMSUIMUDI-UHFFFAOYSA-N 3-pyrroline Chemical compound C1NCC=C1 JVQIKJMSUIMUDI-UHFFFAOYSA-N 0.000 title abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 120
- -1 primary amine compound Chemical class 0.000 claims abstract description 75
- 150000001875 compounds Chemical class 0.000 claims abstract description 19
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 claims abstract description 18
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 201
- 239000002994 raw material Substances 0.000 claims description 58
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 43
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 claims description 28
- 125000000217 alkyl group Chemical group 0.000 claims description 27
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Substances ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 17
- 125000003118 aryl group Chemical group 0.000 claims description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- 229910001961 silver nitrate Inorganic materials 0.000 claims description 14
- 206010011224 Cough Diseases 0.000 claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 12
- WKCISEKGRBGHNP-UHFFFAOYSA-N 2-phenyl-4-(trifluoromethyl)-2,5-dihydro-1H-pyrrole Chemical class C1(=CC=CC=C1)C1NCC(=C1)C(F)(F)F WKCISEKGRBGHNP-UHFFFAOYSA-N 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 125000001072 heteroaryl group Chemical group 0.000 claims description 9
- ZHEKKPZJHDBGOG-UHFFFAOYSA-N CN(CC(C(F)(F)F)=C1)C1C1=CC=CC=C1 Chemical class CN(CC(C(F)(F)F)=C1)C1C1=CC=CC=C1 ZHEKKPZJHDBGOG-UHFFFAOYSA-N 0.000 claims description 8
- GGDBRIYJMJXWAN-UHFFFAOYSA-N 1-benzyl-3-(trifluoromethyl)-2,5-dihydropyrrole Chemical class C(C1=CC=CC=C1)N1CC=C(C1)C(F)(F)F GGDBRIYJMJXWAN-UHFFFAOYSA-N 0.000 claims description 7
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 7
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 7
- 229920005556 chlorobutyl Polymers 0.000 claims description 7
- 150000003233 pyrroles Chemical class 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- MFYLRNKOXORIPK-UHFFFAOYSA-N (3-nitrophenyl)-phenylmethanone Chemical class [O-][N+](=O)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 MFYLRNKOXORIPK-UHFFFAOYSA-N 0.000 claims description 5
- ZYMCBJWUWHHVRX-UHFFFAOYSA-N (4-nitrophenyl)-phenylmethanone Chemical class C1=CC([N+](=O)[O-])=CC=C1C(=O)C1=CC=CC=C1 ZYMCBJWUWHHVRX-UHFFFAOYSA-N 0.000 claims description 5
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 5
- 125000006281 4-bromobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Br)C([H])([H])* 0.000 claims description 5
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 claims description 5
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 5
- 125000006181 4-methyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])C([H])([H])* 0.000 claims description 5
- 125000001318 4-trifluoromethylbenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])*)C(F)(F)F 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- UJHSIDUUJPTLDY-UHFFFAOYSA-N (2-nitrophenyl)-phenylmethanone Chemical class [O-][N+](=O)C1=CC=CC=C1C(=O)C1=CC=CC=C1 UJHSIDUUJPTLDY-UHFFFAOYSA-N 0.000 claims description 4
- 241001597008 Nomeidae Species 0.000 claims description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 claims description 4
- 125000004185 ester group Chemical group 0.000 claims description 4
- 125000002541 furyl group Chemical group 0.000 claims description 4
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 238000006467 substitution reaction Methods 0.000 claims description 4
- 125000001544 thienyl group Chemical group 0.000 claims description 4
- ILSAFFPOXGEEBL-UHFFFAOYSA-N 1,2-diphenyl-4-(trifluoromethyl)-2,5-dihydropyrrole Chemical class C1C(=CC(N1C2=CC=CC=C2)C3=CC=CC=C3)C(F)(F)F ILSAFFPOXGEEBL-UHFFFAOYSA-N 0.000 claims description 3
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- IPSAEBVRRVTFAO-UHFFFAOYSA-N 2-phenyl-1-(1-phenylethyl)-4-(trifluoromethyl)-2,5-dihydropyrrole Chemical class C1(=CC=CC=C1)C(C)N1C(C=C(C1)C(F)(F)F)C1=CC=CC=C1 IPSAEBVRRVTFAO-UHFFFAOYSA-N 0.000 claims description 3
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 3
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 3
- USIRFGLPTBOGLB-UHFFFAOYSA-N CN1CC=C(C1)C(F)(F)F Chemical class CN1CC=C(C1)C(F)(F)F USIRFGLPTBOGLB-UHFFFAOYSA-N 0.000 claims description 3
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims description 3
- PMDCZENCAXMSOU-UHFFFAOYSA-N N-ethylacetamide Chemical compound CCNC(C)=O PMDCZENCAXMSOU-UHFFFAOYSA-N 0.000 claims description 3
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 3
- MVPPADPHJFYWMZ-IDEBNGHGSA-N chlorobenzene Chemical group Cl[13C]1=[13CH][13CH]=[13CH][13CH]=[13CH]1 MVPPADPHJFYWMZ-IDEBNGHGSA-N 0.000 claims description 3
- 239000003205 fragrance Substances 0.000 claims description 3
- YPRWCJMEQCFZFL-UHFFFAOYSA-N 1-benzyl-2-(phenylmethoxymethyl)-4-(trifluoromethyl)-2,5-dihydropyrrole Chemical class C1C(=CC(N1CC2=CC=CC=C2)COCC3=CC=CC=C3)C(F)(F)F YPRWCJMEQCFZFL-UHFFFAOYSA-N 0.000 claims description 2
- LBSNYSINJYQSOF-UHFFFAOYSA-N 1-benzyl-2-phenyl-4-(trifluoromethyl)-2,5-dihydropyrrole Chemical class C(C1=CC=CC=C1)N1C(C=C(C1)C(F)(F)F)C1=CC=CC=C1 LBSNYSINJYQSOF-UHFFFAOYSA-N 0.000 claims description 2
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 2
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- USIYRFTZKYKHBI-UHFFFAOYSA-N butyl n-ethylcarbamate Chemical compound CCCCOC(=O)NCC USIYRFTZKYKHBI-UHFFFAOYSA-N 0.000 claims description 2
- 150000004702 methyl esters Chemical class 0.000 claims description 2
- 229910052709 silver Inorganic materials 0.000 claims description 2
- 239000004332 silver Substances 0.000 claims description 2
- 150000001555 benzenes Chemical class 0.000 claims 2
- AHVYPIQETPWLSZ-UHFFFAOYSA-N 1-methyl-2,5-dihydropyrrole Chemical class CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 claims 1
- QGHDLJAZIIFENW-UHFFFAOYSA-N 4-[1,1,1,3,3,3-hexafluoro-2-(4-hydroxy-3-prop-2-enylphenyl)propan-2-yl]-2-prop-2-enylphenol Chemical group C1=C(CC=C)C(O)=CC=C1C(C(F)(F)F)(C(F)(F)F)C1=CC=C(O)C(CC=C)=C1 QGHDLJAZIIFENW-UHFFFAOYSA-N 0.000 claims 1
- 230000021615 conjugation Effects 0.000 claims 1
- 238000004440 column chromatography Methods 0.000 abstract description 6
- 238000007363 ring formation reaction Methods 0.000 abstract description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 342
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 190
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 140
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 68
- 239000003208 petroleum Substances 0.000 description 68
- 238000003756 stirring Methods 0.000 description 58
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 57
- 238000005160 1H NMR spectroscopy Methods 0.000 description 57
- 238000004293 19F NMR spectroscopy Methods 0.000 description 55
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 44
- 238000010898 silica gel chromatography Methods 0.000 description 41
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 39
- 239000012230 colorless oil Substances 0.000 description 36
- 239000007787 solid Substances 0.000 description 35
- 239000002904 solvent Substances 0.000 description 29
- 239000012043 crude product Substances 0.000 description 28
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- 239000000741 silica gel Substances 0.000 description 25
- 229910002027 silica gel Inorganic materials 0.000 description 25
- 238000003818 flash chromatography Methods 0.000 description 24
- 229910052757 nitrogen Inorganic materials 0.000 description 22
- 239000000463 material Substances 0.000 description 16
- 229910052740 iodine Inorganic materials 0.000 description 13
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 12
- 239000011630 iodine Substances 0.000 description 12
- 238000001514 detection method Methods 0.000 description 11
- 238000005086 pumping Methods 0.000 description 11
- 238000009423 ventilation Methods 0.000 description 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 8
- NBVXSUQYWXRMNV-UHFFFAOYSA-N monofluoromethane Natural products FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- 150000007980 azole derivatives Chemical class 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000012544 monitoring process Methods 0.000 description 6
- 238000001035 drying Methods 0.000 description 5
- 238000003810 ethyl acetate extraction Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 229910014263 BrF3 Inorganic materials 0.000 description 4
- 0 CC*C1N(*)CC(C(F)(F)F)=C1 Chemical compound CC*C1N(*)CC(C(F)(F)F)=C1 0.000 description 4
- 229910020323 ClF3 Inorganic materials 0.000 description 4
- 208000035126 Facies Diseases 0.000 description 4
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
- 239000011737 fluorine Substances 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical class FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical class CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 3
- RSEBUVRVKCANEP-UHFFFAOYSA-N 2-pyrroline Chemical compound C1CC=CN1 RSEBUVRVKCANEP-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- ZVJHJDDKYZXRJI-UHFFFAOYSA-N 1-Pyrroline Chemical compound C1CC=NC1 ZVJHJDDKYZXRJI-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 description 2
- VVJKKWFAADXIJK-UHFFFAOYSA-N Allylamine Chemical compound NCC=C VVJKKWFAADXIJK-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000000975 bioactive effect Effects 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 150000002391 heterocyclic compounds Chemical class 0.000 description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- RLKHFSNWQCZBDC-UHFFFAOYSA-N n-(benzenesulfonyl)-n-fluorobenzenesulfonamide Chemical compound C=1C=CC=CC=1S(=O)(=O)N(F)S(=O)(=O)C1=CC=CC=C1 RLKHFSNWQCZBDC-UHFFFAOYSA-N 0.000 description 2
- 239000002547 new drug Substances 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 150000003141 primary amines Chemical class 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- RQEUFEKYXDPUSK-SSDOTTSWSA-N (1R)-1-phenylethanamine Chemical class C[C@@H](N)C1=CC=CC=C1 RQEUFEKYXDPUSK-SSDOTTSWSA-N 0.000 description 1
- YMVFJGSXZNNUDW-UHFFFAOYSA-N (4-chlorophenyl)methanamine Chemical class NCC1=CC=C(Cl)C=C1 YMVFJGSXZNNUDW-UHFFFAOYSA-N 0.000 description 1
- HMTSWYPNXFHGEP-UHFFFAOYSA-N (4-methylphenyl)methanamine Chemical class CC1=CC=C(CN)C=C1 HMTSWYPNXFHGEP-UHFFFAOYSA-N 0.000 description 1
- IDPURXSQCKYKIJ-UHFFFAOYSA-N 1-(4-methoxyphenyl)methanamine Chemical class COC1=CC=C(CN)C=C1 IDPURXSQCKYKIJ-UHFFFAOYSA-N 0.000 description 1
- RIYVPRLCZRVXAM-UHFFFAOYSA-N 1-(trifluoromethyl)-2,5-dihydropyrrole Chemical class FC(F)(F)N1CC=CC1 RIYVPRLCZRVXAM-UHFFFAOYSA-N 0.000 description 1
- WOXFMYVTSLAQMO-UHFFFAOYSA-N 2-Pyridinemethanamine Chemical class NCC1=CC=CC=N1 WOXFMYVTSLAQMO-UHFFFAOYSA-N 0.000 description 1
- AIDLAEPHWROGFI-UHFFFAOYSA-N 2-methylbenzene-1,3-dicarboxylic acid Chemical compound CC1=C(C(O)=O)C=CC=C1C(O)=O AIDLAEPHWROGFI-UHFFFAOYSA-N 0.000 description 1
- ZRNSSRODJSSVEJ-UHFFFAOYSA-N 2-methylpentacosane Chemical compound CCCCCCCCCCCCCCCCCCCCCCCC(C)C ZRNSSRODJSSVEJ-UHFFFAOYSA-N 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- 150000004066 3-pyrrolines Chemical class 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- FMKFOJIFDWBVHW-UHFFFAOYSA-N C=CC(C(C1)C1C1CCC1)N Chemical compound C=CC(C(C1)C1C1CCC1)N FMKFOJIFDWBVHW-UHFFFAOYSA-N 0.000 description 1
- QNSOTEQPJMJBIG-UHFFFAOYSA-O CC1[NH+](CC2CC2)C1 Chemical compound CC1[NH+](CC2CC2)C1 QNSOTEQPJMJBIG-UHFFFAOYSA-O 0.000 description 1
- UYPUZKGPDYVJQR-UHFFFAOYSA-N CCCC(CC)C(C)NC Chemical compound CCCC(CC)C(C)NC UYPUZKGPDYVJQR-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- HBWSVVKBQOPKBP-UHFFFAOYSA-N FC(C1=CC(c2ccccc2)N(Cc2ccc[s]2)C1)(F)F Chemical compound FC(C1=CC(c2ccccc2)N(Cc2ccc[s]2)C1)(F)F HBWSVVKBQOPKBP-UHFFFAOYSA-N 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- MZTCCUSKMMNHNV-UHFFFAOYSA-N N1C=CCC1.[F] Chemical compound N1C=CCC1.[F] MZTCCUSKMMNHNV-UHFFFAOYSA-N 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 238000006161 Suzuki-Miyaura coupling reaction Methods 0.000 description 1
- PRDBLLIPPDOICK-UHFFFAOYSA-N [4-(trifluoromethyl)phenyl]methanamine Chemical class NCC1=CC=C(C(F)(F)F)C=C1 PRDBLLIPPDOICK-UHFFFAOYSA-N 0.000 description 1
- ZGBSOTLWHZQNLH-UHFFFAOYSA-N [Mg].S(O)(O)(=O)=O Chemical compound [Mg].S(O)(O)(=O)=O ZGBSOTLWHZQNLH-UHFFFAOYSA-N 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000006254 arylation reaction Methods 0.000 description 1
- 150000003851 azoles Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 229960003328 benzoyl peroxide Drugs 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 229960002624 bretylium tosilate Drugs 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- CZKMPDNXOGQMFW-UHFFFAOYSA-N chloro(triethyl)germane Chemical compound CC[Ge](Cl)(CC)CC CZKMPDNXOGQMFW-UHFFFAOYSA-N 0.000 description 1
- 150000008422 chlorobenzenes Chemical class 0.000 description 1
- GKIRPKYJQBWNGO-OCEACIFDSA-N clomifene Chemical compound C1=CC(OCCN(CC)CC)=CC=C1C(\C=1C=CC=CC=1)=C(\Cl)C1=CC=CC=C1 GKIRPKYJQBWNGO-OCEACIFDSA-N 0.000 description 1
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 1
- 238000006264 debenzylation reaction Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 235000015177 dried meat Nutrition 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- KWBIXTIBYFUAGV-UHFFFAOYSA-N ethylcarbamic acid Chemical compound CCNC(O)=O KWBIXTIBYFUAGV-UHFFFAOYSA-N 0.000 description 1
- 150000002171 ethylene diamines Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 description 1
- UTVVREMVDJTZAC-UHFFFAOYSA-N furan-2-amine Chemical class NC1=CC=CO1 UTVVREMVDJTZAC-UHFFFAOYSA-N 0.000 description 1
- JMANVNJQNLATNU-UHFFFAOYSA-N glycolonitrile Natural products N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- DAKZISABEDGGSV-UHFFFAOYSA-N n-(2-aminoethyl)acetamide Chemical compound CC(=O)NCCN DAKZISABEDGGSV-UHFFFAOYSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 150000004812 organic fluorine compounds Chemical class 0.000 description 1
- 238000006362 organocatalysis Methods 0.000 description 1
- 229940117803 phenethylamine Drugs 0.000 description 1
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
Classifications
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- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/20—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
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- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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Abstract
本发明涉及一种式(III)所示的4‑三氟甲基‑2,4‑二取代‑2,5‑二氢吡咯衍生物及其制备方法，在银盐的作用下，2‑三氟甲基‑1,3‑共轭烯炔类化合物与伯胺类化合物发生环化反应，经过滤、浓缩、柱层析得到所述4‑三氟甲基‑2,4‑二取代‑2,5‑二氢吡咯衍生物。本发明制备方法反应条件温和，操作简单，获得了4‑三氟甲基‑2,4‑二取代‑2,5‑二氢吡咯化合物结构骨架。
Description
技术领域
本发明涉及一类含氟二氢吡咯衍生物的制备方法，具体涉及一类4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物及其制备方法，属于化学物质及其制备技术领域。
背景技术
3-吡咯啉(2,5-二氢吡咯)是一种非常重要的含氮五元杂环化合物，是许多天然产物和生物活性化合物的结构骨架。3-吡咯啉也是通用的前导化合物，可用来合成吡咯烷、吡咯和吡咯烷酮等非常有适用价值的五元含氮杂环化合物。由于其在生物和合成上的重要性，因此发展3-吡咯啉(2,5-二氢吡咯)的合成方法学研究一直是当前有机合成化学研究的热点领域之一，很多过渡金属催化和有机催化合成3-吡咯啉的方法被研究报道(for areview:(a)M.Brichacek,J.T.Njardarson,Org.Biomol.Chem.2009,7,1761；for selectedvery recent examples for 3-pyrrolines synthesis via transition-meta-ororgano-catalysis,please see:(b)L.Lei,J.Zhang,Org.Lett.2011,13,5940；(c)W.Sun,X.Ma,L.Hong,R.Wang,J.Org.Chem.2011,76,7826；(d)M.Sampath,P.-Y.BeatrixLee,T.-P.Loh,Chem.Sci.,2011,2,1988；(e)D.-H.Zhang,L.-F.Yao,Y.Wei,M.Shi,Angew.Chem.Int.Ed.2011,50,2583；(f)I.P.Andrews,B.R.Blank,O.Kwon,Chem.Commun.,2012,48,5373；(g)A.Desmarchelier,V.Coeffard,X.Moreau,C.Greck,Chem.Eur.J.2012,18,13222；(h)X.Han,F.Zhong,Y.Wang,Y.Lu,Angew.Chem.Int.Ed.2012,51,767；(i)X.Han,F.Zhong,Y.Wang,Y.Lu,Angew.Chem.Int.Ed.2012,51,767；(j)S.S.K.Boominathan,W.-P.Hu,G.C.Senadi,J.-J.Wang,Adv.Synth.Catal.2013,355,3570；(k)J.Brioche,C.Meyer,J.Cossy,Org.Lett.2013,15,1626；(l)C.E.Henry,Q.Xu,Y.C.Fan,T.J.Martin,L.Belding,T.Dudding,O.Kwon,J.Am.Chem.Soc.2014,136,11890；(m)Y.H.Shin,M.Maheswara,J.Y.Hwang,E.J.Kang,Eur.J.Org.Chem.2014,2305；(n)I.Chogii,J.T.Njardarson,Angew.Chem.Int.Ed.2015,54,13706；(o)J.Chen,J.Li,J.Wang,H.Li,W.Wang,Y.Guo,Org.Lett.2015,17,2214；(p)C.Zheng,Y.Wang,R.Fan,Org.Lett.2015,17,916)。另一方面，同样类似的分子骨架，相比不含氟的有机分子，含氟有机分子一般具有较高的反应活性、亲油性和生物活性((a)J.-P.Béguéand D.Bonnet-Delpon,Bioorganic and MedicinalChemistry of Fluorine,Wiley-VCH,Weinheim,2008；(b)A.Tressaud and G.Haufe,Fluorine and Health:Molecular Imaging,Biomedical Materials andPharmaceuticals,Elsevier,Oxford,2008；(c)K.Uneyama,Organofluorine Chemistry,Blackwell,Oxford,2006)。例如，在新药和候选药物中引入三氟甲基基团来提高药物的氧化代谢稳定性是生物化学家们常采用的一个策略，((a)R.Filler,Y.Kobayashi,L.M.Yagupolskii,Organofluorine Compounds in Medicinal Chemistry andBiomedical Applications,Elsevier:Amsterdam,1993；(b)W.K.Hagmann,J.Med.Chem.2008,51,4359；(c)D.Barnes-Seeman,M.Jain,L.Bell,S.Ferreira,S.Cohen,X.-H.Chen,J.Amin,B.Snodgrass,P.Hatsis,ACS Med.Chem.Lett.2013,4,514)。因此发展含三氟甲基取代的3-吡咯啉合成方法学研究吸引了众多有机合成化学家的关注((a)C.D.Cox,M.J.Breslin,D.B.Whitman,P.J.Coleman,R.M.Garbaccio,M.E.Fraley,M.M.Zrada,C.A.Buser,E.S.Walsh,K.Hamilton,R.B.Lobell,W.Tao,M.T.Abrams,V.J.South,H.E.Huber,N.E.Kohl,G.D.Hartman,Bioorg.Med.Chem.Lett.2007,17,2697；(b)C.D.Cox,P.J.Coleman,M.J.Breslin,D.B.Whitman,R.M.Garbaccio,M.E.Fraley,C.A.Buser,E.S.Walsh,K.Hamilton,M.D.Schaber,R.B.Lobell,W.Tao,J.P.Davide,R.E.Diehl,M.T.Abrams,V.J.South,H.E.Huber,M.Torrent,T.Prueksaritanont,C.Li,D.E.Slaughter,E.Mahan,C.Fernandez-Metzler,Y.Yan,L.C.Kuo,N.E.Kohl,G.D.Hartman,J.Med.Chem.2008,51,4239；(c)T.Tajima,H.Ishii,T.Fuchigami,Tetrahedron Lett.,2001,42,4857；(d)T.Tajima,A.Nakajima,T.Fuchigami,J.Org.Chem,2006,71,1436；(e)G.Tran,R.Meier,L.Harris,D.L.Browne,S.V.Ley,J.Org.Chem,2012,77,11071；(f)T.Xu,X.Mu,H.Peng,G.Liu,Angew.Chem.Int.Ed.2011,50,8176)。鉴于含三氟甲基-3-吡咯啉化合物的重要性和适用价值，因此发展新颖的、通用的和高效的方法合成含三氟甲基-3-吡咯啉化合物显得尤为重要。
发明内容
本发明进一步丰富了含三氟甲基杂环化合物的合成方法学，提供一种原料易得、反应条件温和、化学选择性好的含三氟甲基二氢吡咯杂环衍生物的合成方法，制备得到一类新的4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物。
本发明提供了一种4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物，结构如式(III)所示，
其中，R1为芳基、杂芳基、烷基或取代烷基；R2为烷基或取代烷基、芳基。
优选地，所述芳基包括苯基、硝基取代的苯基、卤素取代的苯基、甲酰基取代的苯基、乙酰基取代的苯基、氰基取代的苯基、三氟甲基取代的苯基、甲氧基取代的苯基、甲基取代的苯基、酯基取代的苯基；所述杂芳基为呋喃基、噻吩基、吡啶基、环己烯基、二茂铁基；所述烷基或取代烷基包括4-氯丁基、羟甲基、酯甲基、叔丁基二甲基硅氧甲基、苄氧甲基、1-羟基-1-环己基。
进一步地，所述R1为苯基、4-硝基苯基、3-硝基苯基、2-硝基苯基、4-氯苯基、4-溴苯基、4-甲酰基苯基、4-乙酰基苯基、4-甲酯基苯基、4-氰基苯基、4-氟苯基、4-三氟甲基苯基、4-甲基苯基、4-甲氧基苯基、2-萘基、2-噻吩基、2-吡啶基、1-环己烯基、二茂铁基、4-氯丁基、羟甲基、乙酰氧甲基、叔丁基二甲基硅氧甲基、苄氧甲基、1-羟基环己基；所述R2为4-氟苄基、4-氯苄基、4-溴苄基、4-三氟甲基苄基、4-甲基苄基、4-甲氧基苯基、苯乙基、异丙基、烯丙基、2-呋喃甲基、2-噻吩甲基、2-吡啶甲基、(R)-1-苯乙基、羟乙基、氨基乙基、乙酰胺乙基、叔丁基氧酰乙基、苯基。
本发明中，所述式(III)所示的4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物包括1-苄基-2-苯基-4-三氟甲基-2,5-二氢-1H-吡咯，1-苄基-2-(4-硝基苯基)-4-三氟甲基-2,5-二氢-1H-吡咯，1-苄基-2-(3-硝基苯基)-4-三氟甲基-2,5-二氢-1H-吡咯，1-苄基-2-(2-硝基苯基)-4-三氟甲基-2,5-二氢-1H-吡咯，1-苄基-2-(4-氯苯基)-4-三氟甲基-2,5-二氢-1H-吡咯，1-苄基-2-(4-溴苯基)-4-三氟甲基-2,5-二氢-1H-吡咯，1-苄基-2-(4-甲酰基苯基)-4-三氟甲基-2,5-二氢-1H-吡咯，1-苄基-2-(4-乙酰基苯基)-4-三氟甲基-2,5-二氢-1H-吡咯，1-苄基-2-(4-甲酯基苯基)-4-三氟甲基-2,5-二氢-1H-吡咯，1-苄基-2-(4-氰基苯基)-4-三氟甲基-2,5-二氢-1H-吡咯，1-苄基-2-(4-氟苯基)-4-三氟甲基-2,5-二氢-1H-吡咯，1-苄基-2-(4-三氟甲基苯基)-4-三氟甲基-2,5-二氢-1H-吡咯，1-苄基-2-(4-甲基苯基)-4-三氟甲基-2,5-二氢-1H-吡咯，1-苄基-2-(4-甲氧基苯基)-4-三氟甲基-2,5-二氢-1H-吡咯，1-苄基-2-(2-萘基)-4-三氟甲基-2,5-二氢-1H-吡咯，1-苄基-2-(2-噻吩基)-4-三氟甲基-2,5-二氢-1H-吡咯，1-苄基-2-(2-吡啶基)-4-三氟甲基-2,5-二氢-1H-吡咯，1-苄基-2-(1-环己烯基)-4-三氟甲基-2,5-二氢-1H-吡咯，1-苄基-2-二茂铁基-4-三氟甲基-2,5-二氢-1H-吡咯，1-苄基-2-(4-氯丁基)-4-三氟甲基-2,5-二氢-1H-吡咯，2-(1-苄基-4-三氟甲基-2,5-二氢-1H-吡咯)甲醇，乙酸-2-(1-苄基-4-三氟甲基-2,5-二氢-1H-吡咯)甲基酯，1-苄基-2-叔丁基二甲基硅氧甲基-4-三氟甲基-2,5-二氢-1H-吡咯，1-苄基-2-苄氧甲基-4-三氟甲基-2,5-二氢-1H-吡咯，1-(2-(1-苄基-4-三氟甲基-2,5-二氢-1H-吡咯))-1-环己醇，1-(4-氟苄基)-2-苯基-4-三氟甲基-2,5-二氢-1H-吡咯，1-(4-氯苄基)-2-苯基-4-三氟甲基-2,5-二氢-1H-吡咯，1-(4-溴苄基)-2-苯基-4-三氟甲基-2,5-二氢-1H-吡咯，1-(4-三氟甲基苄基)-2-苯基-4-三氟甲基-2,5-二氢-1H-吡咯，1-(4-甲基苄基)-2-苯基-4-三氟甲基-2,5-二氢-1H-吡咯，1-(4-甲氧基苄基)-2-苯基-4-三氟甲基-2,5-二氢-1H-吡咯，1-苯乙基-2-苯基-4-三氟甲基-2,5-二氢-1H-吡咯，1-异丙基-2-苯基-4-三氟甲基-2,5-二氢-1H-吡咯，1-烯丙基-2-苯基-4-三氟甲基-2,5-二氢-1H-吡咯，1-(2-呋喃基)甲基-2-苯基-4-三氟甲基-2,5-二氢-1H-吡咯，1-(2-噻吩基)甲基-2-苯基-4-三氟甲基-2,5-二氢-1H-吡咯，1-(2-吡啶基)甲基-2-苯基-4-三氟甲基-2,5-二氢-1H-吡咯，1-((R)-1-苯乙基))-2-苯基-4-三氟甲基-2,5-二氢-1H-吡咯，2-(2-苯基-4-三氟甲基-2,5-二氢-1H-吡咯)乙醇，2-(2-苯基-4-三氟甲基-2,5-二氢-1H-吡咯)乙胺，N-(2-(2-苯基-4-三氟甲基-2,5-二氢-1H-吡咯))乙基乙酰胺，2-(2-苯基-4-三氟甲基-2,5-二氢-1H-吡咯)乙氨基甲酸丁酯，1-苯基-2-苯基-4-三氟甲基-2,5-二氢-1H-吡咯。
本发明还提出了式(III)所示的4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物的制备方法，以2-三氟甲基-1,3-共轭烯炔类化合物、伯胺类化合物为原料，将其溶于有机溶剂，在银盐的作用下经双氢胺化反应，得到本发明的双取代多官能团化的含三氟甲基二氢吡咯衍生物，即式(III)所示的4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物。
具体地，本发明提供的如式(III)所示的4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物的制备方法包括，在银盐的作用下，式(I)所示的2-三氟甲基-1,3-共轭烯炔类化合物与式(II)所示的伯胺类化合物发生双氢胺化反应(环化反应)，经过滤、浓缩、柱层析得到所述式(III)所示4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物；所述制备方法的反应式如反应式(1)所示，
其中，R1为芳基、杂芳基、烷基或取代烷基；R2为烷基或取代烷基、芳基。
优选地，所述芳基包括苯基、硝基取代的苯基、卤素取代的苯基、甲酰基取代的苯基、乙酰基取代的苯基、氰基取代的苯基、三氟甲基取代的苯基、甲氧基取代的苯基、甲基取代的苯基、酯基取代的苯基；所述杂芳基为呋喃基、噻吩基、吡啶基、环己烯基、二茂铁基；所述烷基或取代烷基包括4-氯丁基、羟甲基、酯甲基、叔丁基二甲基硅氧甲基、苄氧甲基、1-羟基-1-环己基。
进一步地，所述R1为苯基、4-硝基苯基、3-硝基苯基、2-硝基苯基、4-氯苯基、4-溴苯基、4-甲酰基苯基、4-乙酰基苯基、4-甲酯基苯基、4-氰基苯基、4-氟苯基、4-三氟甲基苯基、4-甲基苯基、4-甲氧基苯基、2-萘基、2-噻吩基、2-吡啶基、1-环己烯基、二茂铁基、4-氯丁基、羟甲基、乙酰氧甲基、叔丁基二甲基硅氧甲基、苄氧甲基、1-羟基环己基；所述R2为4-氟苄基、4-氯苄基、4-溴苄基、4-三氟甲基苄基、4-甲基苄基、4-甲氧基苯基、苯乙基、异丙基、烯丙基、2-呋喃甲基、2-噻吩甲基、2-吡啶甲基、(R)-1-苯乙基、羟乙基、氨基乙基、乙酰胺乙基、叔丁基氧酰乙基、苯基。
本发明中，所述式(III)所示的4-三氟甲基-2,4-二取代二氢吡咯衍生物包括1-苄基-2-苯基-4-三氟甲基-2,5-二氢-1H-吡咯，1-苄基-2-(4-硝基苯基)-4-三氟甲基-2,5-二氢-1H-吡咯，1-苄基-2-(3-硝基苯基)-4-三氟甲基-2,5-二氢-1H-吡咯，1-苄基-2-(2-硝基苯基)-4-三氟甲基-2,5-二氢-1H-吡咯，1-苄基-2-(4-氯苯基)-4-三氟甲基-2,5-二氢-1H-吡咯，1-苄基-2-(4-溴苯基)-4-三氟甲基-2,5-二氢-1H-吡咯，1-苄基-2-(4-甲酰基苯基)-4-三氟甲基-2,5-二氢-1H-吡咯，1-苄基-2-(4-乙酰基苯基)-4-三氟甲基-2,5-二氢-1H-吡咯，1-苄基-2-(4-乙酰氧基苯基)-4-三氟甲基-2,5-二氢-1H-吡咯，1-苄基-2-(4-氰基苯基)-4-三氟甲基-2,5-二氢-1H-吡咯，1-苄基-2-(4-氟苯基)-4-三氟甲基-2,5-二氢-1H-吡咯，1-苄基-2-(4-三氟甲基苯基)-4-三氟甲基-2,5-二氢-1H-吡咯，1-苄基-2-(4-甲基苯基)-4-三氟甲基-2,5-二氢-1H-吡咯，1-苄基-2-(4-甲氧基苯基)-4-三氟甲基-2,5-二氢-1H-吡咯，1-苄基-2-(2-萘基)-4-三氟甲基-2,5-二氢-1H-吡咯，1-苄基-2-(2-噻吩基)-4-三氟甲基-2,5-二氢-1H-吡咯，1-苄基-2-(2-吡啶基)-4-三氟甲基-2,5-二氢-1H-吡咯，1-苄基-2-(1-环己烯基)-4-三氟甲基-2,5-二氢-1H-吡咯，1-苄基-2-二茂铁基-4-三氟甲基-2,5-二氢-1H-吡咯，1-苄基-2-(4-氯丁基)-4-三氟甲基-2,5-二氢-1H-吡咯，2-(1-苄基-4-三氟甲基-2,5-二氢-1H-吡咯)甲醇，乙酸-2-(1-苄基-4-三氟甲基-2,5-二氢-1H-吡咯)甲基酯，1-苄基-2-叔丁基二甲基硅氧甲基-4-三氟甲基-2,5-二氢-1H-吡咯，1-苄基-2-苄氧甲基-4-三氟甲基-2,5-二氢-1H-吡咯，1-(2-(1-苄基-4-三氟甲基-2,5-二氢-1H-吡咯))-1-环己醇，1-(4-氟苄基)-2-苯基-4-三氟甲基-2,5-二氢-1H-吡咯，1-(4-氯苄基)-2-苯基-4-三氟甲基-2,5-二氢-1H-吡咯，1-(4-溴苄基)-2-苯基-4-三氟甲基-2,5-二氢-1H-吡咯，1-(4-三氟甲基苄基)-2-苯基-4-三氟甲基-2,5-二氢-1H-吡咯，1-(4-甲基苄基)-2-苯基-4-三氟甲基-2,5-二氢-1H-吡咯，1-(4-甲氧基苄基)-2-苯基-4-三氟甲基-2,5-二氢-1H-吡咯，1-苯乙基-2-苯基-4-三氟甲基-2,5-二氢-1H-吡咯，1-异丙基-2-苯基-4-三氟甲基-2,5-二氢-1H-吡咯，1-烯丙基-2-苯基-4-三氟甲基-2,5-二氢-1H-吡咯，1-(2-呋喃基)甲基-2-苯基-4-三氟甲基-2,5-二氢-1H-吡咯，1-(2-噻吩基)甲基-2-苯基-4-三氟甲基-2,5-二氢-1H-吡咯，1-(2-吡啶基)甲基-2-苯基-4-三氟甲基-2,5-二氢-1H-吡咯，1-((R)-1-苯乙基))-2-苯基-4-三氟甲基-2,5-二氢-1H-吡咯，2-(2-苯基-4-三氟甲基-2,5-二氢-1H-吡咯)乙醇，2-(2-苯基-4-三氟甲基-2,5-二氢-1H-吡咯)乙胺，N-(2-(2-苯基-4-三氟甲基-2,5-二氢-1H-吡咯))乙基乙酰胺，2-(2-苯基-4-三氟甲基-2,5-二氢-1H-吡咯)乙氨基甲酸丁酯，1-苯基-2-苯基-4-三氟甲基-2,5-二氢-1H-吡咯。
在一具体实施方案中，本发明式(III)所示的4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物的制备过程为，将2-三氟甲基-1，3-共轭烯炔类化合物溶解在有机溶剂中，在银盐的作用下，在室温条件下与伯胺类化合物发生环化反应，反应完成后过滤，浓缩，经柱层析得到如式(III)所示的4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物。
本发明制备方法中，反应在有机溶剂中进行。具体地，在制备式(III)所示的4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物的步骤中，所述有机溶剂是氯苯(chlorobenzene)、甲苯、二氯乙烷；优选地，所述有机溶剂为氯苯。所述的有机溶剂不局限于上述有机溶剂。
本发明制备方法中，所述有机溶剂与式(I)所示的2-三氟甲基-1,3-共轭烯炔类化合物的用量比为6.0～8.0mL：1mmol。
本发明制备方法中，所述银盐是离子型银盐，如硝酸银、六氟锑酸银等，优选地，为硝酸银。
本发明制备方法中，所述式(I)所示的2-三氟甲基-1,3-共轭烯炔类化合物、式(II)所示的伯胺类化合物、银盐的摩尔比为1：2：0.1～1.5；优选地为，1：2：0.1。
本发明制备方法中，得到式(III)所示4‐三氟甲基‐2,4‐二取代‐2,5‐二氢吡咯衍生物后，还包括去除溶剂的步骤，去除溶剂的方式包括：加硅藻土过滤，旋蒸去除溶剂(旋蒸温度可以高至70℃)，从而得到粗产品。
本发明制备方法中，所述柱层析是采用体积比为石油醚:乙酸乙酯＝200:1～0:1的淋洗剂。
本发明制备方法的创新之一在于，本发明制备方法反应温度优良，反应温度为25℃～80℃，优选地为，25℃(室温)、80℃。当式(II)所示的伯胺类化合物为烷基伯胺、取代烷基伯胺、烯丙基伯胺时，所述反应优选在室温条件下进行，当式(II)所示的伯胺类化合物为芳香伯胺时，升高温度有利于芳香伯胺的反应，优选温度是80℃。
本发明制备方法中，反应时间为24～48小时；优选地，为24小时。
本发明制备方法中的各原料、包括有机溶剂、银盐等，均可市场购得并直接使用，例如，有机溶剂采用氯苯，银盐采用硝酸银。在一具体实施方案中，本发明制备方法为，先称量2-三氟甲基-1,3-共轭烯炔类化合物和银盐置于干燥的反应管中，在氮气氛围下加入溶剂、按一定比例称取式式(II)伯胺类类化合物类化合物注入反应管中。例如：式(I)2-三氟甲基-1,3-共轭烯炔类化合物：式(II)伯胺类化合物类化合物摩尔比：银盐＝1：2:0.1，先加入2-三氟甲基-1,3-共轭烯炔类化合物和银盐，抽气换气置于氮气保护下，随后向反应管中注入2mL氯苯，最后加入伯胺类化合物。然后，在室温反应条件下反应，搅拌过程中通过薄层层析硅胶板(TLC)监测反应进行程度，反应时间约为24～48小时，反应结束后先用硅藻土过滤并旋蒸去除溶剂，然后，将粗产品进行柱层析，得到式(III)4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物纯品。其中，例如，用体积比为石油醚:乙酸乙酯＝200:1～0:1的淋洗剂进行柱层析。
本发明4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物的制备方法，以2-三氟甲基-1,3-共轭烯炔类化合物，伯胺类化合物为原料，在银盐的作用下反应得到包含烷基，杂芳基，芳基及取代芳基等基团的4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物，产物结构如式(III)所示。
本发明还提出了所述4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物在制备脯氨酸衍生物、三氟芳香吡咯中的应用。
本发明的有益效果包括，原料易得，反应条件温和，操作简单，能快速且高效地合成4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物。本发明通过其它路径开拓了反应产物一系列的合成应用，如实现了脱苄，氧化成吡咯，钯催化双键加氢脱苄基或保留还原制备吡咯啉衍生物，钯催化Suzuki–Miyaura偶联或Heck-Matsuda芳基化反应制备多取代含三氟甲基3-吡咯啉或吡咯衍生物。与NXS(X＝Cl,Br,I)或NFSI反应制备得到含三氟甲基苯单卤或多卤取代的吡咯衍生物。本发明制备的4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物，可以用于合成脯氨酸衍生物，三氟芳香吡咯等一系列生物活性分子，在药学、有机合成领域具有重要的意义。
本发明提供结构多样的含三氟甲基吡咯化合物骨架，不仅对含三氟甲基取代吡咯类化合物的合成具有重要意义，而且对新药的合成筛选和药物研究都具有非常重要意义。
具体实施方式
结合以下具体实施例，对本发明作进一步的详细说明，本发明的保护内容不局限于以下实施例。在不背离发明构思的精神和范围下，本领域技术人员能够想到的变化和优点都被包括在本发明中，并且以所附的权利要求书为保护范围。实施本发明的过程、条件、试剂、实验方法等，除以下专门提及的内容之外，均为本领域的普遍知识和公知常识，本发明没有特别限制内容。
本发明提出的4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物的制备方法，在氯苯中，将如式(I)所示的2-三氟甲基-1,3-共轭烯炔类化合物，如式(II)所示的伯胺类化合物和硝酸银放入干燥的反应管中，其中，2-三氟甲基-1,3-共轭烯炔类化合物：伯胺类化合物：硝酸银＝1：2:0.1，在室温条件下反应,反应完毕过滤除去溶剂，经柱层析得到如式(III)所示的4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物；
其中，R1为烷基、芳基、杂芳基；R2为烷基、芳基。
实施例1-A
将原料(3-(三氟甲基)丁-3-烯-1-炔基)苯(0.5mmol)，硝酸银(10mol％)(以原料(3-(三氟甲基)丁-3-烯-1-炔基)苯为基准)放入干燥反应管中，抽气换气，在氮气保护下加入氯苯，再注入苄胺(1.0mmol)，在室温下充分反应，反应24小时，通过TLC和碘缸显色检测反应，至(3-(三氟甲基)丁-3-烯-1-炔基)苯完全消失。反应结束后加硅藻土过滤，并旋蒸去除溶剂，然后将粗产品直接用硅胶快速柱色谱纯化(石油醚：乙酸乙酯＝200:1)得到4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物纯品III-1(129mg，85％)。
实施例1-B
将原料(3-(三氟甲基)丁-3-烯-1-炔基)苯(0.5mmol)，硝酸银(10mol％)(以原料(3-(三氟甲基)丁-3-烯-1-炔基)苯为基准)放入干燥反应管中，抽气换气，在氮气保护下加入氯苯，再注入苄胺(0.6mmol)，在室温下充分反应，反应24小时，通过TLC和碘缸显色检测反应，至(3-(三氟甲基)丁-3-烯-1-炔基)苯完全消失。反应结束后加硅藻土过滤，并旋蒸去除溶剂，然后将粗产品直接用硅胶快速柱色谱纯化(石油醚：乙酸乙酯＝200:1)得到4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物纯品III-1(129mg，49％)。
实施例1-C
将原料(3-(三氟甲基)丁-3-烯-1-炔基)苯(0.5mmol)，硝酸银(10mol％)(以原料(3-(三氟甲基)丁-3-烯-1-炔基)苯为基准)放入干燥反应管中，抽气换气，在氮气保护下加入氯苯，再注入苄胺(1.5mmol)，在室温下充分反应，反应24小时，通过TLC和碘缸显色检测反应，至(3-(三氟甲基)丁-3-烯-1-炔基)苯完全消失。反应结束后加硅藻土过滤，并旋蒸去除溶剂，然后将粗产品直接用硅胶快速柱色谱纯化(石油醚：乙酸乙酯＝200:1)得到4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物纯品III-1(129mg，89％)。
实施例1-D
将原料(3-(三氟甲基)丁-3-烯-1-炔基)苯(0.5mmol)，六氟锑酸银(10mol％)(以原料(3-(三氟甲基)丁-3-烯-1-炔基)苯为基准)放入干燥反应管中，抽气换气，在氮气保护下加入氯苯，再注入苄胺(1.0mmol)，在室温下充分反应，反应24小时，通过TLC和碘缸显色检测反应，至(3-(三氟甲基)丁-3-烯-1-炔基)苯完全消失。反应结束后加硅藻土过滤，并旋蒸去除溶剂，然后将粗产品直接用硅胶快速柱色谱纯化(石油醚：乙酸乙酯＝200:1)得到4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物纯品III-1(129mg，85％)。
实施例1-E
将原料(3-(三氟甲基)丁-3-烯-1-炔基)苯(0.5mmol)，三氟甲磺酸银(10mol％)(以原料(3-(三氟甲基)丁-3-烯-1-炔基)苯为基准)放入干燥反应管中，抽气换气，在氮气保护下加入氯苯，再注入苄胺(1.0mmol)，在室温下充分反应，反应24小时，通过TLC和碘缸显色检测反应，至(3-(三氟甲基)丁-3-烯-1-炔基)苯完全消失。反应结束后加硅藻土过滤，并旋蒸去除溶剂，然后将粗产品直接用硅胶快速柱色谱纯化(石油醚：乙酸乙酯＝200:1)得到4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物纯品III-1(129mg，73％)。
实施例1-F
将原料(3-(三氟甲基)丁-3-烯-1-炔基)苯(0.5mmol)，硝酸银(10mol％)(以原料(3-(三氟甲基)丁-3-烯-1-炔基)苯为基准)放入干燥反应管中，抽气换气，在氮气保护下加入甲苯，再注入苄胺(1.0mmol)，在室温下充分反应，反应24小时，通过TLC和碘缸显色检测反应，至(3-(三氟甲基)丁-3-烯-1-炔基)苯完全消失。反应结束后加硅藻土过滤，并旋蒸去除溶剂，然后将粗产品直接用硅胶快速柱色谱纯化(石油醚：乙酸乙酯＝200:1)得到4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物纯品III-1(129mg，80％)。
实施例1-G
将原料(3-(三氟甲基)丁-3-烯-1-炔基)苯(0.5mmol)，硝酸银(10mol％)(以原料(3-(三氟甲基)丁-3-烯-1-炔基)苯为基准)放入干燥反应管中，抽气换气，在氮气保护下加入二氯乙烷，再注入苄胺(1.0mmol)，在室温下充分反应，反应24小时，通过TLC和碘缸显色检测反应，至(3-(三氟甲基)丁-3-烯-1-炔基)苯完全消失。反应结束后加硅藻土过滤，并旋蒸去除溶剂，然后将粗产品直接用硅胶快速柱色谱纯化(石油醚：乙酸乙酯＝200:1)得到4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物纯品III-1(129mg，75％)。
实施例1-H
将原料(3-(三氟甲基)丁-3-烯-1-炔基)苯(0.5mmol)，硝酸银(10mol％)(以原料(3-(三氟甲基)丁-3-烯-1-炔基)苯为基准)放入干燥反应管中，抽气换气，在氮气保护下加入氯苯，再注入苄胺(1.0mmol)，在60℃下充分反应，反应24小时，通过TLC和碘缸显色检测反应，至(3-(三氟甲基)丁-3-烯-1-炔基)苯完全消失。反应结束后加硅藻土过滤，并旋蒸去除溶剂，然后将粗产品直接用硅胶快速柱色谱纯化(石油醚：乙酸乙酯＝200:1)得到4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物纯品III-1(129mg，71％)。
实施例1-I
将原料(3-(三氟甲基)丁-3-烯-1-炔基)苯(0.5mmol)，硝酸银(150mol％)(以原料(3-(三氟甲基)丁-3-烯-1-炔基)苯为基准)放入干燥反应管中，抽气换气，在氮气保护下加入氯苯，再注入苄胺(1.0mmol)，在室温下充分反应，反应24小时，通过TLC和碘缸显色检测反应，至(3-(三氟甲基)丁-3-烯-1-炔基)苯完全消失。反应结束后加硅藻土过滤，并旋蒸去除溶剂，然后将粗产品直接用硅胶快速柱色谱纯化(石油醚：乙酸乙酯＝200:1)得到4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物纯品III-1(129mg，73％)。
实施例1-J
将原料(3-(三氟甲基)丁-3-烯-1-炔基)苯(0.5mmol)，硝酸银(10mol％)(以原料(3-(三氟甲基)丁-3-烯-1-炔基)苯为基准)放入干燥反应管中，抽气换气，在氧气保护下加入氯苯，再注入苄胺(1.0mmol)，在室温下充分反应，反应24小时，通过TLC和碘缸显色检测反应，至(3-(三氟甲基)丁-3-烯-1-炔基)苯完全消失。反应结束后加硅藻土过滤，并旋蒸去除溶剂，然后将粗产品直接用硅胶快速柱色谱纯化(石油醚：乙酸乙酯＝200:1)得到4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物纯品III-1(129mg，71％)。
白色固体.Mp 53.4-54.6℃.1H NMR(400MHz,CDCl3)δ7.42(d,J＝7.2Hz,2H),7.35(t,J＝7.4Hz,2H),7.31–7.24(m,5H),7.23–7.18(m,1H),6.19(s,1H),4.71(dd,J＝5.2,2.7Hz,1H),3.93(d,J＝13.2Hz,1H),3.85(dd,J＝13.3,5.2Hz,1H),3.53(d,J＝13.2Hz,1H),3.46(dd,J＝13.3,6.3Hz,1H).19F NMR(282MHz,CDCl3)δ-65.30.13C NMR(100MHz,CDCl3)δ140.67,138.73,136.03(q,J＝5.0Hz),130.48(q,J＝34.6Hz),128.55,128.47,128.36,127.91,127.86,127.13,121.85(q,J＝269.0Hz),73.99,57.00,56.06.HRMS(ESI)calcd for C18H17F3N[M+H+]:304.1308,found:304.1317.
实施例2
将4-硝基-(3-(三氟甲基)丁-3-烯-1-炔基)苯(0.5mmol)，苄胺(1.0mmol)作为原料，其他操作参考实施例1,反应搅拌24h,硅胶柱色谱纯化(石油醚：乙酸乙酯＝50:1)，得到4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物纯品III-2(141mg，81％)。
淡黄色固体.Mp 63.7-66.8℃.1H NMR(400MHz,CDCl3)δ8.23(d,J＝8.8Hz,2H),7.61(d,J＝8.7Hz,2H),7.36–7.19(m,5H),6.17(s,1H),4.92-4.84(m,1H),3.96(dd,J＝14.3,6.2Hz,1H),3.91(d,J＝13.3Hz,1H),3.66(d,J＝13.3Hz,1H),3.62–3.52(m,1H).19FNMR(282MHz,CDCl3)δ-65.44.13C NMR(100MHz,CDCl3)δ148.32,147.59,137.91,134.41(q,J＝4.9Hz),131.62(q,J＝35.0Hz),128.56,128.46,128.44,127.44,123.81,121.47(q,J＝269.2Hz),73.44,57.44,56.42.HRMS(ESI)calcd for C18H16F3N2O2[M+H+]:349.1165,found:349.1158.
实施例3
将3-硝基-(3-(三氟甲基)丁-3-烯-1-炔基)苯(0.5mmol)，苄胺(1.0mmol)作为原料，其他操作参考实施例1,反应搅拌24h,硅胶柱色谱纯化(石油醚：乙酸乙酯＝50:1)，得到4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物纯品III-3(164mg，94％)
黄色油状物.1H NMR(400MHz,CDCl3)δ8.30(t,J＝1.9Hz,1H),8.18-8.12(m,1H),7.80–7.74(m,1H),7.54(t,J＝7.9Hz,1H),7.34–7.18(m,5H),6.20-6.16(m,1H),4.90-4.84(m,1H),3.97(dd,J＝13.6,6.7Hz,1H),3.92(d,J＝13.2Hz,1H),3.67(d,J＝13.2Hz,1H),3.62-3.52(m,1H).19F NMR(282MHz,CDCl3)δ-65.41.13C NMR(100MHz,CDCl3)δ148.40,143.31,137.87,134.54(q,J＝4.9Hz),133.85,131.58(q,J＝35.0Hz),129.49,128.47,128.44,127.38,122.90,122.73,121.48(q,J＝269.2Hz),73.35,57.36,56.35.HRMS(ESI)calcd for C18H16F3N2O2[M+H+]:349.1169,found:349.1158.
实施例4
将2-硝基-(3-(三氟甲基)丁-3-烯-1-炔基)苯(0.5mmol)，苄胺(1.0mmol)作为原料，其他操作参考实施例1,反应搅拌24h,硅胶柱色谱纯化(石油醚：乙酸乙酯＝50:1)，得到4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物纯品III-4(113mg，65％)。
黄色油状物.1H NMR(400MHz,CDCl3)δ8.20(dd,J＝7.9,1.3Hz,1H),7.93(dd,J＝8.1,1.2Hz,1H),7.69(td,J＝7.9,1.1Hz,1H),7.47–7.39(m,1H),7.35–7.17(m,5H),6.41–6.37(m,1H),5.34-5.28(m,1H),3.97(dd,J＝13.6,5.5Hz,1H),3.86(d,J＝13.1Hz,1H),3.63(d,J＝13.1Hz,1H),3.59–3.50(m,1H).19F NMR(282MHz,CDCl3)δ-65.42.13C NMR(100MHz,CDCl3)δ148.87,138.04,136.54,135.11(q,J＝5.0Hz),133.66,130.79(q,J＝69.8,34.9Hz),130.24,128.47,128.43(2C),127.36,124.27,121.58(q,J＝269.2Hz),70.03,58.05,56.31.HRMS(ESI)calcd for C18H16F3N2O2[M+H+]:349.1169,found:349.1158.
实施例5
将4-氯-(3-(三氟甲基)丁-3-烯-1-炔基)苯(0.5mmol)，苄胺(1.0mmol)作为原料，其他操作参考实施例1,反应搅拌24h,硅胶柱色谱纯化(石油醚：乙酸乙酯＝200:1)，得到4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物纯品III-5(159mg，94％)
白色固体.Mp 39.9-41.6℃.1H NMR(400MHz,CDCl3)δ7.40–7.31(m,4H),7.31–7.21(m,5H),6.16(s,1H),4.73-4.67(m,1H),3.91(d,J＝13.2Hz,1H),3.87(dd,J＝13.5,5.4Hz,1H),3.55(d,J＝13.2Hz,1H),3.51-3.43(m,1H).19F NMR(282MHz,CDCl3)δ-65.38.13C NMR(100MHz,CDCl3)δ139.28,138.42,135.47(q,J＝5.0Hz),133.58,130.85(q,J＝34.8Hz),129.19,128.70,128.43,128.40,127.24,121.69(q,J＝269.1Hz),73.31,56.97,56.04.HRMS(ESI)calcd for C18H16ClF3N[M+H+]:338.0918,found:338.0922.
实施例6
将4-溴-(3-(三氟甲基)丁-3-烯-1-炔基)苯(0.5mmol)，苄胺(1.0mmol)
作为原料，其他操作参考实施例1,反应搅拌24h,硅胶柱色谱纯化(石油醚：乙酸乙酯＝200:1)，得到4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物纯品III-6(157mg，82％)。
白色固体.Mp 66.5-68.2℃.1H NMR(400MHz,CDCl3)δ7.50(d,J＝8.3Hz,2H),7.30(d,J＝8.3Hz,2H),7.22-7.34(m,5H),6.16(s,1H),4.69(s,1H),3.91(d,J＝13.2Hz,1H),3.86(dd,J＝13.5,5.3Hz,1H),3.55(d,J＝13.2Hz,1H),3.48(dd,J＝13.4,6.4Hz,1H).19FNMR(282MHz,CDCl3)δ-65.38.13C NMR(100MHz,CDCl3)δ139.81,138.39,135.38(q,J＝5.0Hz),131.65,130.88(q,J＝34.8Hz),129.55,128.42,128.40,127.24,121.73,121.67(q,J＝269.1Hz),73.37,56.98,56.05.HRMS(ESI)calcd for C18H16BrF3N[M+H+]:382.0413,found:382.0418.
实施例7
将4-甲酰基-(3-(三氟甲基)丁-3-烯-1-炔基)苯(0.5mmol)，苄胺(1.0mmol)作为原料，其他操作参考实施例1,反应搅拌24h,硅胶柱色谱纯化(石油醚：乙酸乙酯＝20:1)，得到4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物纯品III-7(116mg，70％)。
白色固体.Mp 50.2-51.5℃.1H NMR(400MHz,CDCl3)δ10.03(s,1H),7.90(d,J＝8.2Hz,2H),7.62(d,J＝8.2Hz,2H),7.34–7.20(m,5H),6.21–6.17(m,1H),4.87-4.80(m,1H),3.93(d,J＝13.2Hz,1H),3.93(dd,J＝13.3,4.5Hz,1H),3.62(d,J＝13.2Hz,1H),3.58-3.50(m,1H).19F NMR(282MHz,CDCl3)δ-65.40.13C NMR(100MHz,CDCl3)δ191.94,147.77,138.19,136.06,134.89(q,J＝4.9Hz),131.25(q,J＝34.9Hz),130.07,128.43,127.33,121.58(q,J＝269.3Hz),73.87,57.37,56.36.HRMS(ESI)calcd for C19H17F3NO[M+H+]:332.1257,found:332.1264.
实施例8
将4-乙酰基-(3-(三氟甲基)丁-3-烯-1-炔基)苯(0.5mmol)，苄胺(1.0mmol)作为原料，其他操作参考实施例1,反应搅拌24h,硅胶柱色谱纯化(石油醚：乙酸乙酯＝50:1)，得到4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物纯品III-8(130mg，75％)。
白色固体.Colorless solid.Mp 80.3-82.2℃.1H NMR(300MHz,CDCl3)δ7.97(d,J＝8.3Hz,2H),7.54(d,J＝8.3Hz,2H),7.34–7.19(m,5H),6.21–6.16(m,1H),4.85–4.76(m,1H),3.92(d,J＝13.2Hz,1H),3.91(dd,J＝13.3,7.3Hz,1H),3.60(d,J＝13.2Hz,1H),3.57–3.47(m,1H),2.61(s,3H).19F NMR(282MHz,CDCl3)δ-65.39.13C NMR(126MHz,CDCl3)δ197.72,146.14,138.31,136.82,135.10(q,J＝4.9Hz),131.14(q,J＝34.8Hz),128.67,128.43,128.41,127.98,127.28,121.65(q,J＝269.2Hz),73.73,57.23,56.25,26.64.HRMS(ESI)calcd for C20H19F3NO[M+H+]:346.1413,found:346.1419.
实施例9
将4-乙酰氧基-(3-(三氟甲基)丁-3-烯-1-炔基)苯(0.5mmol)，苄胺(1.0mmol)作为原料，其他操作参考实施例1,反应搅拌24h,硅胶柱色谱纯化(石油醚：乙酸乙酯＝20:1)，得到4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物纯品III-9(100mg，55％)。
白色固体.Mp 65.0-66.6℃.1H NMR(300MHz,CDCl3)δ8.05(d,J＝8.2Hz,2H),7.51(d,J＝8.2Hz,2H),7.34–7.16(m,5H),6.19(s,1H),4.85–4.75(m,1H),3.92(d,J＝13.2Hz,1H),3.92(s,3H),3.90(dd,J＝13.3,7.3Hz,1H),3.59(d,J＝13.2Hz,1H),3.56–3.45(m,1H).19F NMR(282MHz,CDCl3)δ-65.40.13C NMR(126MHz,CDCl3)δ166.86,145.96,138.34,135.19(q,J＝5.0Hz),131.09(q,J＝34.8Hz),129.90,129.79,128.46,128.40,127.80,127.27,121.67(q,J＝269.2Hz),73.77,57.22,56.24,52.10.HRMS(ESI)calcd forC20H19F3NO2[M+H+]:362.1362,found:362.1373.
实施例10
将4-氰基-(3-(三氟甲基)丁-3-烯-1-炔基)苯(0.5mmol)，苄胺(1.0mmol)作为原料，其他操作参考实施例1,反应搅拌24h,硅胶柱色谱纯化(石油醚：乙酸乙酯＝20:1)，得到4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物纯品III-10(87mg，55％)。
白色固体.Mp 51.0-52.0℃.1H NMR(300MHz,CDCl3)δ7.64(d,J＝8.4Hz,2H),7.53(d,J＝8.4Hz,2H),7.33–7.18(m,5H),6.16–6.11(m,1H),4.84-4.74(m,1H),3.92(dd,J＝13.1,6.0Hz,1H),3.88(d,J＝13.1Hz,1H),3.62(d,J＝13.1Hz,1H),3.58–3.48(m,1H).19FNMR(282MHz,CDCl3)δ-65.38.13C NMR(126MHz,CDCl3)δ146.31,137.96,134.56(q,J＝4.9Hz),132.33,131.42(q,J＝34.9Hz),128.43,128.39(2C),127.34,121.49(q,J＝269.3Hz),118.67,111.64,73.64,57.34,56.33.HRMS(ESI)calcd for C19H16F3N2[M+H+]:329.1260,found:329.1262.
实施例11
将4-氟-(3-(三氟甲基)丁-3-烯-1-炔基)苯(0.5mmol)，苄胺(1.0mmol)作为原料，其他操作参考实施例1,反应搅拌24h,硅胶柱色谱纯化(石油醚：乙酸乙酯＝200:1)，得到4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物纯品III-11(147mg，91％)。
白色固体.Mp 45.3-46.0℃.1H NMR(300MHz,CDCl3)δ7.44–7.34(m,2H),7.33–7.18(m,5H),7.09–7.00(m,2H),6.19–6.13(m,1H),4.75-4.65(m,1H),3.92(d,J＝13.2Hz,1H),3.88(dd,J＝13.1,6.0Hz,1H),3.54(d,J＝13.2Hz,1H),3.51–3.42(m,1H).19F NMR(282MHz,CDCl3)δ-65.38,-114.61.13C NMR(100MHz,CDCl3)δ162.44(d,J＝245.9Hz),138.53,136.46(d,J＝2.6Hz),135.75(q,J＝4.8Hz),130.67(q,J＝34.8Hz),129.42(d,J＝8.1Hz),128.43,128.38,127.20,121.76(q,J＝269.0Hz),115.37(d,J＝21.5Hz),73.25,56.91,56.01.HRMS(ESI)calcd for C18H16F4N[M+H+]:322.1413,found:322.1224.
实施例12
将4-三氟甲基-(3-(三氟甲基)丁-3-烯-1-炔基)苯(0.5mmol)，苄胺(1.0mmol)作为原料，其他操作参考实施例1,反应搅拌24h,硅胶柱色谱纯化(石油醚：乙酸乙酯＝200:1)，得到4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物纯品III-12(127mg，67％)。
白色固体.Mp 61.7-62.5℃.1H NMR(300MHz,CDCl3)δ7.63(d,J＝8.3Hz,2H),7.56(d,J＝8.3Hz,2H),7.34–7.20(m,5H),6.20–6.14(m,1H),4.85-4.75(m,1H),3.91(dd,J＝13.3,6.1Hz,1H),3.92(d,J＝13.2Hz,1H),3.60(d,J＝13.2Hz,1H),3.57–3.47(m,1H).19FNMR(282MHz,CDCl3)δ-62.44,-65.45.13C NMR(126MHz,CDCl3)δ144.92,138.25,135.09(q,J＝4.9Hz),131.24(q,J＝34.8Hz),130.18(q,J＝32.4Hz),128.46,128.44,128.14,127.33,125.54(q,J＝3.8Hz),124.12(d,J＝272.1Hz),121.65(q,J＝269.2Hz),73.65,57.25,56.27.HRMS(ESI)calcd forC19H16F6N[M+H+]:372.1181,found:372.1193.
实施例13
将4-甲基-(3-(三氟甲基)丁-3-烯-1-炔基)苯(0.5mmol)，苄胺(1.0mmol)作为原料，其他操作参考实施例1,反应搅拌24h,硅胶柱色谱纯化(石油醚：乙酸乙酯＝200:1)，得到4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物纯品III-13(124mg，78％)。
白色固体.Mp 56.2-58.2℃.1H NMR(400MHz,CDCl3)δ7.31(d,J＝7.8Hz,2H),7.28–7.19(m,5H),7.17(d,J＝7.8Hz,2H),6.17(s,1H),4.66(s,1H),3.93(d,J＝13.2Hz,1H),3.87–3.79(m,1H),3.50(d,J＝13.2Hz,1H),3.47–3.40(m,1H),2.34(s,3H).19F NMR(282MHz,CDCl3)δ-65.27.13C NMR(100MHz,CDCl3)δ138.82,137.65,137.62,136.22(q,J＝4.9Hz),130.36(q,J＝34.6Hz),129.25,128.48,128.34,127.82,127.10,121.89(q,J＝268.9Hz),73.70,56.90,55.97,21.11.HRMS(ESI)calcd for C19H19F3N[M+H+]:318.1464,found:318.1475.
实施例14
将4-甲氧基-(3-(三氟甲基)丁-3-烯-1-炔基)苯(0.5mmol)，苄胺(1.0mmol)作为原料，其他操作参考实施例1,反应搅拌24h,硅胶柱色谱纯化(石油醚：乙酸乙酯＝50:1)，得到4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物纯品III-14(119mg，71％)。
无色油状物.Colorless oil.1H NMR(400MHz,CDCl3)δ7.34(d,J＝8.6Hz,2H),7.31–7.20(m,5H),6.90(d,J＝8.6Hz,2H),6.20-6.16(m,1H),4.63-4.69(m,1H),3.93(d,J＝13.2Hz,1H),3.81(s,3H),3.82(dd,J＝13.3,6.1Hz,1H),3.51(d,J＝13.2Hz,1H),3.48–3.40(m,1H).19F NMR(282MHz,CDCl3)δ-65.35.13C NMR(100MHz,CDCl3)δ159.33,138.81,136.23(q,J＝5.0Hz),132.70,130.32(q,J＝34.7Hz),129.01,128.46,128.33,127.09,121.87(q,J＝268.9Hz),113.89,73.33,56.78,55.89,55.28.HRMS(ESI)calcd forC19H19F3NO[M+H+]:334.1413,found:334.1418.
实施例15
将2-(3-(三氟甲基)丁-3-烯-1-炔基)萘(0.5mmol)，苄胺(1.0mmol)作为原料，其他操作参考实施例1,反应搅拌24h,硅胶柱色谱纯化(石油醚：乙酸乙酯＝200:1)，得到4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物纯品III-15(92mg，52％)。
无色油状物.1H NMR(300MHz,CDCl3)δ8.19(d,J＝7.7Hz,1H),7.99(d,J＝7.1Hz,1H),7.96–7.92(m,1H),7.86(d,J＝8.2Hz,1H),7.63–7.50(m,3H),7.42–7.26(m,5H),6.46(s,1H),5.51(s,1H),4.08(d,J＝13.3Hz,1H),4.04(dd,J＝12.3,6.0Hz,1H),3.64(d,J＝13.2Hz,1H),3.64–3.54(m,1H).19F NMR(282MHz,CDCl3)δ-65.38.13C NMR(126MHz,CDCl3)δ138.74,135.85(d,J＝5.0Hz),135.36,134.03,131.46,130.45(q,J＝34.8Hz),129.02,128.48,128.44,128.34,127.18,126.14,125.73,125.60,125.48,122.81,121.86(q,J＝269.1Hz),71.18,57.71,56.04.HRMS(ESI)calcd for C22H19F3N[M+H+]:354.1464,found:354.1474.
实施例16
将2-(3-(三氟甲基)丁-3-烯-1-炔基)噻吩(0.5mmol)，苄胺(1.0mmol)作为原料，其他操作参考实施例1,反应搅拌24h,硅胶柱色谱纯化(石油醚：乙酸乙酯＝100:1)，得到4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物纯品III-16(141mg，91％)。
白色固体.Mp 60.6-62.7℃.1H NMR(300MHz,CDCl3)δ7.40–7.26(m,6H),7.06–6.97(m,2H),6.26(s,1H),5.09(s,1H),4.09(d,J＝13.1Hz,1H),3.83(dd,J＝13.5,4.8Hz,1H),3.59(d,J＝13.1Hz,1H),3.51–3.40(m,1H).19F NMR(282MHz,CDCl3)δ-65.44.13C NMR(126MHz,CDCl3)δ145.96,138.47,135.52(q,J＝5.0Hz),130.65(q,J＝34.9Hz),128.51,128.41,127.25,126.80,125.53,124.67,121.72(q,J＝269.1Hz),69.14,56.89,55.56.HRMS(ESI)calcd for C16H15F3NS[M+H+]:310.0872,found:310.0880.
实施例17
将2-(3-(三氟甲基)丁-3-烯-1-炔基)吡啶(0.5mmol)，苄胺(1.0mmol)作为原料，其他操作参考实施例1,反应搅拌24h,硅胶柱色谱纯化(石油醚：乙酸乙酯＝10:1)，得到4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物纯品III-17(81mg，53％)。
白色固体.Mp 56.2-58.4℃.1H NMR(500MHz,CDCl3)δ8.57-8.54(m,1H),7.76-7.71(m,1H),7.68(d,J＝7.8Hz,1H),7.34–7.29(m,4H),7.26–7.23(m,1H),7.22-7.18(m,1H),6.36-6.32(m,1H),5.00-4.94(m,1H),4.03(d,J＝13.4Hz,1H),3.95(dd,J＝13.5,5.6Hz,1H),3.70(d,J＝13.4Hz,1H),3.59–3.52(m,1H).19F NMR(282MHz,CDCl3)δ-65.37.13C NMR(126MHz,CDCl3)δ160.75,149.09,138.51,137.00,134.92(q,J＝5.0Hz),130.93(q,J＝34.7Hz),128.45,128.43,127.23,122.58,121.71(q,J＝269.2Hz),121.67,76.06,57.88,56.63.HRMS(ESI)calcd for C17H16F3N[M+H+]:305.1260,found:305.1267.
实施例18
将1-(3-(三氟甲基)丁-3-烯-1-炔基)环己烯(0.5mmol)，苄胺(1.0mmol)作为原料，其他操作参考实施例1,反应搅拌24h,硅胶柱色谱纯化(石油醚：乙酸乙酯＝200:1)，得到4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物纯品III-18(123mg，80％)。
白色固体.Mp 51.2-52.4℃.1H NMR(400MHz,CDCl3)δ7.35–7.21(m,5H),6.16–6.11(m,1H),5.71(s,1H),4.04(s,1H),3.98(d,J＝13.4Hz,1H),3.74(dd,J＝13.2,5.3Hz,1H),3.44(d,J＝13.4Hz,1H),3.35–3.28(m,1H),2.27–2.17(m,1H),2.07-2.00(m,2H),1.86-1.76(m,1H),1.70–1.52(m,4H).19F NMR(282MHz,CDCl3)δ-65.35.13C NMR(100MHz,CDCl3)δ139.45,136.49,135.46(q,J＝5.0Hz),130.80(q,J＝34.4Hz),128.37,128.32,126.94,125.61,121.84(q,J＝268.9Hz),76.86,56.97,56.20,25.20,24.71,22.70,22.66.HRMS(ESI)calcd for C18H21F3N[M+H+]:308.1621,found:308.1630.
实施例19
将(3-(三氟甲基)丁-3-烯-1-炔基)二茂铁(0.5mmol)，苄胺(1.0mmol)作为原料，其他操作参考实施例1,反应搅拌24h,硅胶柱色谱纯化(石油醚：乙酸乙酯＝10:1)，得到4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物纯品III-19(171mg，83％)。
红色油状物.1H NMR(300MHz,CDCl3)δ7.36–7.22(m,5H),6.54(s,1H),4.72–4.62(m,1H),4.23–4.09(m,9H),3.98(d,J＝13.3Hz,1H),3.73(dd,J＝13.5,4.3Hz,1H),3.58(d,J＝13.3Hz,1H),3.54–3.45(m,1H).19F NMR(282MHz,CDCl3)δ-65.14.13C NMR(126MHz,CDCl3)δ138.90,135.46(q,J＝5.0Hz),130.66(q,J＝34.5Hz),128.49,128.34,127.06,121.90(q,J＝269.1Hz),86.80,68.64,68.47,68.44,67.88,66.55,57.26,56.47.HRMS(ESI)calcd for C22H21F3FeN[M+H+]:412.0970,found:412.0986.
实施例20
将8-氯-2-(三氟甲基)丁-1-烯-3-辛炔(0.5mmol)，苄胺(1.0mmol)作为原料，其他操作参考实施例1,反应搅拌24h,硅胶柱色谱纯化(石油醚：乙酸乙酯＝200:1)，得到4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物纯品III-20(68mg，43％)。
无色油状物.1H NMR(500MHz,CDCl3)δ7.37-7.32(m,4H),7.31–7.26(m,1H),6.25(s,1H),4.03(d,J＝13.3Hz,1H),3.85–3.75(m,2H),3.59(d,J＝13.3Hz,1H),3.55(t,J＝6.6Hz,2H),3.38(d,J＝10.1Hz,1H),1.86–1.76(m,2H),1.68–1.42(m,4H).19F NMR(282MHz,CDCl3)δ-65.36.13C NMR(126MHz,CDCl3)δ139.12,134.90(q,J＝4.9Hz),130.46(q,J＝34.4Hz),128.45,128.42,127.17,121.82(q,J＝268.9Hz),70.37,58.77,57.31,44.80,33.16,32.69,22.77.HRMS(ESI)calcd for C16H20ClF3N[M+H+]:318.1231,found:318.1236.
实施例21
将4-三氟甲基-4-烯-2-炔-1-戊醇(0.5mmol)，苄胺(1.0mmol)作为原料，其他操作参考实施例1,反应搅拌24h,硅胶柱色谱纯化(石油醚：乙酸乙酯＝10:1)，得到4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物纯品III-21(80mg，62％)。
无色油状物.Colorless oil.1H NMR(300MHz,CDCl3)δ7.40–7.27(m,5H),6.27–6.20(m,1H),4.04(d,J＝13.1Hz,1H),3.98-3.90(m,1H),3.85(dd,J＝13.6,5.3Hz,1H),3.67(d,J＝13.1Hz,1H),3.68–3.57(m,2H),3.54-3.44(m,1H),2.64(brs,1H).19F NMR(471MHz,CDCl3)δ-62.73.13C NMR(126MHz,CDCl3)δ138.18,133.47(q,J＝4.9Hz),131.60(q,J＝34.8Hz),128.62,128.47,127.53,121.42(q,J＝269.1Hz),71.67,61.17,58.16,57.33.HRMS(ESI)calcd for C13H15F3O[M+H+]:258.1100,found:258.1104.
实施例22
将乙酸-4-三氟甲基-4-烯-2-炔-1-戊酯(0.5mmol)，苄胺(1.0mmol)作为原料，其他操作参考实施例1,反应搅拌24h,硅胶柱色谱纯化(石油醚：乙酸乙酯＝20:1)，得到4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物纯品III-22(122mg，81％)。
无色油状物.Colorless oil.1H NMR(300MHz,CDCl3)δ7.37–7.24(m,5H),6.29–6.24(m,1H),4.26-4.16(m,1H),4.10(d,J＝13.3Hz,1H),4.08–3.95(m,2H),3.83(dd,J＝15.2,4.1Hz,1H),3.69(d,J＝13.3Hz,1H),3.52–3.40(m,1H),2.07(s,3H).19F NMR(471MHz,CDCl3)δ-65.43.13C NMR(126MHz,CDCl3)δ170.74,138.57,132.23(q,J＝4.9Hz),132.02(q,J＝34.9Hz),128.47,128.44,127.32,121.54(q,J＝269.1Hz),69.22,65.62,59.00,57.39,20.77.HRMS(ESI)calcd for C15H17F3O2N[M+H+]:300.1206,found:300.1216.
实施例23
将叔丁基二甲基硅-(4-三氟甲基-4-烯-2-炔-1-戊基)醚(0.5mmol)，苄胺(1.0mmol)作为原料，其他操作参考实施例1,反应搅拌24h,硅胶柱色谱纯化(石油醚：乙酸乙酯＝100:1)，得到4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物纯品III-23(171mg，92％)。
无色油状物.Colorless oil.1H NMR(500MHz,CDCl3)δ7.36–7.29(m,4H),7.28–7.23(m,1H),6.33(s,1H),4.08(d,J＝13.3Hz,1H),3.89–3.78(m,2H),3.69(d,J＝13.3Hz,1H),3.66–3.61(m,1H),3.57–3.51(m,1H),3.44(d,J＝12.7Hz,1H),0.88(d,J＝1.7Hz,9H),0.04(dd,J＝5.0,1.3Hz,6H).19F NMR(282MHz,CDCl3)δ-65.41.13C NMR(126MHz,CDCl3)δ139.12,133.77(q,J＝4.9Hz),130.88(q,J＝34.4Hz),128.49,128.42,127.19,121.82(q,J＝269.1Hz),72.40,66.01,59.42,57.81,25.84,18.22,-5.43,-5.47.HRMS(ESI)calcd forC19H29F3NOSi[M+H+]:372.1965,found:372.1980.
实施例24
将苄基-(4-三氟甲基-4-烯-2-炔-1-戊基)醚(0.5mmol)，苄胺(1.0mmol)作为原料，其他操作参考实施例1,反应搅拌24h,硅胶柱色谱纯化(石油醚：乙酸乙酯＝100:1)，得到4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物纯品III-24(122mg，70％)。
无色油状物.1H NMR(500MHz,CDCl3)δ7.40–7.27(m,10H),6.36(s,1H),4.58(d,J＝12.2Hz,1H),4.55(d,J＝12.2Hz,1H),4.14(d,J＝13.3Hz,1H),4.01(s,1H),3.84(dd,J＝13.6,4.4Hz,1H),3.70(d,J＝13.3Hz,1H),3.61-3.55(m,1H),3.53–3.48(m,1H),3.46(d,J＝13.7Hz,1H).19F NMR(282MHz,CDCl3)δ-65.41.13C NMR(126MHz,CDCl3)δ138.97,138.05,133.53(q,J＝4.8Hz),131.06(q,J＝34.5Hz),128.48,128.41,127.69,127.61,127.19,121.73(q,J＝269.1Hz),73.47,72.93,70.29,59.29,57.50.HRMS(ESI)calcd forC20H21F3NO[M+H+]:348.1570,found:348.1580.
实施例25
将1-(3-(三氟甲基)丁-3-烯-1-炔基)环己醇(0.5mmol)，苄胺(1.0mmol)作为原料，其他操作参考实施例1,反应搅拌24h,硅胶柱色谱纯化(石油醚：乙酸乙酯＝10:1)，得到4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物纯品III-25(130mg，80％)。
白色固体.Mp 49.9-51.7℃.1H NMR(300MHz,CDCl3)δ7.39–7.23(m,5H),6.31(s,1H),4.12(d,J＝13.8Hz,1H),3.96–3.76(m,2H),3.72(d,J＝13.8Hz,1H),3.40(d,J＝14.8Hz,1H),2.48(s,1H),1.76–1.50(m,7H),1.49–1.30(m,2H),1.29–1.11(m,1H).19F NMR(282MHz,CDCl3)δ-64.83.13C NMR(126MHz,CDCl3)δ138.99,131.81(q,J＝4.6Hz),131.20(q,J＝34.0Hz),128.56,127.97,127.29,121.61(q,J＝269.3Hz),80.71,73.52,63.00,59.08,35.19,33.63,25.79,21.69,21.59.HRMS(ESI)calcd for C18H23F3NO[M+H+]:326.1726,found:326.1738.
实施例26
将(3-(三氟甲基)丁-3-烯-1-炔基)苯(0.5mmol)，4-氟苄胺(1.0mmol)作为原料，其他操作参考实施例1,反应搅拌24h,硅胶柱色谱纯化(石油醚：乙酸乙酯＝200:1)，得到4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物纯品III-26(105mg，65％)。
无色油状物.Colorless oil.1H NMR(400MHz,CDCl3)δ7.43–7.34(m,4H),7.33–7.27(m,1H),7.25–7.19(m,2H),7.00–6.93(m,2H),6.23–6.18(m,1H),4.74-4.66(m,1H),3.89(d,J＝13.2Hz,1H),3.84(dd,J＝13.3,5.3Hz,1H),3.53(d,J＝13.2Hz,1H),3.49–3.41(m,1H).19F NMR(282MHz,CDCl3)δ-65.36,-115.65.13C NMR(100MHz,CDCl3)δ161.98(d,J＝245.0Hz),140.56,136.01(q,J＝5.0Hz),134.44(d,J＝3.1Hz),130.43(q,J＝34.7Hz),129.93(d,J＝8.0Hz),128.58,127.97,127.85,121.80(q,J＝269.0Hz),115.14(d,J＝21.3Hz),73.99,56.30,56.06.HRMS(ESI)calcd for C18H16F4N[M+H+]:322.1213,found:322.1220.
实施例27
将(3-(三氟甲基)丁-3-烯-1-炔基)苯(0.5mmol)，4-氯苄胺(1.0mmol)作为原料，其他操作参考实施例1,反应搅拌24h,硅胶柱色谱纯化(石油醚：乙酸乙酯＝200:1)，得到4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物纯品III-27(113mg，67％)。
白色固体.Mp 49.1-50.8℃.1H NMR(400MHz,CDCl3)δ7.42–7.33(m,4H),7.25(d,J＝8.4Hz,2H),7.33–7.23(m,1H),7.19(d,J＝8.4Hz,2H),6.23–6.18(m,1H),4.74-4.67(m,1H),3.89(d,J＝13.4Hz,1H),3.85(dd,J＝13.3,5.3Hz,1H),3.52(d,J＝13.4Hz,1H),3.48–3.40(m,1H).19F NMR(282MHz,CDCl3)δ-65.35.13C NMR(100MHz,CDCl3)δ140.45,137.26,135.98(q,J＝5.0Hz),132.80,130.41(q,J＝34.8Hz),129.74,128.59,128.49,128.01,127.85,121.77(q,J＝269.0Hz),74.03,56.33,56.08.HRMS(ESI)calcd for C18H16ClF3N[M+H+]:338.0918,found:338.0927.
实施例28
将(3-(三氟甲基)丁-3-烯-1-炔基)苯(0.5mmol)，4-溴苄胺(1.0mmol)作为原料，其他操作参考实施例1,反应搅拌24h,硅胶柱色谱纯化(石油醚：乙酸乙酯＝200:1)，得到4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物纯品III-28(111mg，58％)。
白色固体.Mp 64.6-66.5℃.1H NMR(500MHz,CDCl3)δ7.41(d,J＝8.2Hz,2H),7.40–7.35(m,4H),7.34–7.29(m,1H),7.15(d,J＝8.2Hz,2H),6.22(s,1H),4.72(s,1H),3.88(d,J＝13.4Hz,1H),3.86(dd,J＝13.2,6.0Hz,1H),3.53(d,J＝13.4Hz,1H),3.46(dd,J＝13.2,6.0Hz,1H).19F NMR(282MHz,CDCl3)δ-65.36.13C NMR(126MHz,CDCl3)δ140.38,137.74,135.94(q,J＝5.0Hz),131.46,130.43(q,J＝34.8Hz),130.12,128.60,128.03,127.85,121.76(q,J＝269.1Hz),120.93,74.04,56.39,56.09.HRMS(ESI)calcd for C18H16BrF3N[M+H+]:382.0413,found:382.0423.
实施例29
将(3-(三氟甲基)丁-3-烯-1-炔基)苯(0.5mmol)，4-三氟甲基苄胺(1.0mmol)作为原料，其他操作参考实施例1,反应搅拌24h,硅胶柱色谱纯化(石油醚：乙酸乙酯＝200:1)，得到4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物纯品III-29(130mg，71％)。
无色油状物.1H NMR(400MHz,CDCl3)δ7.56(d,J＝8.0Hz,2H),7.45–7.37(m,4H),7.41(d,J＝8.0Hz,2H),7.36–7.31(m,1H),6.25(s,1H),4.80–4.73(m,1H),4.00(d,J＝13.7Hz,1H),3.90(dd,J＝13.2,5.3Hz,1H),3.66(d,J＝13.7Hz,1H),3.53-3.45(m,1H).19FNMR(282MHz,CDCl3)δ-62.43,-65.39.13C NMR(100MHz,CDCl3)δ142.92,140.35,135.95(q,J＝5.0Hz),130.43(q,J＝34.7Hz),129.44(q,J＝32.3Hz),128.64,128.61,128.10,127.86,125.30(q,J＝3.8Hz),124.18(q,J＝272.0Hz),121.75(q,J＝269.0Hz),74.20,56.64,56.21.HRMS(ESI)calcd for C19H16F6N[M+H+]:372.1181,found:372.1191.
实施例30
将(3-(三氟甲基)丁-3-烯-1-炔基)苯(0.5mmol)，4-甲基苄胺(1.0mmol)作为原料，其他操作参考实施例1,反应搅拌24h,硅胶柱色谱纯化(石油醚：乙酸乙酯＝200:1)，得到4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物纯品III-30(145mg，91％)。
白色固体.Colorless solid.Mp 56.0-58.2℃.1H NMR(400MHz,CDCl3)δ7.49-7.30(m,5H),7.20(d,J＝7.8Hz,2H),7.14(d,J＝7.8Hz,2H),6.23(s,1H),4.75(s,1H),3.94(d,J＝13.1Hz,1H),3.89(dd,J＝13.4,5.0Hz,1H),3.54(d,J＝13.1Hz,1H),3.50(dd,J＝13.4,5.0Hz,1H),2.36(s,3H).19F NMR(282MHz,CDCl3)δ-65.34.13C NMR(100MHz,CDCl3)δ140.72,136.73,136.04(q,J＝5.0Hz),135.63,130.47(q,J＝34.6Hz),129.04,128.54,128.44,127.85,121.84(q,J＝269.1Hz),73.87,56.63,55.96,21.08.HRMS(ESI)calcd forC19H19F3N[M+H+]:318.1464,found:318.1473.
实施例31
将(3-(三氟甲基)丁-3-烯-1-炔基)苯(0.5mmol)，4-甲氧基苄胺(1.0mmol)作为原料，其他操作参考实施例1,反应搅拌24h,硅胶柱色谱纯化(石油醚：乙酸乙酯＝200:1)，得到4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物纯品III-31(122mg，73％)。
无色油状物.Colorless oil.1H NMR(500MHz,CDCl3)δ7.50-7.30(m,5H),7.23(d,J＝8.3Hz,2H),6.88(d,J＝8.3Hz,2H),6.24(s,1H),4.74(s,1H),3.92(d,J＝13.1Hz,1H),3.89(dd,J＝13.4,5.0Hz,1H),3.82(s,3H),3.53(d,J＝13.1Hz,1H),3.54–3.47(m,1H).19FNMR(282MHz,CDCl3)δ-65.34.13C NMR(126MHz,CDCl3)δ158.75,140.75,136.06(q,J＝4.7Hz),130.80,130.49(q,J＝34.6Hz),129.62,128.53,127.85(2C),121.87(q,J＝268.7Hz),113.72,73.84,56.31,55.97,55.19.HRMS(ESI)calcd for C19H19F3NO[M+H+]:334.1413,found:334.1425.
实施例32
将(3-(三氟甲基)丁-3-烯-1-炔基)苯(0.5mmol)，苯乙胺(1.0mmol)作为原料，其他操作参考实施例1,反应搅拌24h,硅胶柱色谱纯化(石油醚：乙酸乙酯＝200:1)，得到4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物纯品III-32(95mg，60％)。
无色油状物.1H NMR(300MHz,CDCl3)δ7.34–7.13(m,8H),7.09(d,J＝7.0Hz,2H),6.16(s,1H),4.66–4.56(m,1H),4.15(dd,J＝13.0,5.3Hz,1H),3.61(dd,J＝13.0,6.2Hz,1H),2.98–2.85(m,1H),2.83–2.61(m,3H).19F NMR(282MHz,CDCl3)δ-65.21.13C NMR(126MHz,CDCl3)δ140.81,139.87,136.11(q,J＝4.9Hz),130.11(q,J＝34.6Hz),128.61,128.47,128.27,127.73,127.64,126.03,121.87(q,J＝269.0Hz),74.50,56.49,54.92,35.35.HRMS(ESI)calcd for C21H17O3F[M+H+]:318.1464,found:318.1471.
实施例33
将(3-(三氟甲基)丁-3-烯-1-炔基)苯(0.5mmol)，异丙胺(1.0mmol)作为原料，其他操作参考实施例1,反应搅拌24h,硅胶柱色谱纯化(石油醚：乙酸乙酯＝200:1)，得到4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物纯品III-33(96mg，75％)。
无色油状物.Colorless oil.1H NMR(400MHz,CDCl3)δ7.32–7.15(m,5H),6.06–6.03(m,1H),4.84–4.63(m,1H),3.91(dd,J＝13.3,5.9Hz,1H),3.68(dd,J＝13.3,5.9Hz,1H),2.89-2.77(m,1H),0.94(d,J＝6.9Hz,3H),0.92(d,J＝6.9Hz,3H).19F NMR(282MHz,CDCl3)δ-65.27.13C NMR(100MHz,CDCl3)δ142.46,136.24(q,J＝4.9Hz),129.58(q,J＝34.4Hz),128.46,127.49,127.48,122.02(q,J＝269.0Hz),71.26,51.98,50.17,22.07,17.75.HRMS(ESI)calcd for C14H17F3N[M+H+]:256.1308,found:256.1312.
实施例34
将(3-(三氟甲基)丁-3-烯-1-炔基)苯(0.5mmol)，烯丙胺(1.0mmol)作为原料，其他操作参考实施例1,反应搅拌24h,硅胶柱色谱纯化(石油醚：乙酸乙酯＝200:1)，得到4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物纯品III-34(86mg，68％)。
无色油状物.1H NMR(300MHz,CDCl3)δ7.42–7.27(m,5H),6.25–6.18(m,1H),5.90-5.74(m,1H),5.22(dd,J＝17.1,1.2Hz,1H),5.12(d,J＝10.1Hz,1H),4.71–4.62(m,1H),4.06(dd,J＝13.4,5.4Hz,1H),3.64–3.52(m,1H),3.43–3.35(m,1H),3.13(dd,J＝13.7,7.4Hz,1H).19F NMR(282MHz,CDCl3)δ-65.34.13C NMR(126MHz,CDCl3)δ140.73,135.98(q,J＝4.9Hz),135.27,130.54(q,J＝34.6Hz),128.53,127.82,127.76,121.88(q,J＝269.0Hz),117.23,73.63,56.17,55.77.HRMS(ESI)calcd for C14H15F3N[M+H+]:254.1151,found:254.1156.
实施例35
将(3-(三氟甲基)丁-3-烯-1-炔基)苯(0.5mmol)，2-呋喃甲胺(1.0mmol)作为原料，其他操作参考实施例1,反应搅拌24h,硅胶柱色谱纯化(石油醚：乙酸乙酯＝100:1)，得到4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物纯品III-35(115mg，78％)。
无色油状物.Colorless oil.1H NMR(400MHz,CDCl3)δ7.45–7.35(m,5H),7.35–7.29(m,1H),6.32(dd,J＝3.1,1.9Hz,1H),6.22-6.17(m,2H),4.81-4.76(m,1H),4.02(dd,J＝13.2,5.4Hz,1H),3.84(d,J＝14.7Hz,1H),3.81–3.74(m,1H),3.70(d,J＝14.7Hz,1H).19FNMR(282MHz,CDCl3)δ-65.32.13C NMR(100MHz,CDCl3)δ152.06,142.22,140.21,135.90(q,J＝5.0Hz),130.46(q,J＝34.7Hz),128.57,127.90,127.79,121.79(q,J＝269.0Hz),110.09,108.38,72.53,55.66,47.70.HRMS(ESI)calcd for C16H15F3NO[M+H+]:294.1100,found:294.1107.
实施例36
将(3-(三氟甲基)丁-3-烯-1-炔基)苯(0.5mmol)，2-噻吩甲胺(1.0mmol)作为原料，其他操作参考实施例1,反应搅拌24h,硅胶柱色谱纯化(石油醚：乙酸乙酯＝100:1)，得到4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物纯品III-36(126mg，81％)。
白色固体.Mp 42.4-43.8℃.1H NMR(400MHz,CDCl3)δ7.47–7.37(m,4H),7.36–7.30(m,1H),7.25(dd,J＝5.1,1.1Hz,1H),6.96(dd,J＝5.1,3.4Hz,1H),6.91(d,J＝3.3Hz,1H),6.23-6.19(m,1H),4.83-4.77(m,1H),4.05(d,J＝14.2Hz,1H),4.03(dd,J＝13.2,5.5Hz,1H),3.89(d,J＝14.2Hz,1H),3.69–3.61(m,1H).19F NMR(282MHz,CDCl3)δ-65.33.13C NMR(100MHz,CDCl3)δ141.73,140.28,135.88(q,J＝5.0Hz),130.29(q,J＝34.7Hz),128.61,127.97,127.76,126.51,125.53,125.14,121.77(q,J＝269.1Hz),73.04,55.78,50.75.HRMS(ESI)calcd for C16H15F3NS[M+H+]:310.0872,found:310.0880.
实施例37
将(3-(三氟甲基)丁-3-烯-1-炔基)苯(0.5mmol)，2-吡啶甲胺(1.0mmol)作为原料，其他操作参考实施例1,反应搅拌24h,硅胶柱色谱纯化(石油醚：乙酸乙酯＝10:1)，得到4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物纯品III-37(96mg，63％)。
白色固体.Mp 47.5-49.6℃.1H NMR(400MHz,CDCl3)δ8.42(d,J＝4.9Hz,1H),7.56-7.49(m,1H),7.34–7.17(m,6H),7.04(dd,J＝6.9,5.2Hz,1H),6.16–6.13(m,1H),4.79-4.72(m,1H),3.96(d,J＝14.2Hz,1H),3.90(dd,J＝13.3,5.4Hz,1H),3.76(d,J＝14.2Hz,1H),3.60–3.53(m,1H).19F NMR(282MHz,CDCl3)δ-65.33.13C NMR(100MHz,CDCl3)δ158.82,148.94,140.46,136.50,135.90(q,J＝5.0Hz),130.52(q,J＝34.7Hz),128.52,127.91,127.84,122.74,122.04,121.77(q,J＝269.1Hz),74.11,58.72,56.41.HRMS(ESI)calcdfor C17H16F3N2[M+H+]:305.1260,found:305.1262.
实施例38
将(3-(三氟甲基)丁-3-烯-1-炔基)苯(0.5mmol)，(R)-1-苯乙胺(1.0mmol)作为原料，其他操作参考实施例1,反应搅拌24h,硅胶柱色谱纯化(石油醚：乙酸乙酯＝200:1)，得到4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物纯品III-38,III-38’(133mg，84％)(dr＝1.3:1)。
无色油状物.The isomer A.47％isolated yield.Colorless solid.Mp 39.3-40.2℃.1H NMR(500MHz,CDCl3)δ7.44–7.23(m,10H),6.11–6.08(m,1H),4.91–4.86(m,1H),3.90(dd,J＝13.6,5.9Hz,1H),3.81(q,J＝6.8Hz,1H),3.64-3.58(m,1H),1.19(d,J＝6.8Hz,3H).19F NMR(282MHz,CDCl3)δ-65.30.13C NMR(126MHz,CDCl3)δ143.97,142.62,136.15(q,J＝4.9Hz),129.15(q,J＝34.5Hz),128.49,128.47,127.48,127.42,127.34,127.09,121.84(q,J＝269.1Hz),72.09,62.49,55.60,23.43.HRMS(ESI)calcd forC19H19F3N[M+H+]:318.1464,found:318.1479.
The isomer B.37％isolated yield.Colorless solid.Mp 39.5-40.5℃.1H NMR(500MHz,CDCl3)δ7.40–7.24(m,10H),6.28-6.25(m,1H),5.03-4.97(m,1H),4.02(q,J＝6.6Hz,1H),3.97(dd,J＝13.6,6.0Hz,1H),3.88-3.84(m,1H),1.51(d,J＝6.6Hz,3H).19FNMR(282MHz,CDCl3)δ-65.24.13C NMR(100MHz,CDCl3)δ143.07,141.66,136.03(q,J＝4.9Hz),129.65(q,J＝34.4Hz),128.22,127.98,127.72,127.64,127.35,126.88,121.91(q,J＝269.0Hz),72.02,58.80,52.69,16.66.HRMS(ESI)calcd for C19H19F3N[M+H+]:318.1464,found:318.1475.
实施例39
将(3-(三氟甲基)丁-3-烯-1-炔基)苯(0.5mmol)，乙醇胺(1.0mmol)作为原料，其他操作参考实施例1,反应搅拌24h,硅胶柱色谱纯化(石油醚：乙酸乙酯＝10:1)，得到4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物纯品III-39(40mg，31％)。
无色油状物.1H NMR(500MHz,CDCl3)δ7.40–7.28(m,5H),6.23-6.19(m,1H),4.69-4.64(m,1H),4.16(dd,J＝13.2,5.4Hz,1H),3.65–3.52(m,2H),3.50-3.44(m,1H),2.93-2.86(m,1H),2.81-2.75(m,1H),2.09(brs,1H).19F NMR(282MHz,CDCl3)δ-65.32.13C NMR(100MHz,CDCl3)δ140.62,135.80(q,J＝5.0Hz),130.24(q,J＝34.8Hz),128.78,128.19,127.62,121.67(q,J＝269.0Hz),74.70,59.87,56.72,55.30.HRMS(ESI)calcd forC13H15F3NO[M+H+]:258.1100,found:258.1106.
实施例40
将(3-(三氟甲基)丁-3-烯-1-炔基)苯(0.5mmol)，乙二胺(1.0mmol)作为原料，其他操作参考实施例1,反应搅拌24h,硅胶柱色谱纯化(石油醚：乙酸乙酯＝200:1)，得到4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物纯品III-40(35mg，27％)。
无色油状物.1H NMR(400MHz,CDCl3)δ7.37–7.24(m,5H),6.17(s,1H),5.45(brs,2H),4.69–4.63(m,1H),4.16–4.07(m,1H),3.64-3.57(m,1H),2.90–2.65(m,4H).19F NMR(471MHz,CDCl3)δ-65.26.13C NMR(126MHz,CDCl3)δ140.34,135.76(q,J＝4.8Hz),130.08(q,J＝34.9Hz),128.79,128.18,127.67,121.63(q,J＝269.1Hz),74.63,56.77,52.72,38.82.HRMS(ESI)calcd for C13H16F3N[M+H+]:257.1260,found:257.1263.
实施例41
将(3-(三氟甲基)丁-3-烯-1-炔基)苯(0.5mmol)，乙酰乙二胺(1.0mmol)作为原料，其他操作参考实施例1,反应搅拌24h,硅胶柱色谱纯化(石油醚：乙酸乙酯＝200:1)，得到4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物纯品III-41(51mg，34％)。
无色油状物.1H NMR(300MHz,CDCl3)δ7.40–7.27(m,5H),6.20–6.15(m,1H),5.59(brs,1H),4.66-4.57(m,1H),4.17–4.07(m,1H),3.62–3.52(m,1H),3.36-3.24(m,1H),3.14–3.02(m,1H),2.81–2.69(m,2H),1.76(s,3H).19F NMR(282MHz,CDCl3)δ-65.32.13C NMR(126MHz,CDCl3)δ169.97,140.97,135.59(q,J＝4.9Hz),130.33(q,J＝34.8Hz),128.74,128.21,127.69,121.63(q,J＝269.1Hz),74.64,56.75,52.45,37.92,22.99.HRMS(ESI)calcd for C15H18F3ON2[M+H+]:299.1366,found:299.1373.
实施例42
将(3-(三氟甲基)丁-3-烯-1-炔基)苯(0.5mmol)，Boc乙二胺(1.0mmol)作为原料，其他操作参考实施例1,反应搅拌24h,硅胶柱色谱纯化(石油醚：乙酸乙酯＝200:1)，得到4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物纯品III-42(130mg，73％)。
无色油状物.1H NMR(300MHz,CDCl3)δ7.40–7.26(m,5H),6.20–6.14(m,1H),4.74–4.55(m,2H),4.12(dd,J＝13.0,5.4Hz,1H),3.56(dd,J＝12.5,5.2Hz,1H),3.25–2.99(m,2H),2.83–2.63(m,2H),1.39(s,9H).19F NMR(282MHz,CDCl3)δ-65.33.13C NMR(100MHz,CDCl3)δ155.88,140.74,135.87(q,J＝4.9Hz),130.14(q,J＝34.7Hz),128.65,128.01,127.65,121.71(q,J＝269.0Hz),79.03,74.63,56.55,52.82,39.13,28.29.HRMS(ESI)calcd for C18H24F3O2N2[M+H+]:357.1784,found:357.1792.
实施例43
将原料(3-(三氟甲基)丁-3-烯-1-炔基)苯(0.5mmol)，银盐放入干燥反应管中，抽气换气，在氮气保护下加入氯苯，再注入苯胺(1.5mmol)，在80℃下充分反应，反应48小时，通过TLC和碘缸显色检测反应，至(3-(三氟甲基)丁-3-烯-1-炔基)苯完全消失。反应结束后加硅藻土过滤，并旋蒸去除溶剂，然后将粗产品直接用硅胶快速柱色谱纯化(石油醚：乙酸乙酯＝200:1)得到4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物纯品III-43(113mg，78％)。
白色固体.Mp 72.0-73.5℃.1H NMR(400MHz,CDCl3)δ7.31–7.18(m,5H),7.13–7.07(m,2H),6.64(t,J＝7.3Hz,1H),6.44(d,J＝7.9Hz,2H),6.33-6.28(m,1H),5.51-5.45(m,1H),4.58(dd,J＝13.5,6.7Hz,1H),4.40-4.33(m,1H).19F NMR(282MHz,CDCl3)δ-65.17.13CNMR(126MHz,CDCl3)δ145.60,140.10,135.58(q,J＝4.8Hz),129.23,129.10,127.93,127.85(q,J＝35.4Hz),126.23,121.61(q,J＝268.9Hz),117.18,112.26,69.96,53.65.MS(70eV):m/z(％):289(M+,56.34),212(100).HRMS(EI)calcd for C17H14F3N:289.1078,found:289.1081.
实施例44
在氮气下，将前述实施例6制备得到的4-三氟甲基-2,4-二取代二氢吡咯衍生物III-6(0.5mmol)苯硼酸(0.6mmol)，K2CO3(1.0mmol)放入装有磁子的封管中，抽换气三次，向其中注入THF(2mL)和H2O(1mL)，95℃搅拌13h后，冷却到室温，用5.0mL水淬灭，乙酸乙酯(5.0mL*3次)萃取。有机相用饱和食盐水洗涤后，经硫酸镁干燥，旋去溶剂，将粗产品直接用硅胶快速柱色谱纯化(石油醚：乙酸乙酯＝200:1)得到4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物I(180mg，95％)。
白色固体.Mp 101.1-102.5℃.1H NMR(300MHz,CDCl3)δ7.65(d,J＝8.2Hz,4H),7.58-7.44(m,4H),7.43–7.27(m,6H),6.28(s,1H),4.82(s,1H),4.04(d,J＝13.2Hz,1H),3.95(dd,J＝13.2,4.6Hz,1H),3.62(d,J＝13.2Hz,1H),3.55(dd,J＝13.1,6.0Hz,1H).19FNMR(282MHz,CDCl3)δ-65.28.13C NMR(126MHz,CDCl3)δ140.89,140.81,139.73,138.70,135.95(q,J＝4.9Hz),130.62(q,J＝34.6Hz),128.77,128.49,128.38,128.28,127.32,127.16,127.10,121.85(q,J＝269.1Hz),73.71,57.06,56.10.HRMS(ESI)calcd forC24H21F3N[M+H+]:380.1621,found:380.1637.
实施例45
在氮气下，将前述实施例6制备得到的4-三氟甲基-2,4-二取代二氢吡咯衍生物III-6(0.5mmol)溶于2mL二氯乙烷中，加入DDQ(0.6mmol)，搅拌反应24h,过滤除去固体，旋去溶剂，将粗产品直接用硅胶快速柱色谱纯化(石油醚：乙酸乙酯＝200:1)得到4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物II(105mg，92％)。
无色油状物.Colorless oil.1H NMR(300MHz，CDCl3)δ7.50(d，J＝8.5Hz，2H)，7.39-7.29(m，3H)，7.18(d，J＝8.5Hz，2H)，7.07(s，1H)，7.04-6.97(m，2H)，6.44(s，1H)，5.10(s，2H).19FNMR(282MHz,CDCl3)δ-57.23.13C NMR(100MHz,CDCl3)δ137.04,134.61,131.73,130.69,130.63,128.94,127.92,126.49,123.74(q,J＝266.0Hz),122.23,122.03(q,J＝4.8Hz),114.87(q,J＝37.2Hz),106.63(d,J＝2.7Hz),51.05.MS(70eV):m/z(％):379(M+,14.10),381(M++2,13.69),91(100).HRMS(EI)calcd for C18H13BrF3N:379.0183,found:379.0180.
实施例46
将前述实施例1制备得到的4-三氟甲基-2,4-二取代二氢吡咯衍生物III-1(0.38mmol)溶于3mL乙醇中，加入Pd/C(10％)，置于一个大气压的氢气下搅拌反应4h,加硅藻土过滤除去固体，旋去溶剂，将粗产品直接用硅胶快速柱色谱纯化(石油醚：乙酸乙酯＝200:1)得到4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物III(76mg，66％)。
白色固体.Mp 72.0-74.2℃.1H NMR(500MHz,CDCl3)δ7.48(d,J＝7.4Hz,2H),7.35(t,J＝7.5Hz,2H),7.31-7.19(m,6H),3.84(d,J＝13.6Hz,1H),3.45(dd,J＝9.9,6.6Hz,1H),3.25(dd,J＝10.6,2.2Hz,1H),3.00(d,J＝13.6Hz,1H),2.87–2.71(m,1H),2.43–2.35(m,2H),1.96-1.88(m,1H).19F NMR(471MHz,CDCl3)δ-71.58.13C NMR(126MHz,CDCl3)δ141.55,138.82,128.65,128.25,128.15,127.87(q,J＝277.4Hz),127.70,127.54,126.87,69.05,57.02,52.33(q,J＝2.6Hz),39.83(q,J＝28.3Hz),35.66(q,J＝1.7Hz).HRMS(ESI)calcd for C18H19F3N[M+H+]:306.1464,found:306.1474.
实施例47
将前述实施例1制备得到的4-三氟甲基-2,4-二取代二氢吡咯衍生物III-1(0.15mmol)溶于3mL乙醇中，加入Pd/C(10％)和溴化氢(0.2mmol)，置于一个大气压的氢气下搅拌反应12h,在反应中加入1mL 1mol/L氢氧化钠溶液，搅拌15分钟，过滤，乙酸乙酯(5.0mL*3次)萃取。有机相用饱和食盐水洗涤后，经硫酸钠干燥，旋去溶剂将粗产品直接用硅胶快速柱色谱纯化(石油醚：乙酸乙酯＝10:1)得到4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物IV(24mg，74％)。
无色油状物.Colorless oil.1H NMR(300MHz,CDCl3)δ7.43–7.27(m,5H),4.13(dd,J＝10.2,6.4Hz,1H),3.39(dd,J＝11.8,4.2Hz,1H),3.24–3.13(m,1H),3.06–2.84(m,1H),2.52-2.40(m,1H),1.93(brs,1H),1.88-1.76(m,1H).19F NMR(282MHz,CDCl3)δ-70.87.13CNMR(126MHz,CDCl3)δ141.68,128.55,128.00(q,J＝277.2Hz),127.50,126.50,63.33,47.00(q,J＝2.6Hz),43.45(q,J＝27.2Hz),34.78(q,J＝1.4Hz).HRMS(ESI)calcdfor C11H13F3N[M+H+]:216.0995,found:216.0995.
实施例48
将前述实施例21制备得到的4-三氟甲基-2,4-二取代二氢吡咯衍生物III-21(0.55mmol)溶于4mL乙醇中，加入Pd/C(10％)和溴化氢(1.1mmol)，置于一个大气压的氢气下搅拌反应4h,TLC监测原料反应完全，在反应中加入2mL 1mol/L氢氧化钠溶液，搅拌15分钟，过滤，乙酸乙酯(5.0mL*3次)萃取。有机相用饱和食盐水洗涤后，经硫酸钠干燥，旋去溶剂将粗产品直接进行下一步，在氮气保护下，将粗产品溶于4mL二氯甲烷中，加入三乙胺(1.5mmol)，再加入BOC酸酐(0.6mmol)，反应2h后，加入5mL水，分离有机相，水洗两边，硫酸镁干燥，过滤并除去溶剂，将粗产品直接用硅胶快速柱色谱纯化(石油醚：乙酸乙酯＝1:1)得到4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物V(106mg，72％)。
无色油状物.1H NMR(500MHz,CDCl3)δ4.87(s,1H),3.97(d,J＝5.9Hz,1H),3.78(s,1H),3.72-3.60(m,2H),3.31(s,1H),2.90–2.75(m,1H),2.31–2.23(m,1H),1.67(d,J＝7.4Hz,1H),1.45(s,9H).19F NMR(471MHz,CDCl3)δ-70.87.13C NMR(101MHz,CDCl3)δ156.15,126.05(q,J＝276.7Hz),81.19,66.50,60.52,46.56,40.90(q,J＝29.1Hz),28.44(q,J＝2.4Hz),28.29.HRMS(ESI)calcd for C11H18F3NNaO3[M+Na+]:292.1131,found:292.1132.
实施例49
在氮气下，将前述实施例1制备得到的4-三氟甲基-2,4-二取代二氢吡咯衍生物III-1(0.3mmol)溶于2mL二氯甲烷中，在0℃子啊加入m-CPBA(0.6mmol)，搅拌1h，然后移至室温下搅拌反应24h,点板监测，加入5mL碳酸氢钠淬灭，乙酸乙酯萃取，无水硫酸钠干燥，旋去溶剂，将粗产品直接用硅胶快速柱色谱纯化(石油醚：二氯甲烷：乙酸乙酯＝200:10:1)得到4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物VI(67mg，70％)。
无色油状物.Colorless oil.1H NMR(500MHz，CDCl3)δ7.345-7.25(m，10H)，6.59(s，1H），5.49(s，1H)，4.15(d，J＝12.9Hz，1H)，3.96(d，J＝12.9Hz，1H)，3.51(s，2H).19F NMR(471MHz，CDCl3)δ-68.12.13C NMR(126MHz,CDCl3)δ137.40,136.06,131.72,128.94,128.61,128.53,128.29,127.96,127.42,127.02(d,J＝31.9Hz),122.64(q,J＝271.2Hz),78.15,62.54,51.14.MS(70eV):m/z(％):319(M+,6.84),91(100).HRMS(EI)calcd forC18H16F3NO:319.1184,found:319.1186.
实施50
在氮气下，将前述实施例1制备得到的4-三氟甲基-2,4-二取代二氢吡咯衍生物III-1(0.3mmol)溶于2mL二氯甲烷中，在0℃子下加入液溴(0.6mmol)，搅拌半小时，然后移至室温搅拌过夜，直到原料消失为止，然后再冷却至0℃,加入三乙胺(0.9mmol)搅拌反应半小时，然后移至搅拌反应24h,加入硫代硫酸钠淬灭，乙酸乙酯萃取，无水硫酸钠干燥，过滤除去固体，旋去溶剂，将粗产品直接用硅胶快速柱色谱纯化(石油醚：二氯甲烷＝20:1)得到4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物VII(80mg，70％)。
无色油状物.1H NMR(400MHz，CDCl3)δ7.46-7.38(m，3H)，7.34-7.27(m，5H)，7.06(q，J＝0.9Hz，1H)，6.98-6.94(m，2H)，4.98(s，2H).19F NMR(376MHz，CDCl3)δ-58.40.13CNMR(100MHz,CDCl3)δ136.36,134.37,130.77,129.61,128.92,128.88,128.56,128.08,126.96,122.87(q,J＝266.7Hz),121.64(q,J＝5.0Hz),114.32(q,J＝36.2Hz),93.09(q,J＝2.2Hz),52.07.MS(70eV):m/z(％):379(M+,16.44),91(100).HRMS(EI)calcd forC18H13BrF3N:379.0183,found:379.0184.
实施例51
在氮气下，将前述实施例1制备得到的4-三氟甲基-2,4-二取代二氢吡咯衍生物III-1(0.2mmol)溶于2mL乙腈中，加入NBS(0.6mmol)，搅拌反应12h,旋去溶剂，将粗产品直接用硅胶快速柱色谱纯化(石油醚：二氯甲烷＝20:1)得到4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物VIII(80mg，87％)。
A白色固体.Mp 89.5-90.8℃.1H NMR(400MHz，CDCl3)δ7.42-7.32(m，3H)，7.30-7.23(m，3H)，7.22-7.17(m，2H，6.86-6.81(m，2H)，5.12(s，19F NMR(376MHz，CDCl3)δ-56.41.13CNMR(126MHz,CDCl3)δ136.12,135.53,130.77,129.60,129.29,128.74,128.57,127.67,125.95,122.23(q,J＝268.6Hz),113.12(q,J＝35.6Hz),103.94(q,J＝3.3Hz),94.51(q,J＝1.6Hz),50.52.MS(70eV):m/z(％):459(M+,9.64),91(100).HRMS(EI)calcdfor C18H12Br2F3N:456.9289,found:456.9285.
实施例52
在氮气下，将前述实施例1制备得到的4-三氟甲基-2,4-二取代二氢吡咯衍生物III-1(0.2mmol)溶于2mL乙腈中，加入NIS(0.6mmol)，搅拌反应12h,加入饱和硫代硫酸钠除去碘，直至溶液红色消失，乙酸乙酯萃取，无水硫酸钠干燥，过滤旋去溶剂，将粗产品直接用硅胶快速柱色谱纯化(石油醚：二氯甲烷＝20:1)得到4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物IX(81mg，95％)。
白色固体.Mp 62.9-64.6℃.1H NMR(500MHz，CDCl3)δ7.42-7.37(m，3H)，7.30-7.22(m，5H)，7.12(q，J＝0.9Hz，1H)，6.96-6.89(m，2H)，4.96(s，2H).19F NMR(471MHz，CDCl3)δ-58.23.13C NMR(126MHz,CDCl3)δ138.36,136.41,131.04,130.92,129.00,128.84,128.51,128.04,126.96,122.94(q,J＝267.0Hz),122.92(q,J＝5.3Hz),117.36(q,J＝35.9Hz),59.79(q,J＝2.0Hz),52.32.MS(70eV):m/z(％):427(M+,35.56),91(100).HRMS(EI)calcdfor C18H13IF3N:427.0045,found:427.0047.
实施例53
在氮气下，将前述实施例1制备得到的4-三氟甲基-2,4-二取代二氢吡咯衍生物III-1(0.2mmol)溶于2mL乙腈中，加入NFSI(0.6mmol)，搅拌反应12h,旋去溶剂，将粗产品直接用硅胶快速柱色谱纯化(石油醚：二氯甲烷＝20:1)得到4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物X(30mg，47％)。
无色油状物.1H NMR(500MHz，CDCl3)δ7.42-7.25(m，8H)，7.00(d，J＝7.2Hz，2H)，6.26(d，J＝5.2Hz，1H)，5.10(s，2H).19F NMR(471MHz，CDCl3)δ-5631(d，J＝9.6Hz)，-133.56(q，J＝9.6Hz).13C NMR(126MHz,CDCl3)δ145.76–143.44(m),136.32,131.13,129.06,128.88,128.69,128.11,127.82,126.60,126.18,125.54–119.31(m),103.03(q,J＝2.5Hz),93.04-92.05(m),46.59.MS(70eV):m/z(％):319(M+,9.72),91(100).HRMS(EI)calcd for C18H13F4N:319.0984,found:319.0986.
实施例54
在氮气下，将前述实施例1制备得到的4-三氟甲基-2,4-二取代二氢吡咯衍生物III-1(0.2mmol)溶于2mL乙腈中，一次性加入对硝基四氟硼酸重氮盐(0.6mmol)、Pa(dba)2(0.01mmol)、乙酸钠(0.6mmol)，反应立刻冒泡成溶液变成黑色，搅拌反应12h,TLC监测原料反应完全，过滤旋去溶剂，将粗产品直接用硅胶快速柱色谱纯化(石油醚：二氯甲烷＝2:1)过柱，然后用石油醚重结晶得到4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物XI(84mg，99％)。
红色固体.Mp 115.2-116.9℃.1H NMR(300MHz,CDCl3)δ8.28(d,J＝8.6Hz,2H),7.75(d,J＝8.6Hz,2H),7.50-7.36(m,5H),7.36–7.23(m,3H),7.02(d,J＝7.4Hz,2H),6.83(s,1H),5.68(s,2H).19F NMR(282MHz,CDCl3)δ-58.11.13C NMR(126MHz,CDCl3)δ156.58,147.94,141.50(q,J＝2.7Hz),139.89,137.67,130.23,129.31,129.07,128.92,128.82,127.53,125.86,124.64,122.67(q,J＝267.2Hz),122.65,112.03(q,J＝4.3Hz),111.33(q,J＝38.9Hz),49.25.MS(70eV):m/z(％):422(M+,7.88),57(100).HRMS(EI)calcd forC24H17F3N2O2:422.1242,found:422.1250.
实施例55
在氮气下，将前述实施例1制备得到的4-三氟甲基-2,4-二取代二氢吡咯衍生物III-1(0.6mmol)溶于4mL乙腈中，加入NCS(2.4mmol)，搅拌反应24h,TLC监测原料反应完全，加入饱和硫代硫酸钠淬灭，乙酸乙酯萃取，无水硫酸钠干燥，过滤旋去溶剂，将粗产品直接用硅胶快速柱色谱纯化(石油醚：乙酸乙酯＝20:1)得到4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物XII(183mg，70％)。
白色固体.Mp 121.3-123.0℃.1H NMR(500MHz,CDCl3)δ7.57-7.44(m,5H),7.33–7.21(m,5H),5.00(d,J＝14.9Hz,1H),4.32(d,J＝14.9Hz,1H),3.45(s,1H).19F NMR(471MHz,CDCl3)δ-65.11.13C NMR(126MHz,CDCl3)δ163.04,135.41,132.81,130.30,129.47,129.02,128.75,128.27,127.89,121.27(q,J＝283.7Hz),97.17,88.86,70.15(q,J＝30.7Hz),46.66.HRMS(ESI)calcd for C18H13Cl3F3NNaO2[M+Na+]:459.9856,found:459.9852.[M+Na++2]:found:461.9825.
实施例56
在氮气下，将前述实施例1制备得到的4-三氟甲基-2,4-二取代二氢吡咯衍生物III-1(0.4mmol)溶于2mL乙腈中，加入NCS(1.0mmol)，搅拌反应24h,TLC监测原料反应完全，加入饱和硫代硫酸钠淬灭，乙酸乙酯萃取，无水硫酸钠干燥，过滤旋去溶剂，将粗产品直接用硅胶快速柱色谱纯化(石油醚：乙酸乙酯＝20:1)得到4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物XIII(110mg，75％)。
A白色固体.Mp 127.5-129.7℃.1H NMR(500MHz，CDCl3)δ7.43-7.32(m，5H)，7.22–7.14(m，5H)，δ4.68(d，J＝15.0Hz，1H)，4.04(d，＝J15.0Hz，1H)，3.67(brs，1H).19F MHR(376MHz，CDCl3)δ-61.67.13C NMR(126MHz,CDCl3)δ162.58,157.37(q,J＝3.9Hz),136.76,133.27,129.77,128.95,128.91,128.46,127.62,126.29,121.55(q,J＝35.1Hz),119.98(q,J＝271.6Hz),92.04,43.68.HRMS(ESI)calcd forC18H13ClF3NNaO2[M+Na+]:390.0479,found:390.0491.
本发明不局限于以上实施例。在不违背发明构思的精神和范围下，本领域技术人员能够想到的变化和优点都包括在本发明中，并且以所附的权利要求书为保护范围。
Claims (10)
1.一种4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物，其特征在于，其结构如式(III)所示，
其中，R1为芳基、杂芳基、烷基或取代烷基；R2为烷基或取代烷基、芳基；
其中，所述芳基包括苯基、硝基取代的苯基、卤素取代的苯基、甲酰基取代的苯基、乙酰基取代的苯基、氰基取代的苯基、三氟甲基取代的苯基、甲氧基取代的苯基、甲基取代的苯基、酯基取代的苯基；所述杂芳基为呋喃基、噻吩基、吡啶基、环己烯基、二茂铁基；所述烷基或取代烷基包括4-氯丁基、羟甲基、酯甲基、叔丁基二甲基硅氧甲基、苄氧甲基、1-羟基-1-环己基。
2.如权利要求1所述的4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物，其特征在于，所述4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物包括：
1-苄基-2-苯基-4-三氟甲基-2,5-二氢-1H-吡咯，1-苄基-2-(4-硝基苯基)-4-三氟甲基-2,5-二氢-1H-吡咯，1-苄基-2-(3-硝基苯基)-4-三氟甲基-2,5-二氢-1H-吡咯，1-苄基-2-(2-硝基苯基)-4-三氟甲基-2,5-二氢-1H-吡咯，1-苄基-2-(4-氯苯基)-4-三氟甲基-2,5-二氢-1H-吡咯，1-苄基-2-(4-溴苯基)-4-三氟甲基-2,5-二氢-1H-吡咯，1-苄基-2-(4-甲酰基苯基)-4-三氟甲基-2,5-二氢-1H-吡咯，1-苄基-2-(4-乙酰基苯基)-4-三氟甲基-2,5-二氢-1H-吡咯，1-苄基-2-(4-甲酯基苯基)-4-三氟甲基-2,5-二氢-1H-吡咯，1-苄基-2-(4-氰基苯基)-4-三氟甲基-2,5-二氢-1H-吡咯，1-苄基-2-(4-氟苯基)-4-三氟甲基-2,5-二氢-1H-吡咯，1-苄基-2-(4-三氟甲基苯基)-4-三氟甲基-2,5-二氢-1H-吡咯，1-苄基-2-(4-甲基苯基)-4-三氟甲基-2,5-二氢-1H-吡咯，1-苄基-2-(4-甲氧基苯基)-4-三氟甲基-2,5-二氢-1H-吡咯，1-苄基-2-(2-萘基)-4-三氟甲基-2,5-二氢-1H-吡咯，1-苄基-2-(2-噻吩基)-4-三氟甲基-2,5-二氢-1H-吡咯，1-苄基-2-(2-吡啶基)-4-三氟甲基-2,5-二氢-1H-吡咯，1-苄基-2-(1-环己烯基)-4-三氟甲基-2,5-二氢-1H-吡咯，1-苄基-2-二茂铁基-4-三氟甲基-2,5-二氢-1H-吡咯，1-苄基-2-(4-氯丁基)-4-三氟甲基-2,5-二氢-1H-吡咯，2-(1-苄基-4-三氟甲基-2,5-二氢-1H-吡咯)甲醇，乙酸-2-(1-苄基-4-三氟甲基-2,5-二氢-1H-吡咯)甲基酯，1-苄基-2-叔丁基二甲基硅氧甲基-4-三氟甲基-2,5-二氢-1H-吡咯，1-苄基-2-苄氧甲基-4-三氟甲基-2,5-二氢-1H-吡咯，1-(2-(1-苄基-4-三氟甲基-2,5-二氢-1H-吡咯))-1-环己醇，1-(4-氟苄基)-2-苯基-4-三氟甲基-2,5-二氢-1H-吡咯，1-(4-氯苄基)-2-苯基-4-三氟甲基-2,5-二氢-1H-吡咯，1-(4-溴苄基)-2-苯基-4-三氟甲基-2,5-二氢-1H-吡咯，1-(4-三氟甲基苄基)-2-苯基-4-三氟甲基-2,5-二氢-1H-吡咯，1-(4-甲基苄基)-2-苯基-4-三氟甲基-2,5-二氢-1H-吡咯，1-(4-甲氧基苄基)-2-苯基-4-三氟甲基-2,5-二氢-1H-吡咯，1-苯乙基-2-苯基-4-三氟甲基-2,5-二氢-1H-吡咯，1-异丙基-2-苯基-4-三氟甲基-2,5-二氢-1H-吡咯，1-烯丙基-2-苯基-4-三氟甲基-2,5-二氢-1H-吡咯，1-(2-呋喃基)甲基-2-苯基-4-三氟甲基-2,5-二氢-1H-吡咯，1-(2-噻吩基)甲基-2-苯基-4-三氟甲基-2,5-二氢-1H-吡咯，1-(2-吡啶基)甲基-2-苯基-4-三氟甲基-2,5-二氢-1H-吡咯，1-((R)-1-苯乙基))-2-苯基-4-三氟甲基-2,5-二氢-1H-吡咯，2-(2-苯基-4-三氟甲基-2,5-二氢-1H-吡咯)乙醇，2-(2-苯基-4-三氟甲基-2,5-二氢-1H-吡咯)乙胺，N-(2-(2-苯基-4-三氟甲基-2,5-二氢-1H-吡咯))乙基乙酰胺，2-(2-苯基-4-三氟甲基-2,5-二氢-1H-吡咯)乙氨基甲酸丁酯，1-苯基-2-苯基-4-三氟甲基-2,5-二氢-1H-吡咯。
3.一种4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物的制备方法，其特征在于，以2-三氟甲基-1,3-共轭烯炔类化合物、伯胺类化合物为原料，将其溶于有机溶剂，在银盐的作用下，经双氢胺化反应，得到所述4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物；所述反应的方程式如反应式(1)所示，
其中，R1为芳基、杂芳基、烷基或取代烷基；R2为烷基或取代烷基、芳基；
其中，所述芳基包括苯基、硝基取代的苯基、卤素取代的苯基、甲酰基取代的苯基、乙酰基取代的苯基、氰基取代的苯基、三氟甲基取代的苯基、甲氧基取代的苯基、甲基取代的苯基、酯基取代的苯基；所述杂芳基为呋喃基、噻吩基、吡啶基、环己烯基、二茂铁基；所述烷基或取代烷基包括4-氯丁基、羟甲基、酯甲基、叔丁基二甲基硅氧甲基、苄氧甲基、1-羟基-1-环己基。
4.如权利要求3所述的制备方法，其特征在于，所述有机溶剂选自氯苯、甲苯、二氯乙烷。
5.如权利要求3所述的制备方法，其特征在于，所述有机溶剂的用量与式(I)所示的2-三氟甲基-1,3-共轭烯炔类化合物的用量比为6.0～8.0mL：1mmol。
6.如权利要求3所述的制备方法，其特征在于，所述银盐是离子型银盐，如硝酸银、六氟锑酸银。
7.如权利要求3所述的制备方法，其特征在于，所述反应温度为25℃～80℃。
8.如权利要求3所述的制备方法，其特征在于，所述反应的时间为24～48小时。
9.如权利要求3所述的制备方法，其特征在于，所述式(I)所示的2-三氟甲基-1,3-共轭烯炔类化合物、式(II)所示的伯胺类化合物、银盐的摩尔比为2-三氟甲基-1,3-共轭烯炔类化合物：伯胺类化合物：银盐＝1：2：0.1～1.5。
10.如权利要求1所述的4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物在制备脯氨酸衍生物、三氟芳香吡咯中的应用。
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107324982A (zh) * | 2017-06-01 | 2017-11-07 | 华东师范大学 | 1‑三氟甲基‑四取代环戊烯衍生物及其制备方法和应用 |
| CN107324982B (zh) * | 2017-06-01 | 2020-07-14 | 华东师范大学 | 1-三氟甲基-四取代环戊烯衍生物及其制备方法和应用 |
| CN108047114A (zh) * | 2017-08-21 | 2018-05-18 | 华东师范大学 | 卤代三氟甲基吡咯衍生物及其制备方法和应用 |
| CN108047114B (zh) * | 2017-08-21 | 2021-05-25 | 华东师范大学 | 卤代三氟甲基吡咯衍生物及其制备方法和应用 |
| CN110028435A (zh) * | 2019-04-01 | 2019-07-19 | 浙江工业大学 | 一种合成3-甲酸酯-2-吡咯啉类化合物的方法 |
| CN110143910A (zh) * | 2019-06-03 | 2019-08-20 | 华侨大学 | 一种多取代吡咯烷酮衍生物的制备方法 |
| CN110143910B (zh) * | 2019-06-03 | 2022-04-05 | 华侨大学 | 一种多取代吡咯烷酮衍生物的制备方法 |
| CN115417852A (zh) * | 2022-09-22 | 2022-12-02 | 华东师范大学 | 5-三氟甲基-4h-噻喃衍生物及其制备方法 |
| CN115417852B (zh) * | 2022-09-22 | 2023-12-01 | 华东师范大学 | 5-三氟甲基-4h-噻喃衍生物及其制备方法 |
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