CN113501766B - Asymmetric synthesis method of multi-functional cyclopentenone derivative containing difluoroalkyl - Google Patents
Asymmetric synthesis method of multi-functional cyclopentenone derivative containing difluoroalkyl Download PDFInfo
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- CN113501766B CN113501766B CN202110770331.3A CN202110770331A CN113501766B CN 113501766 B CN113501766 B CN 113501766B CN 202110770331 A CN202110770331 A CN 202110770331A CN 113501766 B CN113501766 B CN 113501766B
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- 238000000034 method Methods 0.000 title claims abstract description 56
- BZKFMUIJRXWWQK-UHFFFAOYSA-N Cyclopentenone Chemical class O=C1CCC=C1 BZKFMUIJRXWWQK-UHFFFAOYSA-N 0.000 title claims abstract description 11
- 238000011914 asymmetric synthesis Methods 0.000 title claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims abstract description 62
- -1 furan alkene Chemical class 0.000 claims abstract description 61
- 239000007848 Bronsted acid Substances 0.000 claims abstract description 10
- 239000002994 raw material Substances 0.000 claims abstract description 7
- 239000002841 Lewis acid Substances 0.000 claims abstract description 6
- 150000007517 lewis acids Chemical class 0.000 claims abstract description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000006462 rearrangement reaction Methods 0.000 claims abstract description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 69
- 230000035484 reaction time Effects 0.000 claims description 31
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 25
- 239000011941 photocatalyst Substances 0.000 claims description 17
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 150000004820 halides Chemical class 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- XSVCYDUEICANRJ-UHFFFAOYSA-K dysprosium(3+);trifluoromethanesulfonate Chemical compound [Dy+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F XSVCYDUEICANRJ-UHFFFAOYSA-K 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 3
- 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 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 238000005576 amination reaction Methods 0.000 claims description 2
- 239000012300 argon atmosphere Substances 0.000 claims description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 230000001404 mediated effect Effects 0.000 claims description 2
- 150000003254 radicals Chemical class 0.000 claims description 2
- 239000000376 reactant Substances 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- LTVOKYUPTHZZQH-UHFFFAOYSA-N difluoromethane Chemical group F[C]F LTVOKYUPTHZZQH-UHFFFAOYSA-N 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 4
- 125000000217 alkyl group Chemical group 0.000 abstract description 3
- PQIOSYKVBBWRRI-UHFFFAOYSA-N methylphosphonyl difluoride Chemical group CP(F)(F)=O PQIOSYKVBBWRRI-UHFFFAOYSA-N 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract description 2
- 238000007171 acid catalysis Methods 0.000 abstract 1
- 238000006555 catalytic reaction Methods 0.000 abstract 1
- 238000005481 NMR spectroscopy Methods 0.000 description 121
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 102
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 102
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 72
- 238000004128 high performance liquid chromatography Methods 0.000 description 36
- 239000003208 petroleum Substances 0.000 description 35
- 239000000047 product Substances 0.000 description 35
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 34
- 229960001701 chloroform Drugs 0.000 description 34
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 30
- 238000010898 silica gel chromatography Methods 0.000 description 30
- GGYYSOXWFYFYOJ-UHFFFAOYSA-N 2-(1-phenylethenyl)furan Chemical compound C=1C=CC=CC=1C(=C)C1=CC=CO1 GGYYSOXWFYFYOJ-UHFFFAOYSA-N 0.000 description 25
- 239000003054 catalyst Substances 0.000 description 24
- 239000007810 chemical reaction solvent Substances 0.000 description 24
- IRSJDVYTJUCXRV-UHFFFAOYSA-N ethyl 2-bromo-2,2-difluoroacetate Chemical compound CCOC(=O)C(F)(F)Br IRSJDVYTJUCXRV-UHFFFAOYSA-N 0.000 description 24
- AKCRQHGQIJBRMN-UHFFFAOYSA-N 2-chloroaniline Chemical compound NC1=CC=CC=C1Cl AKCRQHGQIJBRMN-UHFFFAOYSA-N 0.000 description 22
- 239000007858 starting material Substances 0.000 description 22
- 238000002955 isolation Methods 0.000 description 20
- 238000000746 purification Methods 0.000 description 18
- 238000000926 separation method Methods 0.000 description 16
- 229910052692 Dysprosium Inorganic materials 0.000 description 15
- 229910052786 argon Inorganic materials 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 13
- 239000002585 base Substances 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- 239000000463 material Substances 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 8
- 238000004809 thin layer chromatography Methods 0.000 description 7
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 238000001291 vacuum drying Methods 0.000 description 5
- LKUDPHPHKOZXCD-UHFFFAOYSA-N 1,3,5-trimethoxybenzene Chemical compound COC1=CC(OC)=CC(OC)=C1 LKUDPHPHKOZXCD-UHFFFAOYSA-N 0.000 description 4
- PUDDYSBKCDKATP-UHFFFAOYSA-N methyl 2-amino-5-fluorobenzoate Chemical compound COC(=O)C1=CC(F)=CC=C1N PUDDYSBKCDKATP-UHFFFAOYSA-N 0.000 description 4
- VAMXMNNIEUEQDV-UHFFFAOYSA-N methyl anthranilate Chemical compound COC(=O)C1=CC=CC=C1N VAMXMNNIEUEQDV-UHFFFAOYSA-N 0.000 description 4
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 238000012512 characterization method Methods 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000012265 solid product Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000012043 crude product Substances 0.000 description 2
- 238000003818 flash chromatography Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- MAOBFOXLCJIFLV-UHFFFAOYSA-N (2-aminophenyl)-phenylmethanone Chemical compound NC1=CC=CC=C1C(=O)C1=CC=CC=C1 MAOBFOXLCJIFLV-UHFFFAOYSA-N 0.000 description 1
- QRADKVYIJIAENZ-UHFFFAOYSA-N 1-[[bromo(difluoro)methyl]-ethoxyphosphoryl]oxyethane Chemical compound CCOP(=O)(C(F)(F)Br)OCC QRADKVYIJIAENZ-UHFFFAOYSA-N 0.000 description 1
- YKGXVGQPQTWJSA-UHFFFAOYSA-N 2-(1-naphthalen-2-ylethenyl)furan Chemical compound C=C(C1=CC=CO1)C1=CC2=CC=CC=C2C=C1 YKGXVGQPQTWJSA-UHFFFAOYSA-N 0.000 description 1
- ITKIUHZTEFXXQN-UHFFFAOYSA-N 2-[1-(2-methoxyphenyl)ethenyl]furan Chemical compound COC1=CC=CC=C1C(=C)C1=CC=CO1 ITKIUHZTEFXXQN-UHFFFAOYSA-N 0.000 description 1
- XADZBHKNFIIWJC-UHFFFAOYSA-N 2-[1-(3-methoxyphenyl)ethenyl]furan Chemical compound COC1=CC=CC(C(C2=CC=CO2)=C)=C1 XADZBHKNFIIWJC-UHFFFAOYSA-N 0.000 description 1
- FGQBOWXXOVOPGL-UHFFFAOYSA-N 2-[1-(3-methylphenyl)ethenyl]furan Chemical compound CC1=CC(C(C2=CC=CO2)=C)=CC=C1 FGQBOWXXOVOPGL-UHFFFAOYSA-N 0.000 description 1
- ZZWTWSUJONTHPQ-UHFFFAOYSA-N 2-[1-(4-bromophenyl)ethenyl]furan Chemical compound C=C(C1=CC=CO1)C(C=C1)=CC=C1Br ZZWTWSUJONTHPQ-UHFFFAOYSA-N 0.000 description 1
- OXKHLMRPEWRGAY-UHFFFAOYSA-N 2-[1-(4-chlorophenyl)ethenyl]furan Chemical compound C=C(C1=CC=CO1)C(C=C1)=CC=C1Cl OXKHLMRPEWRGAY-UHFFFAOYSA-N 0.000 description 1
- PEMKKSNCBQHJHH-UHFFFAOYSA-N 2-[1-(4-fluorophenyl)ethenyl]furan Chemical compound C=C(C1=CC=CO1)C(C=C1)=CC=C1F PEMKKSNCBQHJHH-UHFFFAOYSA-N 0.000 description 1
- QNQKWMWERGQPRU-UHFFFAOYSA-N 2-[1-(4-methoxyphenyl)ethenyl]furan Chemical compound COC1=CC=C(C=C1)C(=C)C=1OC=CC=1 QNQKWMWERGQPRU-UHFFFAOYSA-N 0.000 description 1
- NZAQSMTYBKZQGZ-UHFFFAOYSA-N 2-[1-(4-methylphenyl)ethenyl]furan Chemical compound CC(C=C1)=CC=C1C(C1=CC=CO1)=C NZAQSMTYBKZQGZ-UHFFFAOYSA-N 0.000 description 1
- YUYRTLJANZZWAC-UHFFFAOYSA-N 2-bromo-2,2-difluoro-1-(4-methoxyphenyl)ethanone Chemical compound BrC(C(=O)C1=CC=C(C=C1)OC)(F)F YUYRTLJANZZWAC-UHFFFAOYSA-N 0.000 description 1
- QRVPSDIABPAOTN-UHFFFAOYSA-N 2-bromo-2,2-difluoro-1-phenylethanone Chemical compound FC(F)(Br)C(=O)C1=CC=CC=C1 QRVPSDIABPAOTN-UHFFFAOYSA-N 0.000 description 1
- LYWHFGULCWQURX-UHFFFAOYSA-N 2-bromo-2,2-difluoro-1-piperidin-1-ylethanone Chemical compound FC(F)(Br)C(=O)N1CCCCC1 LYWHFGULCWQURX-UHFFFAOYSA-N 0.000 description 1
- BYNRYSMTUCTWQO-UHFFFAOYSA-N 2-bromo-2,2-difluoro-n-phenylacetamide Chemical compound FC(F)(Br)C(=O)NC1=CC=CC=C1 BYNRYSMTUCTWQO-UHFFFAOYSA-N 0.000 description 1
- PSUBGTBDOZWLQV-UHFFFAOYSA-N 2-bromo-N-cyclohexyl-2,2-difluoroacetamide Chemical compound FC(F)(Br)C(=O)NC1CCCCC1 PSUBGTBDOZWLQV-UHFFFAOYSA-N 0.000 description 1
- BOHBJODHDSWYFG-UHFFFAOYSA-N 2-bromo-n,n-diethyl-2,2-difluoroacetamide Chemical compound CCN(CC)C(=O)C(F)(F)Br BOHBJODHDSWYFG-UHFFFAOYSA-N 0.000 description 1
- AOPBDRUWRLBSDB-UHFFFAOYSA-N 2-bromoaniline Chemical compound NC1=CC=CC=C1Br AOPBDRUWRLBSDB-UHFFFAOYSA-N 0.000 description 1
- PNPCRKVUWYDDST-UHFFFAOYSA-N 3-chloroaniline Chemical compound NC1=CC=CC(Cl)=C1 PNPCRKVUWYDDST-UHFFFAOYSA-N 0.000 description 1
- QSNSCYSYFYORTR-UHFFFAOYSA-N 4-chloroaniline Chemical compound NC1=CC=C(Cl)C=C1 QSNSCYSYFYORTR-UHFFFAOYSA-N 0.000 description 1
- ODGIMMLDVSWADK-UHFFFAOYSA-N 4-trifluoromethylaniline Chemical compound NC1=CC=C(C(F)(F)F)C=C1 ODGIMMLDVSWADK-UHFFFAOYSA-N 0.000 description 1
- 241000662429 Fenerbahce Species 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000007805 chemical reaction reactant Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 238000004896 high resolution mass spectrometry Methods 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 239000008204 material by function Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- CEKCJQBZVNIMLD-UHFFFAOYSA-N methyl 2-amino-4-methoxybenzoate Chemical compound COC(=O)C1=CC=C(OC)C=C1N CEKCJQBZVNIMLD-UHFFFAOYSA-N 0.000 description 1
- VAQBJVZNPBNHGC-UHFFFAOYSA-N methyl 2-amino-4-methylbenzoate Chemical compound COC(=O)C1=CC=C(C)C=C1N VAQBJVZNPBNHGC-UHFFFAOYSA-N 0.000 description 1
- IGHVUURTQGBABT-UHFFFAOYSA-N methyl 2-amino-5-chlorobenzoate Chemical compound COC(=O)C1=CC(Cl)=CC=C1N IGHVUURTQGBABT-UHFFFAOYSA-N 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- FVNLXKRZPJQKCA-UHFFFAOYSA-N n-benzyl-2-bromo-2,2-difluoroacetamide Chemical compound FC(F)(Br)C(=O)NCC1=CC=CC=C1 FVNLXKRZPJQKCA-UHFFFAOYSA-N 0.000 description 1
- UTUYWZJPVLDHJJ-UHFFFAOYSA-N n-methyl-4-(trifluoromethyl)aniline Chemical compound CNC1=CC=C(C(F)(F)F)C=C1 UTUYWZJPVLDHJJ-UHFFFAOYSA-N 0.000 description 1
- GTDQGKWDWVUKTI-UHFFFAOYSA-N o-aminoacetophenone Chemical compound CC(=O)C1=CC=CC=C1N GTDQGKWDWVUKTI-UHFFFAOYSA-N 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000004575 stone Substances 0.000 description 1
- 238000010200 validation analysis Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/16—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions not involving the amino or carboxyl groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
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- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D295/182—Radicals derived from carboxylic acids
- C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/66—Nitrogen atoms
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4056—Esters of arylalkanephosphonic acids
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4071—Esters thereof the ester moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4075—Esters with hydroxyalkyl compounds
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- C07C2601/10—Systems containing only non-condensed rings with a five-membered ring the ring being unsaturated
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Abstract
The invention provides an asymmetric synthesis method of a multi-functional cyclopentenone derivative containing a difluoro alkyl group. The chiral multifunctional cyclopentenone derivative containing difluoro alkyl is synthesized by combining visible light catalysis, chiral Bronsted acid and achiral Lewis acid catalysis, and carrying out asymmetric three-component aza-Piancateli rearrangement reaction by taking furan alkene, difluoro alkyl halide and aromatic amine compound as raw materials. The method has mild reaction conditions, high yield, excellent enantioselectivity and diastereoselectivity and potential application value in the aspect of drug synthesis.
Description
Technical Field
The invention belongs to the field of asymmetric synthesis in organic chemistry, and particularly relates to an asymmetric synthesis method of a multi-functional cyclopentenone derivative containing difluoro alkyl groups.
Background
Because of the unique properties of fluorine atoms, fluorine-containing organic compounds are widely used in the fields of medicine, pesticides, functional materials, life sciences, and the like. The introduction of difluoroalkyl can obviously improve the metabolic stability and the oral bioavailability of molecules, and has become an important means for drug development. However, there is no report on a method of introducing a difluoroalkyl group in a cyclopentenone side chain which is an important intermediate for organic synthesis. Therefore, it is of great importance to develop a simple and efficient method for achieving asymmetric synthesis of a multi-functional cyclopentenone derivative containing a difluoroalkyl group.
Disclosure of Invention
The invention aims to provide an asymmetric synthesis method of a multi-functional cyclopentenone derivative containing a difluoroalkyl group.
In order to achieve the above purpose, the technical scheme adopted by the invention comprises the following steps:
step S1, carrying out free radical mediated three-component difluoroalkylation amination reaction by taking furan alkene, aromatic amine compound and difluoroalkyl halide as raw materials under visible light, wherein the reaction formula is as follows:
step S2 is to take intermediate IV, add chiral bronsted acid (b×h) and achiral Lewis Acid (LA), and perform an asymmetric rearrangement reaction in an organic solvent to obtain product V, which has the following reaction formula:
wherein the method comprises the steps of
R is phenyl, 2-naphthyl or benzene ring containing substituent, and the substituent on the benzene ring is one of methyl, methoxy or halogen;
R 1 is H or methyl;
ar is benzene ring connected with different groups of electron withdrawing or electron donating, wherein the different groups are one or two of methyl, methoxy, halogen, ester, trifluoromethyl, benzoyl or acetyl.
R F The raw material of the difluoroalkyl halide is selected from one of the following structural formulas of the compounds:
the photocatalyst described in step S1 is mer-Ir (ppy) 3 The alkali is potassium carbonate, and the reaction temperature is room temperature;
the achiral Lewis acid in the step S2 is dysprosium triflate, and the reaction temperature is room temperature;
the chiral bronsted acid in step S2 has the following structural formula:
the implementation operation of the technical scheme comprises the following steps:
step S1, photo-catalyst mer-Ir (ppy) 3 And K 2 CO 3 Placing the mixture in a reaction tube, and placing a magnetic stirrer with proper size. And (3) vacuumizing and drying, replacing three times by using argon, and adding acetonitrile under the protection of the argon. Then furan alkene, aromatic amine compound and difluoro alkyl halide are added in turn. The reaction mixture was degassed with argon for 5 min, then reacted at room temperature under blue LED lamp irradiation, and the reaction was monitored by TLC. When TLC showed complete conversion of arylamine compounds (t 1 ) The reaction mixture was filtered through celite, washed with dichloromethane and concentrated to give crude intermediate IV which was used directly in the next step.
Step S2 Dy (OTf) 3 And Bronsted acid A1 are placed in a reaction tube and placed in a magnetic stirrer of suitable size. Vacuum drying, replacing three times with argon, adding chloroform under the protection of argon, and stirring for 1 min at room temperature. Subsequently, intermediate IV obtained in step 1 was dissolved in chloroform and added to the reaction mixture to react at room temperature. After the reaction is finishedAdult (t) 2 ) After flash column chromatography, 1,3, 5-trimethoxybenzene was used as an internal standard to perform 1 H NMR characterization to determine the nuclear magnetic yield and dr values of the product. The crude product was further purified by column chromatography on silica gel to give the major diastereoisomer of the product and its corresponding isolated yields. The ee value is determined by chiral analysis by liquid chromatography (HPLC).
In the preparation method, the dosage ratio of furan alkene, aromatic amine compound and difluoroalkyl halide in the reaction in the step S1 is 0.24 mmol/0.20 mmol/0.40 mmol.
In the preparation method of the invention, the mer-Ir (ppy) in the step S1 reaction 3 The molar amount of (C) is 0.33% of that of the arylamine compound.
In the preparation method, the dosage ratio of the potassium carbonate to the arylamine compound in the reaction in the step S1 is 0.4mmol to 0.20mmol.
In the preparation method of the invention, the reaction time t in the step S1 reaction 1 10-96h.
In the preparation method, the organic solvent in the reaction in the step S1 is acetonitrile, the volume ratio of the substance amount of the arylamine compound to the acetonitrile is 0.1 mmol/2 mL, and the reaction is carried out in an argon atmosphere.
In the preparation method, visible light is provided by a blue LED lamp with the power of 3W and the wavelength of 460-465nm in the reaction in the step S1, and the distance between the blue lamp and the reactant is 4cm.
In the preparation method of the invention, dy (OTf) in the reaction of the step S2 3 The molar dosage of the chiral Bronsted acid A1 is 0.33 percent and 1 percent of that of the arylamine compound respectively.
In the preparation method of the invention, the organic solvent in the step S2 reaction is chloroform, the solvent dosage is 2mL, and the reaction time t is 2 3-120h.
The asymmetric synthesis method of the multi-functional cyclopentenone derivative containing the difluoro alkyl group has the advantages of mild reaction conditions, excellent enantioselectivity and diastereoselectivity, high chemical yield and potential practical application value in the aspect of drug synthesis.
The specific embodiment is as follows:
the monitoring method in any one of the embodiments of the present invention is: thin layer chromatography.
The structural validation techniques are all general techniques known to those skilled in the art: nuclear magnetic resonance technology, high resolution mass spectrometry.
The invention will be further illustrated with reference to the following examples, which are not intended to limit the same.
Example 1
Synthetic route for 3- ((1 r,2 r) -2- ((2-chlorophenyl) amino) -5-oxo-1-phenylcyclopent-3-en-1-yl) -2, 2-difluoropropionic acid ethyl ester (V-1) of the present invention:
Characterization data of the resulting structural formula 1:
yellow oil, 77% nuclear magnetic yield, 72% isolation yield, 18/1dr. HPLC analysis gave 94% ee (FLM Chiral INB, hexane/i-PrOH=90/10, flow rate=1.0 mL/min, l=254 nm), t r (major)=14.1min,t r (minor)=11.0min;[α] D 20 =–98.7(c=0.82,in CHCl 3 ). 1 H NMR(500MHz,CDCl 3 )δ7.63–7.56(m,1H),7.30–7.26(m,3H),7.21–7.13(m,2H),7.08–7.02(m,2H),6.90(d,J=8.2Hz,1H),6.65(t,J=7.6Hz,1H),6.59(d,J=5.7Hz,1H),5.44(d,J=10.3Hz,1H),4.31(q,J=7.1Hz,2H),3.84(d,J=10.4Hz,1H),3.28–3.00(m,2H),1.34(t,J=7.1Hz,3H). 13 C NMR(126MHz,CDCl 3 )δ207.4,163.5(t,J=32.8),161.7,142.0,138.3,134.6,129.5,128.8,128.1,128.0,127.7,119.9,118.3,115.5(t,J=251.8Hz),111.5,63.4,59.8(t,J=6.3Hz),57.4,39.0(t,J=21.7Hz),13.9. 19 F NMR(377MHz,CDCl 3 )δ-95.8(d,J=262.2Hz),-102.2(d,J=262.3Hz).HRMS(ESI)m/z calcd.For C 22 H 20 ClF 2 NNaO 3 [M+Na] + 442.0992,found 442.1010.
Example 2
3- ((1 r,2 r) -2- ((2-chlorophenyl) amino) -1- (4-methoxyphenyl) -5-oxocyclopent-3-en-1-yl) -2, 2-difluoropropionic acid ethyl ester (V-2):
with 2- (1- (4-methoxyphenyl) vinyl) furan (0.24 mmol,1.2 eq), 2-chloroaniline (0.2 mmol,1.0 eq) and ethyl 2-bromo-2, 2-difluoroacetate (0.4 mmol,2.0 e)q) is used as a reaction raw material, and the reaction time is t 1 =16h,t 2 =16h, the rest of the procedure is the same as in example 1. Purifying by silica gel column chromatography (petroleum ether/ethyl acetate=6/1-4/1) to obtain yellow oily product V-2 with nuclear magnetic resonance yield of 60% and isolation yield of 57%,>20/1dr. HPLC analysis gave 94% ee (FLM Chiral INB, hexane/i-PrOH=90/10, flow rate=1.0 mL/min, l=254 nm), t r (major)=15.3min,t r (minor)=12.6min;[α] D 20 =–101.6(c=0.88,in CHCl 3 ). 1 H NMR(500MHz,CDCl 3 )δ7.61–7.56(m,1H),7.22–7.13(m,2H),6.98(d,J=7.3Hz,2H),6.90(d,J=8.1Hz,1H),6.80(d,J=7.3Hz,2H),6.66(t,J=7.6Hz,1H),6.59–6.56(m,1H),5.39(d,J=10.2Hz,1H),4.30(q,J=7.3,5.0Hz,2H),3.87(d,J=11.4Hz,1H),3.77(s,3H),3.20–2.95(m,2H),1.34(t,J=7.0Hz,3H). 13 C NMR(126MHz,CDCl 3 )δ207.4,163.7(t,J=32.1),161.6,159.1,142.1,134.4,130.2,129.5,128.9,128.0,119.9,118.2,115.2(t,J=260.4Hz),114.2,111.6,63.4,59.7–59.2(m),56.8,55.4,39.1(t,J=22.4Hz),13.9. 19 F NMR(377MHz,CDCl 3 )δ-95.9(d,J=262.2Hz),-102.5(d,J=262.3Hz).HRMS(ESI)m/z calcd.For C 23 H 22 ClF 2 NNaO 4 [M+Na] + 472.1098,found 472.1104.
Example 3
3- ((1 r,2 r) -2- ((2-chlorophenyl) amino) -1- (4-methylphenyl) -5-oxocyclopent-3-en-1-yl) -2, 2-difluoropropionic acid ethyl ester (V-3):
2- (1- (4-methylphenyl) vinyl) furan (0.24 mmol,1.2 eq), 2-chloroaniline (0.2 mmol,1.0 eq) and ethyl 2-bromo-2, 2-difluoroacetate (0.4 mmol,2.0 eq) were used as reaction materials, the reaction time was t 1 =16h,t 2 =16h, 4mL chloroform as reaction solvent used in step 2, 2mol% dy (OTf) as catalyst 3 6mol% A1, the remainder of the procedure being as in example 1. Purification by silica gel column chromatography (petroleum ether/ethyl acetate=8/1-6/1) gives the product V-3 as a yellow oil, nucleiThe magnetic yield is 54%, the separation yield is 52%,>20/1dr. HPLC analysis gave 94% ee (FLM Chiral INB, hexane/i-PrOH=90/10, flow rate=1.0 mL/min, l=254 nm), t r (major)=11.0min,t r (minor)=8.9min;[α] D 20 =–92.9(c=0.90,in CHCl 3 ). 1 H NMR(500MHz,CDCl 3 )δ7.59–7.56(m,1H),7.20–7.13(m,2H),6.97(d,J=8.7Hz,2H),6.90(d,J=8.2Hz,1H),6.80(d,J=8.6Hz,2H),6.65(t,J=7.6Hz,1H),6.58–6.54(m,1H),5.39(d,J=10.3Hz,1H),4.29(q,J=7.1Hz,2H),3.87(d,J=10.3Hz,1H),3.76(s,3H),3.25–2.94(m,2H),1.34(t,J=7.1Hz,3H). 13 C NMR(126MHz,CDCl 3 )δ207.4,163.5(t,J=29.2Hz),161.7,159.1,142.0,134.4,130.2,129.5,128.9,128.0,119.9,118.2,115.4(t,J=223.9Hz),114.2,111.5,63.4,59.9–59.7(m),56.8,55.4,39.1(t,J=22.0Hz),13.9. 19 F NMR(564MHz,CDCl 3 )δ-95.8(d,J=262.5Hz),-102.4(d,J=262.1Hz).HRMS(ESI)m/z calcd.For C 23 H 22 ClF 2 NNaO 3 [M+Na] + 456.1148,found 456.1154.
Example 4
3- ((1 r,2 r) -1- ((1, 1' -biphenyl) -4-yl) -2- ((chlorophenyl) amino) -5-oxocyclopent-3-en-1-yl) -2, 2-difluoropropionic acid ethyl ester (V-4):
2- (1- ((1, 1' -biphenyl) -4-yl) vinyl) furan (0.24 mmol,1.2 eq), 2-chloroaniline (0.2 mmol,1.0 eq) and ethyl 2-bromo-2, 2-difluoroacetate (0.4 mmol,2.0 eq) were used as reaction materials, the reaction time was t 1 =10h,t 2 =34 h, the rest of the procedure is the same as in example 1. Purifying by silica gel column chromatography (petroleum ether/ethyl acetate=10/1-8/1) to obtain yellow solid product V-4 with nuclear magnetic resonance yield of 54% and separation yield of 51%,>20/1dr. HPLC analysis gave 93% ee (Chiralcel AD-H, hexane/i-PrOH=90/10, flow rate=1.0 mL/min, l=254 nm), t r (major)=13.9min,t r (minor)=18.4min;[α] D 20 =–26.9(c=0.90,in CHCl 3 );mp=123–125℃. 1 H NMR(500MHz,CDCl 3 )δ7.65–7.60(m,1H),7.52(d,J=7.4Hz,2H),7.48(d,J=8.2Hz,2H),7.43(t,J=7.5Hz,2H),7.35(t,J=7.2Hz,1H),7.19(t,J=7.8Hz,1H),7.14(d,J=7.9Hz,1H),7.10(d,J=8.2Hz,2H),6.93(d,J=8.2Hz,1H),6.66(t,J=7.6Hz,1H),6.61(d,J=5.7Hz,1H),5.48(d,J=10.0Hz,1H),4.32(q,J=7.1Hz,2H),3.90(d,J=10.5Hz,1H),3.30–3.01(m,2H),1.35(t,J=7.1Hz,3H). 13 C NMR(126MHz,CDCl 3 )δ207.4,163.6(t,J=31.6Hz),161.9,142.0,140.9,140.3,137.2,134.6,129.6,128.7,128.0,127.6,127.4,127.1,120.0,118.4,115.6(t,J=253.2Hz),111.6,63.5,60.0(t,J=3.6Hz),57.3,39.0(t,J=21.9Hz),13.9. 19 F NMR(564MHz,CDCl 3 )δ-95.8(d,J=262.6Hz),-102.3(d,J=262.7Hz).HRMS(ESI)m/z calcd.For C 28 H 24 ClF 2 NNaO 3 [M+Na] + 518.1305,found 518.1312.
Example 5
3- ((1 r,2 r) -2- ((2-chlorophenyl) amino) -1- (4-fluorophenyl) -5-oxocyclopent-3-en-1-yl) -2, 2-difluoropropionic acid ethyl ester (V-5):
2- (1- (4-fluorophenyl) vinyl) furan (0.24 mmol,1.2 eq), 2-chloroaniline (0.2 mmol,1.0 eq) and ethyl 2-bromo-2, 2-difluoroacetate (0.4 mmol,2.0 eq) were used as reaction materials, the reaction time was t 1 =10h,t 2 =11h, the rest of the procedure is the same as in example 1. Purification by column chromatography on silica gel (petroleum ether/ethyl acetate=8/1-5/1) afforded the product V-5 as a yellow oil in 80% nuclear magnetic yield, 74% isolation yield, 19/1dr. HPLC analysis gave 96% ee (FLM Chiral NS, hexane/i-PrOH=90/10, flow rate=1.0 mL/min, l=254 nm), t r (major)=8.3min,t r (minor)=10.3min;[α] D 20 =–105.1(c=0.92,in CHCl 3 ). 1 H NMR(500MHz,CDCl 3 )δ7.63–7.58(m,1H),7.21–7.14(m,2H),7.04–6.99(m,2H),6.95(t,J=8.5Hz,2H),6.91(d,J=8.1Hz,1H),6.67(t,J=7.6Hz,1H),6.60–6.56(m,1H),5.48–5.35(m,1H),4.31(q,J=7.1Hz,2H),3.79(br,1H),3.20–2.99(m,2H),1.35(t,J=7.1Hz,3H). 13 C NMR(126MHz,CDCl 3 )δ207.2,163.4(t,J=32.4Hz),162.1(d,J=248.7Hz),161.8,141.8,134.1(d,J=3.1Hz),134.1,129.6(d,J=2.4Hz),129.5,128.1,119.9,118.5,115.6(d,J=21.5Hz),115.5(t,J=253.7Hz),111.6,63.5,60.0(t,J=3.0Hz),56.9,39.4(t,J=22.2Hz),13.9. 19 F NMR(564MHz,CDCl 3 )δ-96.1(ddd,J=263.0,24.7,14.0Hz),-102.2(ddd,J=263.0,19.9,12.7Hz),-113.9–-113.9(m).HRMS(ESI)m/z calcd.For C 22 H 19 ClF 3 NNaO 3 [M+Na] + 460.0898,found 460.0903.
Example 6
3- ((1 r,2 r) -1- (4-chlorophenyl) -2- ((2-chlorophenyl) amino) -5-oxocyclopent-3-en-1-yl) -2, 2-difluoropropionic acid ethyl ester (V-6):
2- (1- (4-chlorophenyl) vinyl) furan (0.24 mmol,1.2 eq), 2-chloroaniline (0.2 mmol,1.0 eq) and ethyl 2-bromo-2, 2-difluoroacetate (0.4 mmol,2.0 eq) were used as reaction materials, the reaction time was t 1 =16h,t 2 =16h, 4mL chloroform as reaction solvent used in step 2, 2mol% dy (OTf) as catalyst 3 6mol% A1, the remainder of the procedure being as in example 1. Purification by column chromatography on silica gel (petroleum ether/ethyl acetate=10/1-8/1) gave the product V-6 as a yellow oil in a nuclear magnetic yield of 39%, isolation yield of 34%,13/1dr. HPLC analysis gave 91% ee (FLM Chiral INB, hexane/i-PrOH=90/10, flow rate=1.0 mL/min, l=254 nm), t r (major)=15.7min,t r (minor)=12.6min;[α] D 20 =–77.3(c=0.64,in CHCl 3 ). 1 H NMR(500MHz,CDCl 3 )δ7.61–7.60(m,1H),7.23(d,J=8.0Hz,2H),7.18(t,J=8.4Hz,2H),6.97(d,J=7.9Hz,2H),6.91(d,J=8.0Hz,1H),6.68(t,J=7.5Hz,1H),6.58(d,J=5.2Hz,1H),5.45(d,J=10.7Hz,1H),4.31(q,J=6.9Hz,2H),3.80(d,J=10.6Hz,1H),3.22–2.96(m,2H),1.35(t,J=7.0Hz,3H). 13 C NMR(126MHz,CDCl 3 )δ206.9,163.3(t,J=32.3Hz),161.8,141.8,136.8,134.5,134.1,130.4,129.6,129.1,128.8,128.3,128.1,127.8,120.0,118.6,116.0(t,J=252.8Hz),111.6,60.0(t,J=3.8Hz),57.1,39.2(t,J=22.1Hz),13.9. 19 F NMR(564MHz,CDCl 3 )δ-96.0(d,J=262.9Hz),-102.2(d,J=263.3Hz).HRMS(ESI)m/z calcd.For C 22 H 19 Cl 2 F 2 NNaO 3 [M+Na] + 476.0602,found 476.0608.
Example 7
3- ((1 r,2 r) -1- (4-bromophenyl) -2- ((2-chlorophenyl) amino) -5-oxocyclopent-3-en-1-yl) -2, 2-difluoropropionic acid ethyl ester (V-7):
2- (1- (4-bromophenyl) vinyl) furan (0.24 mmol,1.2 eq), 2-chloroaniline (0.2 mmol,1.0 eq) and ethyl 2-bromo-2, 2-difluoroacetate (0.4 mmol,2.0 eq) were used as starting materials for reaction for a period of time t 1 =10h,t 2 =11h, the rest of the procedure is the same as in example 1. Purification by silica gel column chromatography (petroleum ether/ethyl acetate=10/1-8/1) gave the product V-7 as a yellow oil, yield 74% nuclear magnetic resonance, isolation yield 63%,9/1dr. HPLC analysis gave 94% ee (FLM Chiral INB, hexane/i-PrOH=90/10, flow rate=1.0 mL/min, l=254 nm), t r (major)=15.6min,t r (minor)=13.0min;[α] D 20 =–93.8(c=0.88,in CHCl 3 ). 1 H NMR(500MHz,CDCl 3 )δ7.63–7.58(m,1H),7.33–7.28(m,3H),7.21(t,J=7.6Hz,1H),7.10–7.03(m,2H),6.87(d,J=8.0Hz,1H),6.62–6.56(m,2H),5.42(d,J=10.2Hz,1H),4.31(q,J=6.6Hz,2H),3.86(d,J=10.1Hz,1H),3.31–2.97(m,2H),1.35(t,J=6.9Hz,3H). 13 C NMR(126MHz,CDCl 3 )δ207.3,163.5(t,J=32.5Hz),161.6,142.9,138.3,134.6,132.9,128.9,128.7,128.1,127.7,118.8,115.6(t,J=253.6Hz),111.5,110.4,63.4,59.9(t,J=3.4Hz),57.3,38.9(t,J=21.9Hz),13.9. 19 F NMR(564MHz,CDCl 3 )δ-96.0(d,J=262.8Hz),-102.1(d,J=263.0Hz).HRMS(ESI)m/z calcd.For C 22 H 19 BrClF 2 NNaO 3 [M+Na] + 520.0097,found 520.0104.
Example 8
3- ((1 r,2 r) -2- ((2-chlorophenyl) amino) -1- (2-methoxyphenyl) -5-oxocyclopent-3-en-1-yl) -2, 2-difluoropropionic acid ethyl ester (V-8):
2- (1- (2-methoxyphenyl) vinyl) furan (0.24 mmol,1.2 eq), 2-chloroaniline (0.2 mmol,1.0 eq) and ethyl 2-bromo-2, 2-difluoroacetate (0.4 mmol,2.0 eq) were used as reaction materials, the reaction time was t 1 =16h,t 2 =16h, the reaction solvent used in step 2 was 4mL of chloroform; the catalyst dosage is 2mol percent Dy (OTf) 3 6mol% A1, the remainder of the procedure being as in example 1. Purifying by silica gel column chromatography (petroleum ether/ethyl acetate=15/1-10/1) to obtain yellow oily product V-8 with nuclear magnetic resonance yield of 74% and separation yield of 69%,>16/1dr. HPLC analysis gave 92% ee (Chiralcel IA, hexane/i-PrOH=90/10, flow rate=1.0 mL/min, l=254 nm), t r (major)=11.6min,t r (minor)=9.7min;[α] D 20 =–53.8(c=0.78,in CHCl 3 ). 1 H NMR(500MHz,CDCl 3 )δ7.52–7.44(m,1H),7.15(t,J=6.4Hz,1H),7.08–6.97(m,3H),6.82–6.67(m,3H),6.50(t,J=6.5Hz,1H),6.45–6.40(m,1H),5.29(s,1H),4.62–4.18(m,3H),3.58(s,3H),3.30(s,1H),3.05(q,J=16.7Hz,1H),1.35(t,J=6.7Hz,3H). 13 C NMR(126MHz,CDCl 3 )δ208.8,163.6(t,J=32.2Hz),156.7,143.4,142.7,133.8,129.7,129.2,129.2,128.4,127.5,120.8,118.9,117.5,114.8(t,J=253.6Hz),112.1,111.1,63.3,61.4–61.1(m),55.6,54.7,40.0–39.3(m),13.9. 19 F NMR(564MHz,CDCl 3 )δ-99.1(d,J=264.4Hz),-100.2(d,J=264.2Hz).HRMS(ESI)m/z calcd.For C 23 H 22 ClF 2 NNaO 4 [M+Na] + 472.1098,found 472.1103.
Example 9
3- ((1 r,2 r) -2- ((2-chlorophenyl) amino) -1- (3-methoxyphenyl) -5-oxocyclopent-3-en-1-yl) -2, 2-difluoropropionic acid ethyl ester (V-9):
2- (1- (3-methoxyphenyl) vinyl) furan (0.24 mmol,1.2 eq), 2-chloroaniline (0.2 mmol,1.0 eq) and ethyl 2-bromo-2, 2-difluoroacetate (0.4 mmol,2.0 eq) were used as reaction materials, the reaction time was t 1 =16h,t 2 =40 h, the reaction solvent used in step 2 was 4mL chloroform, the catalyst dose was 2mol% dy (OTf) 3 6mol% A1, the remainder of the procedure being as in example 1. Purification by silica gel column chromatography (petroleum ether/chloroform=6/1-4/1) gave the product V-9 as a yellow oil with a nuclear magnetic resonance yield of 49%, a separation yield of 40%,7.2/1dr. HPLC analysis gave 93% ee (FLM Chiral INB, hexane/i-PrOH=90/10, flow rate=1.0 mL/min, l=254 nm), t r (major)=16.3min,t r (minor)=13.1min;[α] D 20 =–110.6(c=0.91,in CHCl 3 ). 1 H NMR(500MHz,CDCl 3 )δ7.61–7.58(m,1H),7.23–7.13(m,3H),6.91(d,J=8.1Hz,1H),6.81(d,J=8.3Hz,1H),6.68–6.57(m,3H),6.54(s,1H),5.43(d,J=10.5Hz,1H),4.31(q,J=7.1Hz,2H),3.92(d,J=10.5Hz,1H),3.65(s,3H),3.24–2.99(m,2H),1.35(t,J=7.1Hz,3H). 13 C NMR(126MHz,CDCl 3 )δ207.1,162.7(t,J=34.9Hz),161.7,159.7,142.1,139.6,134.5,129.8,129.5,128.0,119.8,119.8,118.2,115.7(t,J=249.2Hz),113.9,113.4,111.5,63.4,59.8(t,J=2.7Hz),57.4,55.2,39.0(t,J=21.8Hz),13.9. 19 F NMR(377MHz,CDCl 3 )δ-95.6(d,J=262.2Hz),-102.5(d,J=262.3Hz).HRMS(ESI)m/z calcd.For C 23 H 22 ClF 2 NNaO 4 [M+Na] + 472.1098,found 472.1102.
Example 10
3- ((1 r,2 r) -2- ((2-chlorophenyl) amino) -5-oxo-1- (m-methylphenyl) cyclopent-3-en-1-yl) -2, 2-difluoropropionic acid ethyl ester (V-10):
2- (1- (m-tolyl) vinyl) furan (0.24 mmol,1.2 eq), 2-chloroaniline (0.2 mmol,1.0 eq) and ethyl 2-bromo-2, 2-difluoroacetate (0.4 mmol,2.0 eq) were used as starting materials for reaction for a period of time t 1 =20h,t 2 =3h, 4mL chloroform as reaction solvent used in step 2, 2mol% dy (OTf) as catalyst 3 6mol% A1, the remainder of the procedure being as in example 1. Purifying by silica gel column chromatography (petroleum ether/ethyl acetate=8/1-6/1) to obtain yellow oily product V-10 with nuclear magnetic resonance yield of 42% and separation yield of 39%,>20/1dr. HPLC analysis gave 89% ee (FLM Chiral NS, hexane/i-PrOH=90/10, flow rate=1.0 mL/min, l=254 nm), t r (major)=6.1min,t r (minor)=8.0min;[α] D 20 =–78.5(c=0.45,in CHCl 3 ). 1 H NMR(500MHz,CDCl 3 )δ7.60–7.57(m,1H),7.22–7.13(m,3H),7.08(d,J=7.5Hz,1H),6.91(d,J=8.2Hz,1H),6.82(d,J=10.0Hz,2H),6.65(t,J=7.6Hz,1H),6.58(d,J=5.7Hz,1H),5.43(s,1H),4.30(q,J=7.1Hz,2H),3.87(br,1H),3.25–2.96(m,2H),2.23(s,3H),1.34(t,J=7.1Hz,3H). 13 C NMR(126MHz,CDCl 3 )δ207.5,163.6(t,J=62.5Hz),161.7,142.1,138.5,138.1,134.5,129.5,128.8,128.7,128.5,128.0,124.6,119.8,118.2,115.6(t,J=253.6Hz),111.5,63.4,59.8(t,J=3.5Hz),57.4,39.1(t,J=21.9Hz),21.6,13.9. 19 F NMR(564MHz,CDCl 3 )δ-95.7(d,J=261.8Hz),-102.4(d,J=262.5Hz).HRMS(ESI)m/z calcd.For C 23 H 22 ClF 2 NNaO 3 [M+Na] + 456.1148,found 456.1153.
Example 11
3- ((1 r,2 r) -2- ((2-chlorophenyl) amino) -1- (naphthalen-2-yl) -5-oxocyclopent-3-en-1-yl) -2, 2-difluoropropionic acid ethyl ester (V-11):
2- (1- (naphthalene-2-yl) vinyl) furan (0.24 mmol,1.2 eq), 2-chloroaniline (0.2 mmol,1.0 eq) and ethyl 2-bromo-2, 2-difluoroacetate (0.4 mmol,2.0 eq) were used as reaction materials, the reaction time was t 1 =16h,t 2 =3h, use in step 2The reaction temperature of (2) is 10 ℃, the reaction solvent is 4mL of chloroform, and the catalyst dosage is 2mol% Dy (OTf) 3 6mol% A1, the remainder of the procedure being as in example 1. Purifying by silica gel column chromatography (petroleum ether/chloroform=10/1-8/1) to obtain yellow oily product V-11 with nuclear magnetic resonance yield of 52% and separation yield of 50%,>20/1dr. HPLC analysis gave 94% ee (FLM Chiral INB, hexane/i-PrOH=90/10, flow rate=1.0 mL/min, l=254 nm), t r (major)=13.8min,t r (minor)=13.0min;[α] D 20 =–49.6(c=0.81,in CHCl 3 ). 1 H NMR(500MHz,CDCl 3 )δ7.78(d,J=7.6Hz,1H),7.74(d,J=8.7Hz,1H),7.69(d,J=7.6Hz,1H),7.64–7.60(m,1H),7.50–7.43(m,3H),7.22–7.15(m,2H),7.07(d,J=7.9Hz,1H),6.96(d,J=8.2Hz,1H),6.70–6.61(m,2H),5.52(d,J=10.0Hz,1H),4.32(q,J=7.2Hz,2H),3.87(d,J=10.6Hz,1H),3.39–3.12(m,2H),1.35(t,J=7.2Hz,3H). 13 C NMR(126MHz,CDCl 3 )δ207.2,163.6(t,J=34.4Hz),161.8,142.0,135.5,134.5,133.0,132.5,129.5,128.4,128.2,128.0,127.4,127.4,126.7,126.5,125.2,119.9,118.3,115.7(t,J=253.3Hz),111.6,63.5,60.0(t,J=3.2Hz),57.7,39.3(t,J=21.9Hz),13.9. 19 F NMR(564MHz,CDCl 3 )δ-95.2–-96.3(m),-101.9–-102.8(m).HRMS(ESI)m/z calcd.For C 26 H 22 ClF 2 NNaO 3 [M+Na] + 492.1148,found 492.1173.
Example 12
3- ((1 r,2 r) -2- ((2-bromophenyl) amino) -5-oxo-1-phenylcyclopent-3-en-1-yl) -2, 2-difluoropropionate (V-12):
2- (1-Phenylvinyl) furan (0.24 mmol,1.2 eq), 2-bromoaniline (0.2 mmol,1.0 eq) and ethyl 2-bromo-2, 2-difluoroacetate (0.4 mmol,2.0 eq) were used as starting materials for a reaction time t 1 =16h,t 2 =10h, 4mL chloroform as reaction solvent used in step 2, 2mol% dy (OTf) as catalyst 3 6mol% A1, the remainder of the procedure being as in example 1. Purification by silica gel column chromatography (Stone)Oil ether/ethyl acetate=8/1-6/1), to give the product V-12 as a yellow oil, a nuclear magnetic yield of 42%, a separation yield of 39%,>20/1dr. HPLC analysis gave 95% ee (FLM Chiral INB, hexane/i-PrOH=90/10, flow rate=1.0 mL/min, l=254 nm), t r (major)=14.4min,t r (minor)=10.1min;[α] D 20 =–131.6(c=0.8,in CHCl 3 ). 1 H NMR(500MHz,CDCl 3 )δ7.63–7.58(m,1H),7.34–7.27(m,4H),7.21(t,J=7.5Hz,1H),7.11–7.04(m,2H),6.87(d,J=8.1Hz,1H),6.63–6.55(m,2H),5.42(d,J=10.2Hz,1H),4.31(q,J=6.6Hz,2H),3.86(d,J=10.1Hz,1H),3.27–3.00(m,2H),1.35(t,J=6.9Hz,3H). 13 C NMR(126MHz,CDCl 3 )δ207.3,163.5(t,J=32.4Hz),161.6,142.9,138.3,134.5,132.8,128.9,128.7,128.1,127.7,118.8,115.63(dd,J=255.8,250.4Hz),111.5,110.4,63.4,59.9(t,J=6.3Hz),57.3,38.9(t,J=21.9Hz),13.9. 19 F NMR(564MHz,CDCl 3 )δ-95.8(d,J=262.6Hz),-102.3(d,J=262.5Hz).HRMS(ESI)m/z calcd.For C 22 H 20 BrF 2 NNaO 3 [M+Na] + 486.0487,found 486.0493.
Example 13
3- ((1 r,2 r) -2- ((2-acetylphenyl) amino) -5-oxo-1-phenylcyclopent-3-en-1-yl) -2, 2-difluoropropionate (V-13):
2- (1-Phenylvinyl) furan (0.24 mmol,1.2 eq), 1- (2-aminophenyl) ethan-1-one (0.2 mmol,1.0 eq) and ethyl 2-bromo-2, 2-difluoroacetate (0.4 mmol,2.0 eq) were used as starting materials for a reaction time t 1 =12h,t 2 =42 h, the rest of the procedure is the same as in example 1. Purification by column chromatography on silica gel (petroleum ether/ethyl acetate=8/1-5/1) gave the product V-13 as a yellow oil in 94% nuclear magnetic yield, 76% isolation yield, 4.8/1dr. HPLC analysis gave 92% ee (FLM Chiral INB, hexane/i-PrOH=90/10, flow rate=1.0 mL/min, l=254 nm), t r (major)=17.5min,t r (minor)=14.2min;[α] D 20 =–410.1(c=0.89,in CHCl 3 ). 1 H NMR(500MHz,CDCl 3 )δ8.38(d,J=9.3Hz,1H),7.62(d,J=7.6Hz,2H),7.40(t,J=7.8Hz,1H),7.21–7.21(m,3H),6.99(t,J=8.8Hz,3H),6.64(t,J=7.6Hz,1H),6.60–6.56(m,1H),5.57(d,J=8.4Hz,1H),4.31(q,J=7.1Hz,2H),3.26–3.05(m,2H),2.35(s,3H),1.34(t,J=7.1Hz,3H). 13 C NMR(126MHz,CDCl 3 )δ207.7,200.3 163.6(t,J=32.4Hz),161.9,149.3,138.6,135.1,134.6,132.9,128.4,127.7,127.6,118.6,115.7(t,J=250.4Hz),115.4,111.9,63.4,60.0–59.9(m),57.6,39.3(t,J=21.9Hz),27.8,13.9. 19 F NMR(564MHz,CDCl 3 )δ-95.9(ddd,J=262.1,25.2,14.3Hz),-102.4(ddd,J=262.1,20.1,12.8Hz).HRMS(ESI)m/z calcd.For C 24 H 23 F 2 NNaO 4 [M+Na] + 450.1487,found 450.1508.
Example 14
3- ((1 r,2 r) -2- ((2-benzoylphenyl) amino) -5-oxo-1-phenylcyclopent-3-en-1-yl) -2, 2-difluoropropionate (V-14):
2- (1-Phenylvinyl) furan (0.24 mmol,1.2 eq), (2-aminophenyl) (phenyl) methanone (0.2 mmol,1.0 eq) and ethyl 2-bromo-2, 2-difluoroacetate (0.4 mmol,2.0 eq) were used as starting materials for a reaction time t 1 =16h,t 2 =10h, 4mL chloroform as reaction solvent used in step 2, 2mol% dy (OTf) as catalyst 3 6mol% A1, the remainder of the procedure being as in example 1. Purification by silica gel column chromatography (petroleum ether/ethyl acetate=5/1-4/1) gave the product V-14 as a yellow oil, 77% nuclear magnetic resonance yield, 73% isolation yield, 8.5/1dr. HPLC analysis gave 90% ee (Chiralcel OD, hexane/i-PrOH=90/10, flow rate=1.0 mL/min, l=254 nm), t r (major)=12.6min,t r (minor)=16.5min;[α] D 20 =–358.6(c=0.89,in CHCl 3 ). 1 H NMR(500MHz,CDCl 3 )δ8.05(d,J=10.0Hz,1H),7.70–7.65(m,1H),7.50–7.44(m,1H),7.44–7.37(m,5H),7.33(t,J=7.7Hz,1H),7.15–7.03(m,4H),6.99(d,J=7.3Hz,2H),6.64–6.52(m,2H),5.65(d,J=10.0Hz,1H),4.32(q,J=6.8Hz,2H),3.34–3.09(m,2H),1.35(t,J=7.0Hz,3H). 13 C NMR(126MHz,CDCl 3 )δ207.8,198.5,163.6(t,J=32.3Hz),161.8,149.9,139.9,138.6,135.6,135.0,134.9,130.9,129.0,128.4,127.9,127.6,127.6,118.2,115.8(t,J=253.5Hz),115.1,111.9,63.4,60.0,57.7,39.4(t,J=21.8Hz),13.9. 19 F NMR(564MHz,CDCl 3 )δ-95.8(d,J=261.7Hz),-102.3(d,J=262.0Hz).HRMS(ESI)m/z calcd.For C 29 H 25 F 2 NNaO 4 [M+Na] + 512.1644,found 512.1652.
Example 15
Methyl 2- ((1 r,5 r) -5- (3-ethoxy-2, 2-difluoro-3-oxopropyl) -4-oxo-5-phenyl-cyclopent-2-en-1-yl) amino) benzoate (V-15):
2- (1-Phenylvinyl) furan (0.24 mmol,1.2 eq), methyl 2-aminobenzoate (0.2 mmol,1.0 eq) and ethyl 2-bromo-2, 2-difluoroacetate (0.4 mmol,2.0 eq) were used as starting materials for reaction for a period of time t 1 =53h,t 2 =12h, the rest of the procedure is the same as in example 1. Purification by silica gel column chromatography (petroleum ether/ethyl acetate=10/1-8/1) gave the product V-15 as a yellow oil in a nuclear magnetic yield of 68%, isolation yield of 50%,3/1dr. HPLC analysis gave 92% ee (FLM Chiral INB, hexane/i-PrOH=90/10, flow rate=1.0 mL/min, l=254 nm), t r (major)=14.4min,t r (minor)=11.8min;[α] D 20 =–259.5(c=0.99,in CHCl 3 ). 1 H NMR(500MHz,CDCl 3 )δ7.77(d,J=8.0Hz,1H),7.64–7.60(m,1H),7.40(t,J=7.8Hz,1H),7.23–7.08(m,4H),7.03–6.94(m,3H),6.64(t,J=7.6Hz,1H),6.59(d,J=5.7Hz,1H),5.58(s,1H),4.31(q,J=7.1Hz,2H),3.61(s,3H),3.31–2.95(m,2H),2.43(br,1H),1.35(t,J=7.1Hz,3H). 13 C NMR(126MHz,CDCl 3 )δ207.9,168.0,163.6,162.1,149.3,138.8,134.7,134.6,131.9,128.35,127.7,127.5,116.0,111.7,115.7(t,J=253.3Hz),111.4,63.4,60.2–60.0(m),57.8,51.4,39.4(t,J=21.4Hz),13.9. 19 F NMR(564MHz,CDCl 3 )δ-95.8(ddd,J=262.1,25.3,14.2Hz),-102.4(ddd,J=262.1,20.4,13.1Hz).HRMS(ESI)m/z calcd.For C 24 H 23 F 2 NNaO 5 [M+Na] + 466.1437,found 466.1457.
Example 16
3- ((1 r,2 r) -2- ((3-chlorophenyl) amino) -5-oxo-1-phenylcyclopent-3-en-1-yl) -2, 2-difluoropropionic acid ethyl ester (V-16):
2- (1-Phenylvinyl) furan (0.24 mmol,1.2 eq), 3-chloroaniline (0.2 mmol,1.0 eq) and ethyl 2-bromo-2, 2-difluoroacetate (0.4 mmol,2.0 eq) were used as starting materials, the reaction time was t 1 =16h,t 2 =34 h, the reaction solvent used in step 2 was 4mL chloroform, the catalyst dose was 2mol% dy (OTf) 3 6mol% A1, the remainder of the procedure being as in example 1. Purification by silica gel column chromatography (petroleum ether/ethyl acetate=5/1-4/1) gave the product V-16 as a yellow solid in 61% nuclear magnetic yield, 51% isolation yield, 5.6/1dr. HPLC analysis gave 72% ee (Chiralcel AD-H, hexane/i-PrOH=90/10, flow rate=1.0 mL/min, l=254 nm), t r (major)=10.1min,t r (minor)=13.7min;[α] D 20 =–21.6(c=0.88,in CHCl 3 );mp=89–91℃. 1 H NMR(500MHz,CDCl 3 )δ7.58–7.55(m,1H),7.31–7.27(m,3H),7.09–7.01(m,3H),6.70(d,J=7.9Hz,1H),6.58–6.52(m,1H),6.42(s,1H),6.37(d,J=8.2Hz,1H),5.35(d,J=10.6Hz,1H),4.30(q,J=7.2Hz,2H),3.25–3.00(m,3H),1.35(t,J=7.2Hz,3H). 13 C NMR(126MHz,CDCl 3 )δ206.1,162.4(t,J=32.4Hz),160.8,146.2,137.2,134.1,133.4,129.4,127.6,127.0,126.8,117.4,115.5(t,J=255.0Hz),112.4,110.5,62.4,59.4(d,J=4.3Hz),56.4,38.3(t,J=22.2Hz),12.8. 19 F NMR(564MHz,CDCl 3 )δ-96.0(d,J=263.4Hz),-102.1(d,J=263.0Hz).HRMS(ESI)m/z calcd.For C 22 H 20 ClF 2 NNaO 3 [M+Na] + 442.0992,found 442.0997.
Example 17
3- ((1 r,2 r) -2- ((4-chlorophenyl) amino) -5-oxo-1-phenylcyclopent-3-en-1-yl) -2, 2-difluoropropionic acid ethyl ester (V-17):
2- (1-Phenylvinyl) furan (0.24 mmol,1.2 eq), 4-chloroaniline (0.2 mmol,1.0 eq) and ethyl 2-bromo-2, 2-difluoroacetate (0.4 mmol,2.0 eq) were used as starting materials, the reaction time was t 1 =20h,t 2 =120 h, the photocatalyst used in step 1 was 2mol% mer-Ir (ppy) 3 ,NaHCO 3 (0.6 mmol,3.0 eq) as base; the reaction temperature used in the step 2 was 15 ℃, the reaction solvent was 4mL chloroform, and the catalyst amount was 2mol% Dy (OTf) 3 6mol% A1, the remainder of the procedure being as in example 1. Purification by column chromatography on silica gel (petroleum ether/ethyl acetate=8/1-6/1) gave the product V-17 as a yellow oil in 77% nuclear magnetic yield, 63% isolation yield, 2.7/1dr. HPLC analysis gave 67% ee (FLM Chiral INB, hexane/i-PrOH=90/10, flow rate=1.0 mL/min, l=254 nm), t r (major)=15.9min,t r (minor)=17.2min;[α] D 20 =–26.7(c=0.3,in CHCl 3 ). 1 H NMR(500MHz,CDCl 3 )δ7.61–7.54(m,1H),7.31–7.25(m,3H),7.08(d,J=8.8Hz,2H),7.25–6.99(m,2H),6.59–6.52(m,1H),6.39(d,J=11.3Hz,2H),5.36(d,J=10.0Hz,1H),4.30(q,J=7.2Hz,2H),3.21–2.98(m,3H),1.35(t,J=7.2Hz,3H). 13 C NMR(126MHz,CDCl 3 )δ207.4,163.4(t,J=32.3Hz),162.1,144.7,138.4,134.5,129.3,128.7,128.0,127.9,123.2,115.6(dd,J=255.9,251,5Hz),114.7,63.5,60.8(t,J=2.2Hz),57.6,39.1(t,J=22.5Hz),13.9. 19 F NMR(564MHz,CDCl 3 )δ-95.8(d,J=262.5Hz),-102.3(d,J=262.5Hz).HRMS(ESI)m/z calcd.For C 22 H 20 ClF 2 NNaO 3 [M+Na] + 442.0992,found 442.0995.
Example 18
2, 2-difluoro-3- ((1 r,5 r) -2-oxo-1-phenyl-5- ((4- (trifluoromethyl) phenyl) amino) cyclopent-3-en-1-yl) propanoate (V-18):
2- (1-Phenylvinyl) furan (0.24 mmol,1.2 eq), 4- (trifluoromethyl) aniline (0.2 mmol,1.0 eq) and ethyl 2-bromo-2, 2-difluoroacetate (0.4 mmol,2.0 eq) were used as starting materials for reaction for a period of time t 1 =16h,t 2 =82 h. The reaction solvent used in step 2 was 4mL chloroform, and the catalyst amount was 2mol% Dy (OTf) 3 6mol% A1, the remainder of the procedure being as in example 1. Purification by silica gel column chromatography (petroleum ether/ethyl acetate=5/1-4/1) gave the product V-18 as a yellow oil in a nuclear magnetic yield of 65%, isolation yield of 56%,9/1dr. HPLC analysis gave 80% ee (Chiralcel AD-H, hexane/i-PrOH=90/10, flow rate=1.0 mL/min, l=254 nm), t r (major)=10.7min,t r (minor)=13.2min;[α] D 20 =–115.1(c=0.2,in CHCl 3 ). 1 H NMR(500MHz,CDCl 3 )δ7.59–7.54(m,1H),7.38(d,J=8.2Hz,2H),7.31–7.27(m,3H),7.07–6.99(m,2H),6.61–6.56(m,1H),6.51(d,J=8.2Hz,2H),5.46(d,J=10.5Hz,1H),4.31(q,J=7.4Hz,2H),3.38(d,J=10.8Hz,1H),3.29–2.99(m,2H),1.35(t,J=7.1Hz,3H). 13 C NMR(126MHz,CDCl 3 )δ207.1,163.3(t,J=32.4Hz),161.6,148.7,138.3,134.7,128.7,128.1,127.9,126.9(q,J=3.6Hz),122.5(q,J=270.8Hz),120.2(q,J=32.3Hz),115.6(t,J=253.0Hz),112.6,63.5,60.1(t,J=2.5Hz),57.5,39.2(t,J=22.4Hz),13.9. 19 F NMR(564MHz,CDCl 3 )δ-61.3(s),-95.9(ddd,J=262.4,25.1,13.9Hz),-102.3(ddd,J=259.6,17.1,9.0Hz).HRMS(ESI)m/z calcd.F For C 23 H 20 F 5 NNaO 3 [M+Na] + 476.1256,found 476.1274.
Example 19
2- (((1 r,5 r) -5- (3-ethoxy-2, 2-difluoro-3-oxopropyl) -4-oxo-5-phenylcyclopent-2-en-1-yl) amino) -4-methoxybenzoate (V-19):
2- (1-Phenylvinyl) furan (0.24 mmol,1.2 eq), methyl 2-amino-4-methoxybenzoate (0.2 mmol,1.0 eq) and ethyl 2-bromo-2, 2-difluoroacetate (0.4 mmol,2.0 eq) were used as starting materials, the reaction time was t 1 =16h,t 2 =10h. The reaction temperature used in the step 2 was 10 ℃, the reaction solvent was 4mL chloroform, and the catalyst amount was 2mol% Dy (OTf) 3 6mol% A1, the remainder of the procedure being as in example 1. Purification by silica gel column chromatography (petroleum ether/ethyl acetate=5/1-4/1) gave the product V-19 as a yellow oil in a nuclear magnetic yield of 87%, isolation yield of 67%,4/1dr. HPLC analysis gave 92% ee (FLM Chiral INB, hexane/i-PrOH=90/10, flow rate=1.0 mL/min, l=254 nm), t r (major)=12.9min,t r (minor)=14.7min;[α] D 20 =–186.3(c=0.96,in CHCl 3 ). 1 H NMR(500MHz,CDCl 3 )δ7.71(d,J=8.9Hz,1H),7.64–7.55(m,1H),7.39(d,J=10.3Hz,1H),7.20–7.14(m,3H),7.03–6.88(m,2H),6.65–6.56(m,1H),6.50(s,1H),6.21(d,J=8.9Hz,1H),5.57(d,J=10.3Hz,1H),4.31(q,J=7.0Hz,2H),3.86(s,3H),3.58(s,3H),3.31–3.05(m,2H),1.35(t,J=7.1Hz,3H). 13 C NMR(126MHz,CDCl 3 )δ207.8,167.7,164.9,163.5(t,J=32.5Hz),162.0,151.4,138.8,134.6,133.7,128.4,127.7,127.5,115.9(dd,J=256.8,253.2Hz),104.7,103.6,95.5,63.4,60.1–59.9(m),58.0,55.3,51.1,39.6(t,J=21.8Hz),13.9. 19 F NMR(564MHz,CDCl 3 )δ-95.3(d,J=260.6Hz),-102.7(d,J=260.6Hz).HRMS(ESI)m/z calcd.For C 25 H 25 F 2 NNaO 6 [M+Na] + 496.1542,found 496.1548.
Example 20
2- ((1 r,5 r) -5- (3-ethoxy-2, 2-difluoro-3-oxopropyl) -4-oxo-5-phenylcyclopent-2-en-1-yl) amino) -4-methylbenzoate (V-20):
with 2- (1-phenylvinyl) furan (0.24 mmol,1.2 eq), methyl 2-amino-4-methylbenzoate (0.2 mmol,1.0 eq) and ethyl 2-bromo-2, 2-difluoroacetate (0.4 mmol,2.0 eq) as reaction starting materials for a reaction time t 1 =11h,t 2 =40 h, the rest of the procedure is the same as in example 1. Purification by silica gel column chromatography (petroleum ether/ethyl acetate=5/1-4/1) gave the product V-20 as a yellow oil in a nuclear magnetic yield of 70%, isolation yield of 53%,3.5/1dr. HPLC analysis gave 93% ee (FLM Chiral NS, hexane/i-PrOH=90/10, flow rate=1.0 mL/min, l=254 nm), t r (major)=8.4min,t r (minor)=9.7min;[α] D 20 =–241.9(c=0.81,in CHCl 3 ). 1 H NMR(500MHz,CDCl 3 )δ7.66(d,J=8.1Hz,1H),7.63–7.57(m,1H),7.22–7.16(m,4H),7.01–6.94(m,2H),6.83(s,1H),6.60–6.56(m,1H),6.46(d,J=8.1Hz,1H),5.58(s,1H),4.31(q,J=7.1Hz,2H),3.58(s,3H),3.26–3.03(m,2H),2.35(s,3H),1.35(t,J=7.1Hz,3H). 13 C NMR(126MHz,CDCl 3 )δ207.9,168.0,163.6,162.2,149.3,145.5,138.8,134.4,131.8,128.4,127.7,127.5,117.3,115.7(t,J=251.1Hz),112.1,109.0,63.4,60.1–59.9(m),57.9,51.3,39.4(t,J=21.9Hz),22.2,13.9. 19 F NMR(564MHz,CDCl 3 )δ-95.7(ddd,J=262.0,25.1,14.4Hz),-102.6(ddd,J=262.7,20.1,12.9Hz).HRMS(ESI)m/z calcd.For C 25 H 25 F 2 NNaO 5 [M+Na] + 480.1593,found480.1615.
Example 21
2- ((1 r,5 r) -5- (3-ethoxy-2, 2-difluoro-3-oxopropyl) -4-oxo-5-phenylcyclopent-2-en-1-yl) amino-5-fluorobenzoic acid methyl ester (V-21):
2- (1-Phenylvinyl) furan (0.24 mmol,1.2 eq), methyl 2-amino-5-fluorobenzoate (0.2 mmol,1.0 eq) and ethyl 2-bromo-2, 2-difluoroacetate (0.4 mmol,2.0 eq) were used as starting materials, the reaction time was t 1 =87h,t 2 =40 h, the rest of the procedure is the same as in example 1. Purification by silica gel column chromatography (petroleum ether/ethyl acetate=6/1-4/1) gave the product V-21 as a yellow oil in a nuclear magnetic yield of 79%, isolation yield 70%,8.6/1dr. HPLC analysis gave 91% ee (Chiralcel OD, hexane/i-PrOH=90/10, flow rate=1.0 mL/min, l=254 nm), t r (major)=9.0min,t r (minor)=9.9min;[α] D 20 =–294.0(c=0.8,in CHCl 3 ). 1 H NMR(500MHz,CDCl 3 )δ7.64–7.56(m,1H),7.49–7.43(m,1H),7.20–7.13(m,4H),7.06(d,J=10.3Hz,1H),6.94(t,J=11.6Hz,3H),6.62–6.58(m,1H),5.53(d,J=10.4Hz,1H),4.31(q,J=7.0Hz,2H),3.62(s,3H),3.28–2.93(m,2H),1.35(t,J=7.1Hz,3H). 13 C NMR(126MHz,CDCl 3 )δ207.7,167.0(d,J=2.6Hz),163.5(t,J=32.4Hz),161.8,153.6(d,J=235.4Hz),146.1,138.7,134.7,128.3,127.7,127.5,122.2(d,J=22.9Hz),117.3(d,J=23.4Hz),115.7(dd,J=255.7,250.2Hz),113.0(d,J=7.6Hz),111.6(d,J=6.4Hz),60.8–60.5(m),57.7,51.7,39.4(t,J=21.8Hz),13.9. 19 F NMR(564MHz,CDCl 3 )δ-95.8(d,J=261.7Hz),-102.4(d,J=262.0Hz),-128.4(s).HRMS(ESI)m/z calcd.For C 24 H 22 F 3 NNaO 5 [M+Na] + 484.1342,found 484.1348.
Example 22
Methyl 5-chloro-2- ((1 r,5 r) -5- (3-ethoxy-2, 2-difluoro-3-oxopropyl) -4-oxo-5-phenylcyclopent-2-en-1-yl) amino) benzoate (V-22):
2- (1-Phenylvinyl) furan (0.24 mmol,1.2 eq), methyl 2-amino-5-chlorobenzoate (0.2 mmol,1.0 eq) and ethyl 2-bromo-2, 2-difluoroacetate (0.4 mmol,2.0 eq) were used as starting materials for a reaction time t 1 =48h,t 2 =18h, the rest of the procedure is the same as in example 1. Purification by silica gel column chromatography (petroleum ether/ethyl acetate=6/1-4/1) gave the product V-22 as a yellow solid in a nuclear magnetic yield of 76%, isolation yield of 70%,14/1dr. HPLC analysis gave 90% ee (FLM Chiral INB, hexane/i-PrOH=90/10, flow rate=1.0 mL/min, l=254 nm), t r (major)=13.6min,t r (minor)=12.4min;[α] D 20 =–214.9(c=0.87,in CHCl 3 );mp=64–66℃. 1 H NMR(500MHz,CDCl 3 )δ7.74(s,1H),7.65–7.52(m,1H),7.34(d,J=8.9Hz,1H),7.24–7.13(m,4H),6.95(s,3H),6.64–6.57(m,1H),5.53(d,J=10.2Hz,1H),4.31(q,J=6.9Hz,2H),3.62(s,3H),3.26–3.01(m,2H),1.35(t,J=7.0Hz,3H). 13 C NMR(126MHz,CDCl 3 )δ207.5,167.0,163.5(t,J=32.5Hz),161.5,147.9,138.6,134.8,134.5,131.2,128.4,127.7,127.6,120.6,115.7(t,J=256.4,253.4Hz),113.2,112.3,63.5,60.3–60.2(m),57.7,51.7,39.4(t,J=21.9Hz),13.9. 19 F NMR(564MHz,CDCl 3 )δ-95.8(d,J=261.9Hz),-102.4(d,J=262.0Hz).HRMS(ESI)m/z calcd.For C 24 H 22 ClF 2 NNaO 5 [M+Na] + 500.1047,found500.1053.
Example 23
3- ((1 r,2 r) -2- ((4-chlorophenyl) (methyl) amino) -5-oxo-1-phenylcyclopent-3-en-1-yl) -2, 2-difluoropropionic acid ethyl ester (V-23):
2- (1-Phenylvinyl) furan (0.24 mmol,1.2 eq), N-methyl-4- (trifluoromethyl) aniline (0.2 mmol,1.0 eq) and ethyl 2-bromo-2, 2-difluoroacetate (0.4 mmol,2.0 eq) were used as starting materials, the reaction time was t 1 =87h,t 2 =40 h, the reaction solvent used in step 2 was 4mL chloroform, the catalyst dose was 2mol% dy (OTf) 3 6mol% A1, the remainder of the procedure being as in example 1. Purifying by silica gel column chromatography (petroleum ether/ethyl acetate=6/1-5/1) to obtain yellow solid product V-23 with nuclear magnetic resonance yield of 77%, separation yield of 75%,>20/1dr. HPLC analysis gave 60% ee (FLM Chiral INB, hexane/i-PrOH=95/5, flow rate=1.0 mL/min, l=254 nm), t r (major)=15.9min,t r (minor)=15.0min;[α] D 20 =60.2(c=0.99,in CHCl 3 );mp=107–109℃. 1 H NMR(500MHz,CDCl 3 )δ7.53(d,J=7.8Hz,3H),7.24–7.14(m,3H),6.96(d,J=7.6Hz,2H),6.82(d,J=8.2Hz,2H),6.64–6.60(m,1H),5.89(s,1H),4.32(q,J=7.0Hz,2H),3.22–2.99(m,2H),1.84(s,3H),1.35(t,J=7.0Hz,3H). 13 C NMR(126MHz,CDCl 3 )δ207.3,163.3(t,J=32.4Hz),161.2,151.0,138.3,134.8,128.5,128.2,127.7,127.0(q,J=271.1Hz),125.0(q,J=3.5Hz),118.7(q,J=32.8Hz),115.6(t,J=256.5,251.2Hz),111.0,66.0,60.4,58.1,41.9(t,J=21.7Hz),33.5,13.9. 19 F NMR(564MHz,CDCl 3 )δ-61.0(s),-95.6(ddd,J=261.9,25.6,15.0Hz),-102.1(ddd,J=262.0,19.7,12.9Hz).HRMS(ESI)m/z calcd.For C 24 H 22 F 5 NNaO 3 [M+Na] + 490.1412,found 490.1417.
Example 24
(4 r,5 r) -4- ((2-chlorophenyl) amino) -5- (2, 2-difluoro-3-oxo-3-phenylpropyl) -5-phenylcyclopent-2-en-1-one (V-24):
2- (1-Phenylvinyl) furan (0.24 mmol,1.2 eq), methyl 2-aminobenzoate (0.2 mmol,1.0 eq) and 2-bromo-2, 2-difluoro-1-phenylethane-1-one (0.4 mmol,2.0 eq) were used as starting materials for a reaction time t 1 =10h,t 2 =17 h, the photocatalyst used in step 1 was 2mol% mer-Ir (ppy) 3 ,NaHCO 3 (0.6 mmol,3.0 eq) as base; the reaction solvent used in step 2 was 4mL chloroform, and the catalyst amount was 2mol% Dy (OTf) 3 6mol% A1; the rest of the procedure is the same as in example 1. Purification by silica gel column chromatography (petroleum ether/ethyl acetate=15/1-10/1) gave the product V-24 as a yellow oil, 62% nuclear magnetic yield, 60% isolation yield, 4.7/1dr. HPLC analysis gave 96% ee (Chiralcel OD, hexane/i-PrOH=90/10, flow rate=1.0 mL/min, l=254 nm), t r (major)=10.4min,t r (minor)=8.7min;[α] D 20 =–265.9(c=0.96,in CHCl 3 ). 1 H NMR(500MHz,CDCl 3 )δ8.08(d,J=7.6Hz,2H),7.77(d,J=8.0Hz,1H),7.69–7.64(m,1H),7.62(t,J=7.7Hz,1H),7.49(t,J=7.8Hz,2H),7.39(t,J=7.9Hz,1H),7.25(s,1H),7.18–7.14(m,3H),7.06–6.95(m,3H),6.65–6.61(m,2H),5.69(d,J=10.1Hz,1H),4.96(d,J=9.1Hz,0.22H),3.61(s,3H),3.44–3.32(m,1H),3.26–3.16(m,1H). 13 C NMR(500MHz,CDCl 3 )δ8.08(d,J=7.6Hz,2H),7.77(d,J=8.0Hz,1H),7.69–7.64(m,1H),7.62(t,J=7.7Hz,1H),7.49(t,J=7.8Hz,2H),7.39(t,J=7.9Hz,1H),7.25(s,1H),7.18–7.14(m,3H),7.06–6.95(m,3H),6.65–6.61(m,2H),5.69(d,J=10.1Hz,1H),4.96(d,J=9.1Hz,0.22H),3.61(s,3H),3.44–3.32(m,1H),3.26–3.16(m,1H). 19 F NMR(377MHz,CDCl 3 )δ-92.6(d,J=276.0Hz),-96.3(d,J=275.8Hz).HRMS(ESI)m/z calcd.For C 28 H 23 F 2 NNaO 4 [M+Na] + 498.1487,found 498.1506.
Example 25
(4R, 5R) -4- ((2-chlorophenyl) amino) -5- (2, 2-difluoro-3- (4-methoxyphenyl) -3-oxopropyl) -5-phenylcyclopent-2-en-1-one (V-25):
2- (1-phenylvinyl) furan (0.24 mmol,1.2 eq), 2-chloroaniline (0.2 mmol,1.0 eq) and 2-bromo-2, 2-difluoro-1- (4-methoxyphenyl) ethane-1-one (0.4 mmol,2.0 eq) were used as reaction materials, the reaction time was t 1 =14h,t 2 =16h, the photocatalyst used in step 1 was 2mol% mer-Ir (ppy) 3 The method comprises the steps of carrying out a first treatment on the surface of the The reaction solvent used in step 2 was 4mL chloroform, and the catalyst amount was 2mol% Dy (OTf) 3 6mol% A1, the remainder of the procedure being as in example 1. Purifying by silica gel column chromatography (petroleum ether/ethyl acetate=10/1-8/1) to obtain yellow oily product V-25, nuclear magnetic yield 71%, separation yield 68%,>20/1dr. HPLC analysis gave 94% ee (FLM Chiral INB, hexane/i-PrOH=80/20, flow rate=1.0 mL/min, l=254 nm), t r (major)=19.4min,t r (minor)=17.0min;[α] D 20 =–162.0(c=0.89,in CHCl 3 ). 1 H NMR(500MHz,CDCl 3 )δ8.08(d,J=8.4Hz,2H),7.67–7.59(m,1H),7.25(s,3H),7.20–7.10(m,2H),7.09–7.04(m,2H),7.01–6.88(m,3H),6.72–6.56(m,2H),5.57(d,J=10.5Hz,1H),3.86(d,J=2.8Hz,4H),3.44–3.28(m,1H),3.25–3.11(m,1H). 13 C NMR(126MHz,CDCl 3 )δ208.1,186.9(t,J=29.5Hz),164.7,161.8,142.1,138.4,134.6,133.0,129.5,128.8,128.0,127.7,124.3,124.2,121.7,119.9,119.7(dd,J=258.4,252.8Hz),118.2,114.1,113.9,111.6,59.9(d,J=6.4Hz),57.6,55.6,38.5(t,J=21.1Hz). 19 F NMR(377MHz,CDCl 3 )δ-92.5(d,J=272.4Hz),-95.8(d,J=272.6Hz).HRMS(ESI)m/z calcd.For C 27 H 22 ClF 2 NNaO 3 [M+Na] + 504.1148,found 504.1162.
Example 26
N-benzyl-3- ((1 r,2 r) -2- ((2-chlorophenyl) amino) -5-oxo-1-phenylcyclopent-3-en-1-yl) -2, 2-difluoropropionamide (V-26):
2- (1-Phenylvinyl) furan (0.24 mmol,1.2 eq), 2-chloroaniline (0.2 mmol,1.0 eq) and N-benzyl-2-bromo-2, 2-difluoroacetamide (0.4 mmol,2.0 eq) were used as starting materials, the reaction time was t 1 =12h,t 2 =43 h, the photocatalyst used in step 1 was 2mol% mer-Ir (ppy) 3 ,NaHCO 3 (0.6 mmol,3.0 eq) as base; the reaction solvent used in step 2 was 4mL chloroform, and the catalyst amount was 2mol% Dy (OTf) 3 6mol% A1; the rest of the procedure is the same as in example 1. Purifying by silica gel column chromatography (petroleum ether/ethyl acetate=6/1-4/1) to obtain yellow oily product V-26 with nuclear magnetic resonance yield of 52%, separation yield of 47%,>20/1dr. HPLC analysis gave 93% ee (Chiralcel IA, hexane/i-PrOH=80/20, flow rate=1.0 mL/min, l=254 nm), t r (major)=11.6min,t r (minor)=10.2min;[α] D 20 =–30.3(c=0.72,in CHCl 3 ). 1 H NMR(500MHz,CDCl 3 )δ7.57–7.51(m,1H),7.36–7.24(m,8H),7.15(t,J=7.9Hz,1H),7.11(d,J=7.9Hz,1H),7.06–6.99(m,2H),6.92(d,J=8.2Hz,1H),6.82(br,1H),6.63(t,J=7.7Hz,1H),6.55–6.49(m,1H),5.41(d,J=10.5Hz,1H),4.45(dd,J=14.9,5.9Hz,1H),4.35(dd,J=14.9,5.5Hz,1H),3.83(d,J=10.5Hz,1H),3.35–3.19(m,1H),3.16–3.00(m,1H). 13 C NMR(126MHz,CDCl 3 )δ207.9,163.8(t,J=28.6Hz),161.7,142.0,138.1,136.7,134.5,129.5,128.9,128.8,128.1,128.0,127.9,127.7,119.8,118.3,117.4(dd,J=257.9,253.4Hz),111.7,60.3(d,J=4.8Hz),57.5,43.7,39.0(t,J=22.1Hz). 19 F NMR((377MHz,CDCl 3 )δ-97.1(d,J=254.5Hz),-101.4(d,J=254.6Hz).HRMS(ESI)m/z calcd.For C 27 H 23 ClF 2 N 2 NaO 2 [M+Na] + 503.1308,found 503.1326.
Example 27
3- ((1 r,2 r) -2- ((2-chlorophenyl) amino) -5-oxo-1-phenylcyclopent-3-en-1-yl) -N-cyclohexyl-2, 2-difluoropropane (27):
2- (1-Phenylvinyl) furan (0.24 mmol,1.2 eq), 2-chloroaniline (0.2 mmol,1.0 eq) and 2-bromo-N-cyclohexyl-2, 2-difluoroacetamide (0.4 mmol,2.0 eq) were used as starting materials, the reaction time was t 1 =72h,t 2 =12 h, the photocatalyst used in step 1 was 2mol% mer-Ir (ppy) 3 ,NaHCO 3 (0.6 mmol,3.0 eq) as base; the reaction solvent used in step 2 was 4mL chloroform, and the catalyst amount was 2mol% Dy (OTf) 3 6mol% A1; the rest of the procedure is the same as in example 1. Purifying by silica gel column chromatography (petroleum ether/ethyl acetate=6/1-5/1) to obtain yellow oily product V-27 with nuclear magnetic resonance yield of 36% and separation yield of 34%,>20/1dr. HPLC analysis gives 84% ee (Chiralcel ID, hexane/i-PrOH=95/5, flow rate=1.0 mL/min, l=254 nm), t r (major)=40.1min,t r (minor)=29.6min;[α] D 20 =–96.8(c=0.84,in CHCl 3 ). 1 H NMR(500MHz,CDCl 3 )δ7.62–7.58(m,1H),7.29–7.25(m,3H),7.17(t,J=7.9Hz,1H),7.12(d,J=7.8Hz,1H),7.08–7.03(m,2H),6.94(d,J=8.2Hz,1H),6.64(t,J=7.7Hz,1H),6.61–6.55(m,1H),6.18(d,J=8.1Hz,1H),5.45(d,J=10.6Hz,1H),3.84(d,J=10.6Hz,1H),3.77–3.67(m,1H),3.32–3.18(m,1H),3.11–2.96(m,1H),1.94(d,J=12.5Hz,1H),1.88(d,J=12.4Hz,1H),1.75–1.58(m,4H),1.41–1.31(m,2H),1.22–1.16(m,2H). 13 C NMR(126MHz,CDCl 3 )δ208.0,163.0(t,J=26.7Hz),161.7,142.0,138.2,134.6,129.4,128.7,128.0,127.9,127.7,119.8,118.2,116.3(t,J=254.5Hz),111.7,60.2(d,J=4.6Hz),57.5,48.8,39.0(t,J=22.2Hz),32.6,32.5,25.3,24.6. 19 F NMR(377MHz,CDCl 3 )δ-97.6(d,J=253.1Hz),-101.3(d,J=253.2Hz).HRMS(ESI)m/z calcd.For C 26 H 27 ClF 2 N 2 NaO 2 [M+Na] + 495.1621,found 495.1636.
Example 28
3- ((1 r,2 r) -2- ((2-chlorophenyl) amino) -5-oxo-1-phenylcyclopent-3-en-1-yl) -2, 2-difluoro-N-phenylpropylamine (V-28):
2- (1-phenylvinyl) furan (0.24 mmol,1.2 eq), 2-chloroaniline (0.2 mmol,1.0 eq) and 2-bromo-2, 2-difluoro-N-phenylacetamide (0.4 mmol,2.0 eq) were used as starting materials for reaction for a period of time t 1 =24h,t 2 =40 h, the photocatalyst used in step 1 was 2mol% mer-Ir (ppy) 3 ,NaHCO 3 (0.6 mmol,3.0 eq) as base; the reaction solvent used in step 2 was 4mL chloroform, and the catalyst amount was 2mol% Dy (OTf) 3 6mol% A1; the rest of the procedure is the same as in example 1. Purifying by silica gel column chromatography (petroleum ether/ethyl acetate=3/1-2/1) to obtain white solid product V-28 with nuclear magnetic resonance yield of 51% and separation yield of 49%,>20/1dr. HPLC analysis gave 91% ee (Chiralcel OD, hexane/i-PrOH=80/20, flow rate=1.0 mL/min, l=254 nm), t r (major)=14.0min,t r (minor)=12.4min;[α] D 20 =–130.3(c=0.72,in CHCl 3 );mp=175–177℃. 1 H NMR(500MHz,DMSO)δ10.57(s,1H),7.88–7.82(m,1H),7.67(d,J=8.0Hz,2H),7.36(t,J=7.0Hz,2H),7.29–7.23(m,3H),7.19–7.08(m,5H),6.92(d,J=8.2Hz,1H),6.70–6.64(m,1H),6.59(t,J=7.7Hz,1H),5.31(d,J=9.5Hz,1H),4.14(d,J=9.4Hz,1H),3.50–3.37(m,1H),3.17–3.03(m,1H). 13 C NMR(126MHz,DMSO)δ207.2,162.6,161.6(t,J=29.6Hz),141.9,138.3,137.1,134.2,129.0,128.7,128.3,128.0,127.6,127.4,124.9,121.0,118.2,117.8,111.8,117.3(t,J=256.2Hz),60.1,56.6,37.8(t,J=21.9Hz). 19 F NMR(377MHz,DMSO)δ-95.9(d,J=255.6Hz),-99.2(d,J=255.6Hz).HRMS(ESI)m/z calcd.For C 26 H 21 ClF 2 N 2 NaO 2 [M+Na] + 489.1152,found 489.1173.
Example 29
(4 r,5 r) -4- ((2-chlorophenyl) amino) -5- (2, 2-difluoro-3-oxo-3- (piperidin-1-yl) propyl) -5-phenylcyclopent-2-en-1-one (V-29):
2- (1-Phenylvinyl) furan (0.24 mmol,1.2 eq), 2-chloroaniline (0.2 mmol,1.0 eq) and 2-bromo-2, 2-difluoro-1- (piperidin-1-yl) ethan-1-one (0.4 mmol,2.0 eq) were used as starting materials for a reaction time t 1 =12h,t 2 =4h, the photocatalyst used in step 1 was 2mol% mer-Ir (ppy) 3 ,NaHCO 3 (0.6 mmol,3.0 eq) as base; the reaction solvent used in step 2 was 4mL chloroform, and the catalyst amount was 2mol% Dy (OTf) 3 6mol% A1; the rest of the procedure is the same as in example 1. Purifying by silica gel column chromatography (petroleum ether/ethyl acetate=6/1-5/1) to obtain yellow oily product V-29, nuclear magnetic yield 78%, separation yield 75%,>20/1dr. HPLC analysis gave 92% ee (FLM Chiral INB, hexane/i-PrOH=80/20, flow rate=1.0 mL/min, l=254 nm), t r (major)=11.7min,t r (minor)=9.4min;[α] D 20 =–147.9(c=0.94,in CHCl 3 ). 1 H NMR(500MHz,CDCl 3 )δ7.62–7.58(m,1H),7.27–7.24(m,3H),7.18–7.03(m,4H),6.91(d,J=8.1Hz,1H),6.62(t,J=7.8Hz,1H),6.59–6.55(m,1H),5.52(d,J=10.4Hz,1H),3.84(d,J=10.4Hz,1H),3.64–3.51(m,4H),3.35–3.13(m,2H),1.69–1.58(m,6H). 13 C NMR(126MHz,CDCl 3 )δ208.1,161.8,161.4(t,J=28.2Hz),142.1,138.6,134.5,129.4,128.7,128.0,127.9,127.7,119.8,119.0(dd,J=259.1,252.6Hz),118.1,111.7,59.7(d,J=6.4Hz),57.4,46.9(t,J=6.0Hz),44.7,39.3(t,J=21.4Hz),26.4,25.6,24.4. 19 F NMR(377MHz,CDCl 3 )δ-91.3(d,J=268.4Hz),-94.8(d,J=267.8Hz).HRMS(ESI)m/z calcd.For C 25 H 25 ClF 2 N 2 NaO 2 [M+Na] + 481.1465,found 481.1480.
Example 30
(4 r,5 r) -4- ((2-chlorophenyl) amino) -5- (2, 2-difluoro-3-morpholin-3-oxypropyl) -5-phenylcyclopent-2-en-1-one (V-30):
2- (1-phenylvinyl) furan (0.24 mmol,1.2 eq), 2-chloroaniline (0.2 mmol,1.0 eq) and 2-bromo-2, 2-difluoro-1-morpholone (0.4 mmol,2.0 eq) were used as reaction materials, the reaction time was t 1 =83h,t 2 =4h, the photocatalyst used in step 1 was 2mol% mer-Ir (ppy) 3 ,NaHCO 3 (0.6 mmol,3.0 eq) as base, 2mL dichloromethane as solvent; the reaction solvent used in step 2 was 4mL chloroform, and the catalyst amount was 2mol% Dy (OTf) 3 6mol% A1, the remainder of the procedure being as in example 1. Purifying by silica gel column chromatography (petroleum ether/ethyl acetate=3/1-2/1) to obtain yellow oily product V-30 with nuclear magnetic resonance yield of 38% and separation yield of 36%,>20/1dr. HPLC analysis gave 89% ee (FLM Chiral NS, hexane/i-PrOH=70/30, flow rate=1.0 mL/min, l=254 nm), t r (major)=10.4min,t r (minor)=8.2min;[α] D 20 =–142.7(c=0.71,in CHCl 3 ). 1 H NMR(500MHz,CDCl 3 )δ7.63–7.58(m,1H),7.29–7.25(m,3H),7.19–7.11(m,2H),7.10–7.05(m,2H),6.90(d,J=8.1Hz,1H),6.64(t,J=7.7Hz,1H),6.61–6.56(m,1H),5.49(d,J=10.5Hz,1H),3.85(d,J=10.5Hz,1H),3.77–3.59(m,8H),3.33–3.13(m,2H). 13 C NMR(126MHz,CDCl 3 )δ208.0,161.9,161.5(t,J=29.5Hz),142.0,138.4,134.5,129.5,128.8,128.0,128.0,127.7,119.8,118.8(dd,J=258.8,251.8Hz),118.2,111.6,66.6,59.7(d,J=6.0Hz),57.4,46.6(t,J=5.6Hz),43.6,39.1(t,J=21.4Hz). 19 F NMR(377MHz,CDCl 3 )δ-91.0(d,J=270.3Hz),-95.0(d,J=270.3Hz).HRMS(ESI)m/z calcd.For C 24 H 23 ClF 2 N 2 NaO 3 [M+Na] + 483.1257,found 483.1294.
Example 31
3- ((1 r,2 r) -2- ((2-chlorophenyl) amino) -5-oxo-1-phenylcyclopent-3-en-1-yl) -N, N-diethyl-2, 2-difluoropropane (V-31):
2- (1-Phenylvinyl) furan (0.24 mmol,1.2 eq), 2-chloroaniline (0.2 mmol,1.0 eq) and 2-bromo-N, N-diethyl-2, 2-difluoroacetamide (0.4 mmol,2.0 eq) were used as starting materials for a reaction time t 1 =11h,t 2 =4h, the photocatalyst used in step 1 was 2mol% mer-Ir (ppy) 3 ,NaHCO 3 (0.6 mmol,3.0 eq) as base; the reaction solvent used in step 2 was 4mL chloroform, and the catalyst amount was 2mol% Dy (OTf) 3 6mol% A1, the remainder of the procedure being as in example 1. Purifying by silica gel column chromatography (petroleum ether/ethyl acetate=10/1-8/1) to obtain yellow oily product V-32 with nuclear magnetic resonance yield of 82% and separation yield of 80%,>20/1dr. HPLC analysis gave 88% ee (FLM Chiral INB, hexane/i-PrOH=80/20, flow rate=1.0 mL/min, l=254 nm), t r (major)=9.0min,t r (minor)=6.9min;[α] D 20 =–130.3(c=0.92,in CHCl 3 ). 1 H NMR(500MHz,CDCl 3 )δ7.62–7.56(m,1H),7.27–7.23(m,3H),7.18–7.05(m,4H),6.92(d,J=8.2Hz,1H),6.62(t,J=7.7Hz,1H),6.59–6.59(m,1H),5.52(d,J=10.5Hz,1H),3.84(d,J=10.3Hz,1H),3.51–3.32(m,4H),3.29–3.19(m,2H),1.22–1.13(m,6H). 13 C(126MHz,CDCl 3 )δ208.1,162.5(t,J=28.4Hz),161.8,142.1,138.6,134.5,129.4,128.7,128.0,127.9,127.8,119.8,118.9(dd,J=258.9,252.5Hz),118.1,111.7,59.6(d,J=6.0Hz),57.4,42.1(t,J=5.1Hz),41.9,39.5(t,J=21.7Hz),14.3,12.3. 19 F NMR(377MHz,CDCl 3 )δ-91.8(d,J=267.7Hz),-95.4(d,J=267.7Hz).HRMS(ESI)m/z calcd.For C 24 H 25 ClF 2 N 2 NaO 2 [M+Na] + 469.1465,found 469.1465.
Example 32
Diethyl (2- ((1 r,2 r) -2- ((2-chlorophenyl) amino) -5-oxo-1-phenylcyclopent-3-en-1-yl) -1, 1-difluoroethyl) phosphonate (V-32):
2- (1-Phenylvinyl) furan (0.24 mmol,1.2 eq), 2-chloroaniline (0.2 mmol,1.0 eq) and diethyl (bromodifluoromethyl) phosphonate (0.4 mmol,2.0 eq) were used as starting materials, the reaction time was t 1 =96h,t 2 =15 h, the photocatalyst used in step 1 was 2mol% mer-Ir (ppy) 3 ,NaHCO 3 (0.6 mmol,3.0 eq) as base; the reaction solvent used in step 2 was 4mL chloroform, and the catalyst amount was 2mol% Dy (OTf) 3 The procedure of example 1 was followed by purification by silica gel column chromatography (petroleum ether/ethyl acetate=8/1-6/1) to give product V-32 as a yellow oil in a nuclear magnetic resonance yield of 55%, isolation yield of 53%,>20/1dr. HPLC analysis gave 87% ee (FLM Chiral INB, hexane/i-PrOH=80/20, flow rate=1.0 mL/min, l=254 nm), t r (major)=13.8min,t r (minor)=7.5min;[α] D 20 =–87.9(c=0.79,in CHCl 3 ). 1 H NMR(500MHz,CDCl 3 )δ7.60–7.56(m,1H),7.26(s,2H),7.19–7.10(m,2H),7.07–7.01(m,2H),6.93(d,J=8.3Hz,1H),6.68–6.56(m,2H),5.50(d,J=10.5Hz,1H),4.45–4.22(m,4H),3.82(d,J=10.6Hz,1H),3.29–3.01(m,2H),1.44–1.36(m,6H),1.35–1.23(m,1H). 13 C NMR(126MHz,CDCl 3 )δ207.7,161.3,142.1,138.2,134.4,129.5,128.8,125.1(dt,J=255.8,212.9Hz),119.8,118.2,111.6,65.0(dd,J=17.9,6.8Hz),59.9,59.8,57.4,57.3,38.1(q,J=18.6,17.8Hz),16.4,16.4. 19 F NMR(377MHz,CDCl 3 )δ-102.9(dd,J=295.5,110.3Hz),-107.6(dd,J=295.7,101.5Hz).HRMS(ESI)m/z calcd.For C 23 H 25 ClF 2 NNaO 4 P[M+Na] + 506.1070,found506.1101.
Example 33
(3- ((1 r,2 r) -2- ((2-chlorophenyl) amino) -5-oxo-1-phenylcyclopent-3-en-1-yl) -2, 2-difluoroalkyl) -L-phenylalanine ethyl ester (V-33):
2- (1-Phenylvinyl) furan (0.24 mmol,1.2 eq), 2-chloroaniline (0.2 mmol,1.0 eq) and ethyl (2-bromo-2, 2-difluoroacetyl) -L-phenylpropionate (0.4 mmol,1.0 eq) were used as starting materials, the reaction time was t 1 =34h,t 2 =16h, the photocatalyst used in step 1 was 2mol% mer-Ir (ppy) 3 ,NaHCO 3 (0.6 mmol,3.0 eq) as base; the reaction solvent used in step 2 was 4mL chloroform, and the catalyst amount was 2mol% Dy (OTf) 3 6mol% A1, the remainder of the procedure being as in example 1. Purifying by silica gel column chromatography (petroleum ether/ethyl acetate=6/1-5/1) to obtain yellow oily product V-33, nuclear magnetic resonance yield 45%, separation yield 43%,>20/1syn: anti. HPLC analysis gave 89% de (Chiralcel IA, hexane/i-PrOH=80/20, flow rate=1.0 mL/min, l=254 nm), t r (major)=9.0min,t r (minor)=10.7min;[α] D 20 =–66.7(c=0.91,in CHCl 3 ). 1 H NMR(500MHz,CDCl 3 )δ7.59–7.55(m,1H),7.28–7.22(m,5H),7.20–7.14(m,2H),7.11(d,J=7.7Hz,3H),7.05–7.00(m,2H),6.89(d,J=8.3Hz,1H),6.83(d,J=8.1Hz,1H),6.63(t,J=7.7Hz,1H),6.60–6.56(m,1H),5.38(d,J=10.7Hz,1H),4.82(q,J=6.9Hz,1H),4.20(q,J=7.5Hz,2H),3.83(d,J=10.5Hz,1H),3.21–3.04(m,3H),3.02–2.90(m,1H),1.25(t,J=7.0Hz,3H). 13 C NMR(126MHz,CDCl 3 )δ207.7,170.4,163.3(t,J=29.4Hz),161.5,142.0,138.2,135.1,134.6,129.4,129.4,128.7,128.0,128.0,127.7,127.4,119.8,118.2,117.2(t,J=253.9Hz),111.7,61.9,60.0(d,J=4.9Hz),57.3,53.2,38.8(t,J=21.7Hz),37.8,14.1. 19 F NMR(377MHz,CDCl 3 )δ-98.4(d,J=255.1Hz),-101.8(d,J=255.0Hz).HRMS(ESI)m/z calcd.For C 31 H 29 ClF 2 N 2 NaO 4 [M+Na] + 589.1676,found 589.1697.
Example 34
(1 s,2r,5 s) -2-isopropyl-5-methylcyclohexyl 3- ((1 r,2 r) -2- ((2-chlorophenyl) amino) -5-oxo-1-phenylcyclopent-3-en-1-yl) -2, 2-difluoropropionate (V-34):
2- (1-Phenylvinyl) furan (0.24 mmol,1.2 eq), 2-chloroaniline (0.2 mmol,1.0 eq) and (1S, 2R, 5S) -2-isopropyl-5-methylcyclohexyl 2-bromo-2, 2-difluoroacetic acid (0.4 mmol,2.0 eq) were used as starting materials for reaction for a period of time t 1 =20h,t 2 =24 h, the photocatalyst used in step 1 was 2mol% mer-Ir (ppy) 3 ,NaHCO 3 (0.6 mmol,3.0 eq) as base; the reaction solvent used in step 2 was 4mL chloroform, and the catalyst amount was 2mol% Dy (OTf) 3 And 6mol% A1, the remainder of the procedure being as in example 1. Purifying by silica gel column chromatography (petroleum ether/ethyl acetate=20/1-15/1) to obtain yellow oily product V-34 with nuclear magnetic resonance yield of 61% and isolation yield of 59%,>20/1syn: anti. HPLC analysis gave 94% de (Chiralcel ID, hexane/i-PrOH=90/10, flow rate=1.0 mL/min, l=254 nm), t r (major)=5.7min,t r (minor)=7.1min;[α] D 20 =–110.8(c=0.97,in CHCl 3 ). 1 H NMR(500MHz,CDCl 3 )δ7.62–7.54(m,1H),7.31–7.26(m,3H),7.20–7.11(m,2H),7.08–7.02(m,2H),6.90(d,J=8.1Hz,1H),6.64(t,J=7.8Hz,1H),6.60–6.56(m,1H),5.45(d,J=10.3Hz,1H),4.86–4.76(m,1H),3.82(d,J=10.5Hz,1H),3.26–3.01(m,2H),2.08(d,J=12.2Hz,1H),1.91–1.81(m,1H),1.72–1.65(m,2H),1.54–1.45(m,2H),1.14–1.01(m,2H),0.96–0.86(m,7H),0.75(d,J=7.0Hz,3H). 13 C NMR(126MHz,CDCl 3 )δ207.3,163.1(t,J=32.2Hz),161.5,142.0,138.4,134.6,129.5,128.8,128.0,127.7,119.9,118.2,115.8(dd,J=255.6Hz,255.6Hz),111.5,78.1,59.8(d,J=3.7Hz),57.3,46.8,40.2,38.8(t,J=21.6Hz),34.0,31.5,26.2,23.4,22.0,20.7,16.2. 19 F NMR(377MHz,CDCl 3 )δ-96.1(d,J=261.6Hz),-101.9(d,J=261.6Hz).HRMS(ESI)m/z calcd.For C 30 H 34 ClF 2 NNaO 3 [M+Na] + 552.2087,found 552.2117.
Expansion experiments of the invention
Synthetic route for 3- ((1 r,2 r) -2- ((2-chlorophenyl) amino) -5-oxo-1-phenylcyclopent-3-en-1-yl) -2, 2-difluoropropionic acid ethyl ester (V-1):
Drawings
FIG. 1 shows the chemical formula of the technical scheme adopted by the invention
FIG. 2 is a structural formula of a series of difluoroalkyl group containing chiral multi-functional cyclopentenone derivatives
The raw material sources used for each of the above chemical reactions are listed below:
reagent name | CAS number | Purity of | Specification of specification | Manufacturer' s |
Potassium carbonate | 584-08-7 | AR | 500g | Color-dawn |
Dysprosium triflate | 139177-62-1 | 98% | 25g | Adamas |
Trichloromethane | 887144-97-0 | 98% | 5g | Bi De medicine |
Acetonitrile | 75-05-8 | AR | 500mL | Color-dawn |
Petroleum ether | 8032-32-4 | AR | 15kg | Color-dawn |
Acetic acid ethyl ester | 141-78-6 | AR | 20kg | Color-dawn |
Dichloromethane (dichloromethane) | 75-09-2 | AR | 25kg | Color-dawn |
Claims (8)
1. A process for the asymmetric synthesis of a difluoroalkyl group containing polyfunctional cyclopentenone derivative, comprising the steps of:
step S1 is a free radical-mediated three-component difluoroalkylation amination reaction which is carried out by taking furan alkene, aromatic amine compound and difluoroalkyl halide as raw materials under visible light, wherein the reaction formula is as follows:
step S2, taking an intermediate IV, adding chiral Bronsted acid and achiral Lewis acid, and carrying out asymmetric rearrangement reaction in an organic solvent to obtain a product V, wherein the reaction formula is as follows:
wherein the method comprises the steps of
R is phenyl, 2-naphthyl or benzene ring containing substituent, and the substituent on the benzene ring is one of methyl, methoxy or halogen;
R 1 is H or methyl;
ar is benzene ring connected with different groups of electron withdrawing or electron donating, wherein the different groups are one or two of methyl, methoxy, halogen, ester, trifluoromethyl, benzoyl or acetyl;
R F the raw material of the difluoromethylene with different groups is difluoroalkyl halide III selected from one of the following compounds:
the photocatalyst described in step S1 is mer-Ir (ppy) 3 The alkali is potassium carbonate, and the reaction temperature is room temperature;
the visible light in the step S1 is provided by a blue LED lamp with the power of 3W and the wavelength of 460-465 nm;
the achiral Lewis acid in the step S2 is dysprosium triflate, and the reaction temperature is room temperature;
the chiral bronsted acid in step S2 has the following structural formula:
2. the method of claim 1, wherein: the dosage ratio of furan alkene, aromatic amine compound and difluoroalkyl halide in the reaction of step S1 is 0.24mmol:0.20mmol:0.40mmol.
3. The method of claim 1, wherein: mer-Ir (ppy) in step S1 reaction 3 The molar amount of the potassium carbonate and the aromatic amine compound is 0.33 percent, and the molar amount ratio of the potassium carbonate to the aromatic amine compound is 0.4mmol to 0.20mmol.
4. The method of claim 1, wherein: step S1 reaction time t 1 10-96h.
5. The method of claim 1, wherein: the organic solvent in the reaction in the step S1 is acetonitrile, the ratio of the amount of the substance of the arylamine compound to the volume of the acetonitrile is 0.1 mmol/2 mL, and the reaction is carried out under the argon atmosphere.
6. The method of claim 1, wherein: the visible light in the reaction of step S1 was provided by a blue LED lamp with a power of 3W and a wavelength of 460-465nm, the distance between the blue lamp and the reactant being 4cm.
7. The method of claim 1, wherein: dy (OTf) in step S2 reaction 3 The molar dosage of the chiral Bronsted acid A1 is 0.33 percent and 1 percent of that of the arylamine compound respectively.
8. The method of claim 1, wherein: the organic solvent in the step S2 reaction is chloroform, the solvent dosage is 2mL, and the reaction time t 2 3-120h.
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Non-Patent Citations (4)
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Guanglong Pan 等.Heterogeneous photocatalytic cyanomethylarylation of alkenes with acetonitrile: synthesis of diverse nitrogenous heterocyclic compounds .《Beilstein J. Org. Chem.》.2021,第17卷第 1171-1180 页. * |
Huilin Li 等.Catalytic Enantioselective Aza-Piancatelli Rearrangement.《Angew. Chem. Int. Ed.》.2016,第55卷第 15125-15 128 页. * |
Lei Xu 等.Ln(III)/Chiral Brønsted Acid catalyzed Asymmetric Cascade Ring Opening/Aza-Piancatelli Rearrangement of D-A Cyclopropanes.《Org. Lett.》.2020,第22卷第 9016-902 1 页. * |
Yunfei Cai 等.Catalytic Asymmetric Piancatelli Rearrangement: Brønsted Acid Catalyzed 4p Electrocyclization for the Synthesis of Multisubstituted Cyclopentenones.《Angew. Chem. Int. Ed.》.2016,第55卷第 14126-14 130 页. * |
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