CN114621158A - Benzoxazine compound and synthesis method and application thereof - Google Patents
Benzoxazine compound and synthesis method and application thereof Download PDFInfo
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- CN114621158A CN114621158A CN202210288871.2A CN202210288871A CN114621158A CN 114621158 A CN114621158 A CN 114621158A CN 202210288871 A CN202210288871 A CN 202210288871A CN 114621158 A CN114621158 A CN 114621158A
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- -1 Benzoxazine compound Chemical class 0.000 title claims abstract description 42
- 238000001308 synthesis method Methods 0.000 title claims description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 48
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 24
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 23
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 15
- 150000002367 halogens Chemical class 0.000 claims abstract description 15
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 12
- 125000002541 furyl group Chemical group 0.000 claims abstract description 11
- 125000001624 naphthyl group Chemical group 0.000 claims abstract description 11
- 125000001544 thienyl group Chemical group 0.000 claims abstract description 11
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 8
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 7
- 239000001257 hydrogen Substances 0.000 claims abstract description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 6
- 150000002431 hydrogen Chemical class 0.000 claims abstract 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 90
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 35
- 150000001875 compounds Chemical class 0.000 claims description 31
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 20
- 239000003054 catalyst Substances 0.000 claims description 19
- 239000002904 solvent Substances 0.000 claims description 11
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 10
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 10
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 8
- 230000002194 synthesizing effect Effects 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 4
- 125000004799 bromophenyl group Chemical group 0.000 claims description 3
- 125000000068 chlorophenyl group Chemical group 0.000 claims description 3
- 125000001207 fluorophenyl group Chemical group 0.000 claims description 3
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical group C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 3
- AVRPFRMDMNDIDH-UHFFFAOYSA-N 1h-quinazolin-2-one Chemical compound C1=CC=CC2=NC(O)=NC=C21 AVRPFRMDMNDIDH-UHFFFAOYSA-N 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 239000012948 isocyanate Substances 0.000 abstract description 7
- 150000002513 isocyanates Chemical class 0.000 abstract description 6
- 238000006555 catalytic reaction Methods 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 238000005580 one pot reaction Methods 0.000 abstract description 2
- 125000006239 protecting group Chemical group 0.000 abstract description 2
- VYGALKFTVWDPBT-UHFFFAOYSA-N 4h-1,2-benzoxazine Chemical class C1=CC=C2CC=NOC2=C1 VYGALKFTVWDPBT-UHFFFAOYSA-N 0.000 abstract 1
- 238000006352 cycloaddition reaction Methods 0.000 abstract 1
- 238000003541 multi-stage reaction Methods 0.000 abstract 1
- 238000010189 synthetic method Methods 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 208
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 78
- 238000004896 high resolution mass spectrometry Methods 0.000 description 54
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 52
- 238000005160 1H NMR spectroscopy Methods 0.000 description 52
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 52
- 238000012512 characterization method Methods 0.000 description 30
- 238000004128 high performance liquid chromatography Methods 0.000 description 27
- 230000014759 maintenance of location Effects 0.000 description 26
- 239000000047 product Substances 0.000 description 24
- 238000005712 Baylis-Hillman reaction Methods 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- 239000000203 mixture Substances 0.000 description 12
- 235000019439 ethyl acetate Nutrition 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- 238000010898 silica gel chromatography Methods 0.000 description 9
- VXTHXGKVRHXATD-UHFFFAOYSA-N 3,4-dihydroquinazolin-2-one Chemical compound C1=CC=C2CNC(=O)[N]C2=C1 VXTHXGKVRHXATD-UHFFFAOYSA-N 0.000 description 8
- 229940125782 compound 2 Drugs 0.000 description 8
- 239000003208 petroleum Substances 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 125000001424 substituent group Chemical group 0.000 description 6
- 239000007832 Na2SO4 Substances 0.000 description 5
- 229910052794 bromium Inorganic materials 0.000 description 5
- 229910052801 chlorine Inorganic materials 0.000 description 5
- 239000000460 chlorine Substances 0.000 description 5
- 125000004185 ester group Chemical group 0.000 description 5
- 229910052731 fluorine Inorganic materials 0.000 description 5
- 229910052938 sodium sulfate Inorganic materials 0.000 description 5
- FMDGXCSMDZMDHZ-UHFFFAOYSA-N 1-isocyanato-4-methoxybenzene Chemical compound COC1=CC=C(N=C=O)C=C1 FMDGXCSMDZMDHZ-UHFFFAOYSA-N 0.000 description 4
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 4
- CMLFRMDBDNHMRA-UHFFFAOYSA-N 2h-1,2-benzoxazine Chemical compound C1=CC=C2C=CNOC2=C1 CMLFRMDBDNHMRA-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 238000007363 ring formation reaction Methods 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- QVCUKHQDEZNNOC-UHFFFAOYSA-N 1,2-diazabicyclo[2.2.2]octane Chemical compound C1CC2CCN1NC2 QVCUKHQDEZNNOC-UHFFFAOYSA-N 0.000 description 3
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 3
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 229920002554 vinyl polymer Polymers 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 238000006757 chemical reactions by type Methods 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 125000006575 electron-withdrawing group Chemical group 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 230000000269 nucleophilic effect Effects 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 150000004893 oxazines Chemical class 0.000 description 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 2
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 2
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- QKLXBIHSGMPUQS-FGZHOGPDSA-M (3r,5r)-7-[4-(4-fluorophenyl)-2,5-dimethyl-1-phenylpyrrol-3-yl]-3,5-dihydroxyheptanoate Chemical compound CC1=C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)C(C=2C=CC(F)=CC=2)=C(C)N1C1=CC=CC=C1 QKLXBIHSGMPUQS-FGZHOGPDSA-M 0.000 description 1
- UTOIEVWJKDLJGE-AQRBRUGDSA-N (4r,6s)-6-[(e)-2-[4-(4-fluorophenyl)-2,6-di(propan-2-yl)pyrimidin-5-yl]ethenyl]-4-hydroxyoxan-2-one Chemical compound C=1C=C(F)C=CC=1C1=NC(C(C)C)=NC(C(C)C)=C1\C=C\[C@@H]1C[C@@H](O)CC(=O)O1 UTOIEVWJKDLJGE-AQRBRUGDSA-N 0.000 description 1
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- 238000007115 1,4-cycloaddition reaction Methods 0.000 description 1
- RWZYAGGXGHYGMB-WGGUOBTBSA-N 2-aminobenzoic acid Chemical class NC1=CC=CC=C1[14C](O)=O RWZYAGGXGHYGMB-WGGUOBTBSA-N 0.000 description 1
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- KGWNRZLPXLBMPS-UHFFFAOYSA-N 2h-1,3-oxazine Chemical compound C1OC=CC=N1 KGWNRZLPXLBMPS-UHFFFAOYSA-N 0.000 description 1
- CTOUNZIAEBIWAW-UHFFFAOYSA-N 3,4-dihydro-1h-quinazolin-2-one Chemical class C1=CC=C2NC(=O)NCC2=C1 CTOUNZIAEBIWAW-UHFFFAOYSA-N 0.000 description 1
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 description 1
- 125000005917 3-methylpentyl group Chemical group 0.000 description 1
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 125000006306 4-iodophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1I 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- REDUQXCPUSNJOL-UHFFFAOYSA-N C(C1=CC=CC=C1)NC(CN(C(C1=CC=C(C=C1)C(C)C)=O)CC1=CC=C(C=C1)C(NO)=O)=O Chemical compound C(C1=CC=CC=C1)NC(CN(C(C1=CC=C(C=C1)C(C)C)=O)CC1=CC=C(C=C1)C(NO)=O)=O REDUQXCPUSNJOL-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- CYSWUSAYJNCAKA-FYJFLYSWSA-N ClC1=C(C=CC=2N=C(SC=21)OCC)OC1=CC=C(C=N1)/C=C/[C@H](C)NC(C)=O Chemical compound ClC1=C(C=CC=2N=C(SC=21)OCC)OC1=CC=C(C=N1)/C=C/[C@H](C)NC(C)=O CYSWUSAYJNCAKA-FYJFLYSWSA-N 0.000 description 1
- 239000002879 Lewis base Substances 0.000 description 1
- 229910010084 LiAlH4 Inorganic materials 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- FHKPLLOSJHHKNU-INIZCTEOSA-N [(3S)-3-[8-(1-ethyl-5-methylpyrazol-4-yl)-9-methylpurin-6-yl]oxypyrrolidin-1-yl]-(oxan-4-yl)methanone Chemical compound C(C)N1N=CC(=C1C)C=1N(C2=NC=NC(=C2N=1)O[C@@H]1CN(CC1)C(=O)C1CCOCC1)C FHKPLLOSJHHKNU-INIZCTEOSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
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- 150000001299 aldehydes Chemical class 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- SRVFFFJZQVENJC-IHRRRGAJSA-N aloxistatin Chemical compound CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C SRVFFFJZQVENJC-IHRRRGAJSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
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- 150000005130 benzoxazines Chemical class 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 238000007036 catalytic synthesis reaction Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 150000001923 cyclic compounds Chemical class 0.000 description 1
- 238000013461 design Methods 0.000 description 1
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- 238000001914 filtration Methods 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- JXDYKVIHCLTXOP-UHFFFAOYSA-N isatin Chemical group C1=CC=C2C(=O)C(=O)NC2=C1 JXDYKVIHCLTXOP-UHFFFAOYSA-N 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000007527 lewis bases Chemical class 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- QAPTWHXHEYAIKG-RCOXNQKVSA-N n-[(1r,2s,5r)-5-(tert-butylamino)-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 QAPTWHXHEYAIKG-RCOXNQKVSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- RWZYAGGXGHYGMB-UHFFFAOYSA-N o-aminobenzenecarboxylic acid Natural products NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 description 1
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- UAWABSHMGXMCRK-UHFFFAOYSA-L samarium(ii) iodide Chemical compound I[Sm]I UAWABSHMGXMCRK-UHFFFAOYSA-L 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 125000005415 substituted alkoxy group Chemical group 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000002424 x-ray crystallography Methods 0.000 description 1
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- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
- C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
- C07D265/14—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
- C07D239/80—Oxygen atoms
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—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
- C07D405/02—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
- 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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- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention belongs to the field of organic synthesis, and particularly relates to a benzoxazine compound, which has a structure shown in a general formula I:wherein R is1Is alkyl or benzyl; r2Is hydrogen, alkyl or halogen; r3Selected from phenyl, phenyl substituted by halogen, alkyl or alkoxy, naphthyl, furyl, thienyl, alkyl. The invention also discloses a synthetic method of the benzoxazine compound, which has the advantages that: the yield is high (63-98%); one-pot methodSynthesis without stepwise reaction; protecting raw materials without protecting groups such as Boc and the like; the reaction condition is mild, and the reaction can be carried out at room temperature. Enantioselectivity [4+2] of 4H-benzoxazine Compounds with isocyanates Using organophosphine catalysis]And performing cycloaddition reaction to construct chiral 3, 4-dihydroquinazoline-2-ketone compounds with various structures.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a benzoxazine compound and a synthesis method and application thereof.
Background
The Morita-Baylis-Hillman (MBH) reaction has simple and convenient operation, simple raw materials, mild reaction conditions and high efficiency, and is an important reaction for forming carbon-carbon bonds; and simultaneously, functional groups such as double bonds, ester groups or nitro groups can be introduced into target molecules, which lays a foundation for subsequent functional group conversion. With the intensive studies on the MBH reaction, MBH adducts, which are products of the MBH reaction, have also been attracting attention. The compound has a plurality of functional groups and a plurality of reaction sites, and is widely applied to organic catalytic asymmetric allyl alkylation and [3+ n ], [1+4] cyclization reactions as a general synthon. However, the structure of the MBH adduct is limited to the aldehyde and isatin skeleton, and the reaction site is unchanged, resulting in curing of the reaction type. Currently, there are few reports on the asymmetric reactions of the novel MBH adducts catalyzed organically. Therefore, the development of a new MBH addition product and a related organic catalytic asymmetric reaction not only can enrich the reaction types of the MBH addition product, but also can promote the application of the compound in asymmetric organic synthesis; has very important significance.
Disclosure of Invention
The invention aims to provide a benzoxazine compound with a novel structure.
It is another object of the present invention to provide a method for synthesizing the benzoxazine compound.
Another object of the present invention is to provide uses of the benzoxazine compound: constructing chiral 3, 4-dihydroquinazoline-2 ketone compounds.
In order to achieve one of the purposes, the invention adopts the following technical scheme:
the design idea of the invention is to introduce ester groups on carbon-carbon double bonds in vinyl 4H-benzo [1,3] oxazine molecules and modify the molecules into novel MBH addition compounds. The introduction of the ester group improves the reaction activity of vinyl double bonds, and the vinyl double bonds can be attacked by a chiral nucleophilic organic catalyst to form dipoles with nitrogen anion nucleophilic sites, and then the dipoles and the dipoles are subjected to asymmetric cyclization to obtain a novel chiral cyclic compound.
A benzoxazine compound having the structure of formula i:
wherein R is1Is alkyl or benzyl;
R2is hydrogen, alkyl or halogen;
R3selected from phenyl, phenyl substituted by halogen, alkyl or alkoxy, naphthyl, furyl, thienyl, alkyl.
Further, said R1Is (C1-C4) alkyl or benzyl.
Further, said R1Selected from methyl, ethyl, n-butyl, isobutyl, tert-butyl and benzyl.
Further, said R2Hydrogen, (C1-C4) alkyl or halogen.
Further, said R2Selected from hydrogen, methyl, fluorine, chlorine, bromine.
Further, said R3Selected from phenyl, naphthyl, furyl, thienyl, alkyl substituted by halogen, alkyl or alkoxy.
Further, said R3Selected from the group consisting of fluorophenyl, chlorophenyl, bromophenyl, (C1-C4) alkyl-substituted phenyl, (C1-C4) alkoxy-substituted phenyl, naphthyl, furyl, thienyl, and (C1-C4) alkyl.
Further, said R3Selected from the group consisting of fluorophenyl, chlorophenyl, bromophenyl, methoxy-substituted phenyl, methyl-substituted phenyl, naphthyl, furyl, thienyl, (C1-C4) alkyl.
Further, said R3Selected from 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methylphenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methylphenyl, 2-methoxyphenyl, 1-naphthyl, 2-furyl, 2-thienyl, n-butyl.
Further, said R3Selected from naphthyl, furyl, thienyl and (C1-C4) alkyl.
Further, said R3Selected from 1-naphthyl, 2-furyl, 2-thienyl and n-butyl.
Further, the benzoxazine compound is selected from the following compounds:
a method of synthesizing a benzoxazine compound comprising the steps of: compound M1 is reacted as follows in the presence of di-tert-butyl dicarbonate and a catalyst
Wherein R is1、R2、R3As described above; the catalyst is 1, 4-diazabicyclo [2.2.2]Octane or 4-dimethylaminopyridine.
Further, the molar ratio of the compound M1 to di-tert-butyl dicarbonate is 1: (1-3).
Further, the amount of the catalyst used was 10 mol% or more (relative to compound M1).
Further, the reaction takes toluene, dichloromethane, chloroform, ethyl acetate or acetonitrile as a solvent.
Further, the temperature of the reaction is above 20 ℃, and the time of the reaction is at least 24 h.
The application of the benzoxazine compound in synthesizing chiral quinazolinone: reacting compound I with compound M2 using a chiral phosphine catalyst to obtain a chiral quinazolinone compound:
wherein R is1、R2、R3As described above; ar is selected from phenyl substituted by halogen, alkyl or alkoxy; the chiral phosphine catalyst is one of the following:
further, Ar is selected from phenyl substituted by halogen, (C1-C4) alkyl or (C1-C4) alkoxy.
Further, Ar is selected from phenyl substituted with halogen, methyl or methanoxy.
Further, Ar is selected from 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-iodophenyl, 4-methylphenyl, 3-methylphenyl.
Further, the molar ratio of compound i to compound M2 is 1: (1-3).
Further, the amount of the chiral phosphine catalyst is more than 10 mol% (relative to the compound I).
Further, the reaction takes toluene, dichloromethane, dichloroethane, tetrahydrofuran, ethyl acetate or acetonitrile as a solvent.
Further, the reaction temperature is above-5 ℃, and the reaction time is at least 24 h.
As used herein, "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-methylpentyl.
As used herein, "alkoxy" refers to-O- (alkyl) and-O- (cycloalkyl), where alkyl, cycloalkyl are defined herein, and non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentyloxy, 2-pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, 2-hexyloxy, 3-methylpentyloxy, cyclopropyloxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. Alkoxy groups typically have 1 to 7 carbon atoms connected by an oxygen bridge. Alkoxy also includes substituted alkoxy. Alkoxy groups may be optionally substituted one or more times with halo.
As used herein, "halogen" refers to fluorine, chlorine, bromine and iodine.
"benzyl" as used herein refers to PhCH2-。
The "substitution" of the "substituted phenyl" or "substituted phenyl" as described herein may be mono-or polysubstituted; "substituted phenyl" or "substituted phenyl" includes: (1) the phenyl ring has a non-hydrogen substituent; (2) the benzene ring has two or more non-hydrogen substituents which may be the same or different. The substituted position may be any of positions of benzene rings 2, 3,4, 5, 6.
"furyl" includes 2-furyl, 3-furyl.
"thienyl" includes 2-thienyl, 3-thienyl.
The invention has the following beneficial effects:
the MBH addition product has a novel structural framework, and can be further converted into chiral 3, 4-dihydroquinazoline-2 ketone compounds.
The synthesis method of the invention is to use diazabicyclo [2.2.2]In the presence of octane, MBH alcohol is first reacted with Boc2The reaction of O to form MBH carbonate and subsequent intramolecular cyclization to obtain 4H-benzoxazine compound has the advantages of: the yield is high (63-98%); the synthesis is carried out by a one-pot method, and the economy is realized; step-by-step reaction is not needed, the operation is simple, and the practicability is strong; the raw material does not need to be protected by a protecting group such as BocIs simple and easy to obtain; the reaction condition is mild, and the reaction can be carried out at room temperature; the substrate has wide range and contains various electron-withdrawing or electron-donating substituents.
The 4H-benzoxazine compound and isocyanate are subjected to enantioselective [4+2] cycloaddition reaction under the catalysis of organic phosphine, so that chiral 3, 4-dihydroquinazoline-2 ketone compounds with various structures can be constructed, the reaction yield is high, the enantioselectivity is good, and the reaction conditions are mild.
Detailed Description
Unless otherwise indicated, starting materials and solvents were commercially available without further purification. Thin Layer Chromatography (TLC) used 60F254 silica gel plates, 254 and 365nm uv light. Silica gel with the particle size of 300-400 meshes is used for silica gel column chromatography. The NMR spectra were recorded using a Brucker-400MHz NMR spectrometer with chemical shifts in ppm and coupling constants in Hz. High Resolution Mass Spectrometry (HRMS) uses ESI ionization. High performance liquid chromatography analysis used Agilent 1200 (UV detection at 254 nm). Chiralpak IF-3, IB column was purchased from Daicel chemical industries, Inc. Optical rotation was measured using Rudolph Research Analytical (Atopol I).
Example 1
Synthesis of starting materials
Step 1: at 0 ℃ to LiAlH4(60mmol, 2.0 equiv.) in THF (60mL) was added dropwise a solution of substituted 2-aminobenzoic acid (30mmol, 1.0 equiv.) in THF (60mL) and the resulting mixture was allowed to warm to room temperature and stirred for 2 h. After the reaction was complete, the mixture was hydrolyzed by the addition of water (6mL) and 5 wt% NaOH solution (10.0 mL). The suspension was filtered and the residue was washed with EtOAc. The organic phase was washed successively with water and saturated aqueous NaCl solution, anhydrous Na2SO4Drying, concentration under reduced pressure and purification by silica gel column chromatography (petroleum ether/ethyl acetate 1/1) gave the product S2.
Step 2: to S2(20mmol, 1.0 equiv.) and Et at 0 deg.C3N (40mmol, 2.0 equiv.) in THF (100mL) was added slowlyR3COCl (20.0mmol, 1.0 equiv.). After completion, the mixture was gradually warmed to room temperature and stirred for 12 hours. The solvent was removed under reduced pressure and the crude product S3 was used directly in the next reaction without further purification.
And step 3: a500 mL round bottom flask was charged with S3(20mmol, 1.0 equiv.), PCC (pyridinium chlorochromate, 30mmol, 1.5 equiv.), and DCM (250mL), and the mixture was stirred at room temperature for 24 hours, after which it was filtered through celite. Concentration gave the crude product which was then purified by silica gel column chromatography (petroleum ether/ethyl acetate 20:1) to give product S4.
And 4, step 4: a250 mL round bottom flask was charged with S4(10mmol,1.0 equiv.), DABCO (10mmol,1.0 equiv.), N (C)2H4OH)3(8mmol,0.8 equiv.), THF (100mL), and methyl acrylate (30mmol, 3.0 equiv.). After stirring at room temperature for 72 h, the mixture was concentrated and dissolved in DCM (50mL) and then sequentially with saturated NaHCO3Washing with aqueous solution, saturated NaCl aqueous solution, and anhydrous Na2SO4Drying, removal of solvent and purification of the residue by silica gel column chromatography (petroleum ether/ethyl acetate 4:1) gave product 1.
Example 2
The benzoxazine compound 2a was obtained in 47% yield under 4-Dimethylaminopyridine (DMAP) conditions using MBH alcohol 1a as a substrate. By substitution of 1, 4-diazabicyclo [2.2.2]Octane (DABCO) as Lewis base catalyst gave the product 2a in 96% yield. The solvent and the catalyst are screened, and the optimal reaction conditions are determined: MBH alcohol 1a (0.1mmol), Boc2O (0.15mmol), DABCO (20 mol%) and CH2Cl2(0.5mL) of the mixed system was reacted at room temperature for 24 hours.
TABLE 1
Reaction conditions are as follows: 1a (0.1mmol), Boc2The mixture of O (0.15mmol) and catalyst (20 mmol%) in solvent (0.5mL) was stirred at Room Temperature (RT) for 24 h.
Compound 2a characterization data:
yellow oil, 28.1mg, 96% yield.1H NMR(400MHz,CDCl3)δ8.23–8.01(m,2H),7.52–7.46(m,1H),7.46–7.39(m,2H),7.39–7.30(m,2H),7.20(m,J=7.5,4.3Hz,1H),7.04(m,J=7.5,0.9Hz,1H),6.44(d,J=11.6Hz,2H),5.53(s,1H),3.84(s,3H)。13C NMR(101MHz,CDCl3) δ 165.9,156.2,139.5,138.9,132.5,131.6,129.5,128.4,128.1,126.7,125.3,125.2,123.1,73.6, 52.3. HRMS accurate mass calculation [ M + H]+(C18H16NO3) m/z 294.1125, found m/z 294.1124.
Examples 2 to 27 extended the substrate. The synthesis method is suitable for MBH alcohol 1 with various substituent groups, and the reaction yield is generally high. Having different ester groups (CO)2R1) The MBH alcohol 1a-e is obtained with the yield of 82-96%; when R1 is benzyl Bn, the yield is moderate (63%); both electron withdrawing groups (F, Cl, Br) and electron donating groups (Me, MeO) can be introduced into the substituent (R)3) In the aromatic ring, the product is obtained with a yield of 81-98%; the product is obtained by the 1-naphthyl and heteroaryl with large steric hindrance in 81-87% yield; the yield of the MBH alcohol containing the aliphatic substituent is 71 percent; substituent R2The electronic properties and positions of (A) have almost no influence on the reaction, and the yield of the corresponding product is 81-95%. These results indicate that the method of the present invention is a synthesis of 4H-benzo [ d ]][1,3]An efficient method for oxazine compounds.
To a solution of compound 1(0.1mmol,1.0 eq) and DABCO (0.02mmol,0.2 eq) in DCM (0.5mL) was added slowly (Boc)2O (0.15mmol,1.5 equiv.). After stirring at room temperature for 24 hours, the reaction mixture was successively diluted with dilute hydrochloric acid (1mol/L) and saturated NaHCO3Aqueous solution, saturated NaClThe aqueous solution was washed, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether/ethyl acetate 10/1) to obtain product 2.
Example 3
Compound 2b characterization data: yellow oil, 28mg, 91% yield.1H NMR(400MHz,CDCl3)δ8.16–8.06(m,2H),7.53–7.46(m,1H),7.45–7.38(m,2H),7.39–7.32(m,2H),7.20(m,J=7.5,5.4,3.3Hz,1H),7.07–7.00(m,1H),6.44(d,J=13.4Hz,2H),5.52(s,1H),4.29(q,J=7.1Hz,2H),1.31(t,J=7.1Hz,3H)。13C NMR(101MHz,CDCl3) δ 165.5,156.3,139.5,139.2,132.6,131.6,129.5,129.3,128.4,128.2,126.7,125.3,125.2,123.2,73.8,61.4, 14.3. HRMS accurate mass calculation [ M + H]+(C19H18NO3) m/z for 308.1281, found m/z 308.1277.
Example 4
Compound 2c characterization data: yellow oil, 30.6mg, 91% yield.1H NMR(400MHz,CDCl3)δ8.23–7.98(m,2H),7.52–7.46(m,1H),7.42(m,J=7.4,1.7Hz,2H),7.38–7.33(m,2H),7.20(m,J=7.4,5.4,3.3Hz,1H),7.06–7.00(m,1H),6.44(d,J=12.8Hz,2H),5.52(s,1H),4.24(t,J=6.6Hz,2H),1.71–1.61(m,2H),1.43–1.31(m,2H),0.92(t,J=7.4Hz,3H)。13C NMR(101MHz,CDCl3) δ 165.6,156.3,139.5,139.2,132.6,131.6,129.5,129.3,128.4,128.1,126.7,125.3,125.2,123.2,73.9,65.3,30.8,19.3, 13.8. HRMS accurate mass calculation [ M + H]+(C21H22NO3) m/z for 336.1594, found m/z 336.1589.
Example 5
Compound 2d characterization data: yellow oil, 28.0mg, 84% yield.1H NMR(400MHz,CDCl3)δ8.16–7.93(m,2H),7.52–7.45(m,1H),7.45–7.39(m,2H),7.37–7.32(m,2H),7.20(m,J=7.6,5.0,3.6Hz,1H),7.04(d,J=7.4Hz,1H),6.45(d,J=8.4Hz,2H),5.53(s,1H),4.02(d,J=6.6Hz,2H),1.98(m,J=13.4,6.7Hz,1H),0.93(d,J=6.7Hz,6H)。13C NMR(101MHz,CDCl3) δ 165.6,156.3,139.5,139.2,132.7,131.6,129.5,129.4,128.4,128.2,126.7,125.3,125.2,123.2,73.9,71.5,27.9,19.2, 19.2. HRMS accurate mass calculation [ M + H]+(C21H22NO3) m/z for 336.1594, found m/z 336.1591.
Example 6
Compound 2e characterization data: yellow oil, 27.6mg, 82% yield.1H NMR(400MHz,CDCl3)δ8.21–8.00(m,2H),7.51–7.45(m,1H),7.45–7.38(m,2H),7.37–7.29(m,2H),7.22–7.14(m,1H),7.02(m,J=7.6,1.1Hz,1H),6.41(s,1H),6.32(s,1H),5.44(s,1H),1.49(s,9H)。13C NMR(101MHz,CDCl3) δ 164.7,156.3,140.5,139.5,132.7,131.5,129.4,128.3,128.1,126.6,125.2,125.1,123.4,81.8,74.1,28.1, 27.5. HRMS accurate mass calculation [ M + H]+(C21H22NO3) m/z for 336.1594, found m/z 336.1592.
Example 7
Characterization data for compound 2 f: yellow oil, 23.1mg, 63% yield.1H NMR(400MHz,CDCl3)δ8.19–7.90(m,2H),7.52–7.43(m,1H),7.43–7.29(m,9H),7.19(m,J=7.5,5.7,2.9Hz,1H),7.05–6.99(m,1H),6.47(s,2H),5.52(s,1H),5.46–5.15(m,2H)。13C NMR(101MHz,CDCl3) δ 165.4,156.3,139.5,138.9,135.7,132.6,131.6,123.0,129.6,128.8,128.5,128.4,128.4,128.2,126.8,125.3,125.3,123.0,73.7, 67.1. HRMS accurate mass calculation [ M + H]+(C24H20NO3) m/z for 370.1438, found m/z 370.1433.
Example 8
Characterization data for compound 2 g: yellow oil, 28.5mg, 92% yield.1H NMR(400MHz,CDCl3)δ8.13–7.91(m,2H),7.43–7.37(m,2H),7.37–7.30(m,2H),7.20(m,J=7.3,2.0Hz,1H),7.05–7.00(m,1H),6.43(d,J=3.9Hz,2H),5.51(s,1H),3.83(s,3H)。13C NMR(126MHz,CDCl3)δ165.9,163.9(JCF=257.9Hz),155.3,139.2,138.8,137.8,131.1,129.7(JCF=10.5Hz),129.4,128.7,127.0,125.3(JCF=3.2Hz),122.9,115.5(JCF21.8Hz),73.8, 52.4. HRMS accurate mass calculation [ M + H]+(C18H15FNO3) m/z 312.1030, found m/z 312.1024.
Example 9
Compound 2h characterization data: yellow oil, 30.4mg, 93% yield.1H NMR(400MHz,CDCl3)δ8.06–7.98(m,2H),7.44–7.37(m,2H),7.36–7.30(m,2H),7.21(m,J=7.2,1.9Hz,1H),7.03(m,J=7.6,1.2Hz,1H),6.43(d,J=4.0Hz,2H),5.51(s,1H),3.83(s,3H)。13C NMR(101MHz,CDCl3) δ 165.9,155.3,139.3,138.8,137.9,131.1,129.8,129.3,128.7,127.0,125.3,123.0,73.8, 52.4. HRMS accurate mass calculation [ M + H]+(C18H15ClNO3) m/z 328.0735, found m/z 328.0733.
Example 10
Characterization data for compound 2 i: yellow oil, 34.8mg, 94% yield.1H NMR(400MHz,CDCl3)δ8.11–7.87(m,2H),7.59–7.51(m,2H),7.40–7.29(m,2H),7.21(m,J=7.1,1.9Hz,1H),7.06–6.99(m,1H),6.43(d,J=3.8Hz,2H),5.51(s,1H),3.83(s,3H)。13C NMR(101MHz,CDCl3) δ 165.9,155.4,139.3,138.8,131.7,131.6,129.7,129.6,127.0,127.0,126.4,125.3,125.3,123.0,73.8, 52.4. HRMS accurate mass calculation [ M + H]+(C18H15BrNO3) m/z 372.0230, found m/z 372.0224.
Example 11
Compound 2j characterization data: yellow oil, 24.7mg, 81% yield.1H NMR(400MHz,CDCl3)δ8.18–7.82(m,2H),7.38–7.31(m,2H),7.24(s,1H),7.22(s,1H),7.18(m,J=7.5,6.0,2.6Hz,1H),7.06–7.01(m,1H),6.42(d,J=8.3Hz,2H),5.52(d,J=1.1Hz,1H),3.84(s,3H),2.40(s,3H)。13C NMR(101MHz,CDCl3) δ 166.1,156.5,142.2,139.7,139.0,129.8,129.5,129.4,129.2,128.2,126.5,125.3,125.2,123.2,73.57,52.4, 21.7. HRMS accurate mass calculation [ M + H]+(C19H18NO3) m/z 308.1281, found m/z 308.1276.
Example 12
Compound 2k characterization data: yellow oil, 30.8mg, 96% yield.1H NMR(400MHz,CDCl3)δ8.09–8.00(m,2H),7.40–7.28(m,2H),7.17(m,J=7.1,2.1Hz,1H),7.09–6.99(m,1H),6.97–6.86(m,2H),6.41(d,J=2.5Hz,2H),5.51(s,1H),3.85(s,3H),3.84(s,3H)。13C NMR(101MHz,CDCl3) δ 166.1,162.6,156.3,139.8,138.9,130.0,129.5,129.4,126.3,125.3,125.0,125.0,123.1113.8, 73.5,55.5, 52.4. HRMS accurate mass calculation [ M + H]+(C19H18NO4) m/z 324.1230, found m/z 324.1226.
Example 13
Characterization data for compound 2 l: yellow oil, 26.4mg, 82% yield.1H NMR(400MHz,CDCl3)δ7.71–7.62(m,2H),7.35(m,J=3.7,1.0Hz,2H),7.32(d,J=7.9Hz,1H),7.20(m,J=7.5,5.0,3.6Hz,1H),7.04(m,J=8.2,1.1Hz,2H),6.43(d,J=7.2Hz,2H),5.52(s,1H),3.87(s,3H),3.84(s,3H)。13C NMR(101MHz,CDCl3) δ 166.0,159.7,156.2,139.5,138.9,134.0,129.5,129.4,126.8,125.3,125.2,123.1,120.7,118.3,112.6,73.7,55.5, 52.4. HRMS accurate mass calculation [ M + H]+(C19H18NO4) m/z 324.1230, found m/z 324.1226.
Example 14
Characterization data for compound 2 m: yellow oil, 28.8mg, 94% yield.1H NMR(400MHz,CDCl3)δ8.09–7.87(m,2H),7.38–7.32(m,2H),7.24(d,J=1.7Hz,1H),7.22(s,1H),7.19(m,J=7.4,5.9,2.8Hz,1H),7.06–6.93(m,1H),6.42(d,J=8.4Hz,2H),5.52(s,1H),3.84(s,3H),2.40(s,3H)。13C NMR(101MHz,CDCl3) δ 166.0,156.5,142.1,139.6,138.9,129.8,129.5,129.4,129.2,128.2,126.5,125.3,125.2,123.2,73.5,52.4, 21.7. HRMS accurate mass calculation [ M + H]+(C19H18NO3) m/z 308.1281, found m/z 308.1276.
Example 15
Characterization data for compound 2 n: yellow oil, 31.4mg, 98% yield.1H NMR(400MHz,CDCl3)δ7.71–7.62(m,2H),7.35(m,J=3.8,0.9Hz,2H),7.32(d,J=7.9Hz,1H),7.20(m,J=7.4,4.9,3.6Hz,1H),7.04(m,J=8.3,1.2Hz,2H),6.43(d,J=7.3Hz,2H),5.52(s,1H),3.87(s,3H),3.84(s,3H)。13C NMR(101MHz,CDCl3) δ 166.0159.7,156.2,139.5,138.9,134.0129.6,129.4,126.8,125.3,125.3,123.1,120.7,118.3,112.6, 73.7,55.5, 52.4. HRMS accurate mass calculation [ M + H]+(C19H18NO4) m/z 324.1230, found m/z 324.1225.
Example 16
Compound 2o characterization data: yellow oil, 29.1mg, 87% yield.1H NMR(400MHz,CDCl3)δ9.01(m,J=8.6,1.1Hz,1H),7.96(m,J=8.1,3.9,1.1Hz,2H),7.90–7.84(m,1H),7.59(m,J=8.5,6.8,1.5Hz,1H),7.55–7.49(m,2H),7.49–7.43(m,1H),7.40(m,J=7.6,1.5Hz,1H),7.33–7.19(m,1H),7.10–6.97(m,1H),6.55(d,J=7.3Hz,2H),5.66(s,1H),3.87(s,3H)。13C NMR(101MHz,CDCl3) δ 166.0,157.1,139.3,138.9,134.1,131.9,131.3,130.3,129.8,129.6,129.0,128.6,127.2,127.1,126.2,126.1,125.4,125.1,124.9,122.8,74.0, 52.4. HRMS accurate mass calculation [ M + H]+(C22H18NO3) m/z 344.1281, found m/z 344.1278.
Example 17
Compound 2p characterization data: yellow oil, 22.9mg, 81% yield.1H NMR(400MHz,CDCl3)δ7.59(s,1H),7.36(m,J=15.1,7.7Hz,2H),7.19(t,J=7.3Hz,1H),7.07–6.97(m,2H),6.55–6.48(m,1H),6.44(s,1H),6.38(s,1H),5.56(s,1H),3.83(s,3H)。13C NMR(101MHz,CDCl3) δ 165.8,149.2,146.6,145.9,138.8,138.6,129.8,129.7,126.9,125.4,125.3,123.1,115.2,112.0,73.6, 52.4. HRMS accurate mass calculation [ M + H]+(C16H14NO4) m/z 284.0917, found m/z 284.0914.
Example 18
Compound 2q characterization data: yellow oil, 28.2mg, 87% yield.1H NMR(400MHz,CDCl3)δ7.68(m,J=3.7,1.2Hz,1H),7.48(m,J=5.0,1.2Hz,1H),7.39–7.28(m,2H),7.18(m,J=7.2,1.7Hz,1H),7.08(m,J=5.0,3.7Hz,1H),7.02(d,J=7.5Hz,1H),6.41(d,J=12.7Hz,2H),5.53(s,1H),3.84(s,3H)。13C NMR(101MHz,CDCl3) δ 165.9,152.9,139.4,138.7,136.9,130.7,130.3,129.6,129.6,127.9,126.6,125.3,125.0,123.0,73.9, 52.4. HRMS accurate mass calculation [ M + H]+(C16H14NO3S) m/z 300.0689, found m/z 300.0685.
Example 19
Compound 2r characterization data: yellow oil, 19.4mg, 71% yield.1H NMR(400MHz,CDCl3)δ7.29(m,J=8.5,8.1,1.7Hz,1H),7.24–7.08(m,2H),6.90(d,J=7.5Hz,1H),6.43(s,1H),6.25(s,1H),5.45(s,1H),3.82(s,3H),2.55–2.18(m,2H),1.59(m,J=15.5,7.8,4.6Hz,2H),1.36(m,J=14.6,9.4,5.4Hz,2H),0.90(t,J=7.3Hz,3H)。13C NMR(101MHz,CDCl3) δ 165.9,162.6,139.0,138.7,129.6,129.7,126.4,125.0,124.4,122.2,73.2,52.3,35.0,28.3,22.7, 13.8. HRMS accurate mass calculation [ M + H]+(C16H20NO3) m/z 273.1365, found m/z 274.1433.
Example 20
Compound 2s characterization data: yellow oil, 25.6mg, 83% yield.1H NMR(400MHz,CDCl3)δ8.07(m,J=8.3,1.3Hz,2H),7.50–7.44(m,1H),7.44–7.38(m,2H),7.25(d,J=10.9Hz,1H),7.18–7.10(m,1H),6.83(s,1H),6.41(d,J=7.7Hz,2H),5.53(s,1H),3.84(s,3H),2.34(s,3H)。13C NMR(101MHz,CDCl3) δ 166.1,155.6,139.0,137.1,136.7,132.8,131.5,130.2,129.6,128.4,128.0,125.7,125.1,122.9,73.6,52.4, 21.4. HRMS accurate mass calculation [ M + H]+(C19H18NO3) m/z 308.1281, found m/z 308.1277.
Example 21
Compound 2t characterization data: yellow oil, 28.0mg, 90% yield.1H NMR(400MHz,CDCl3)δ8.20–7.97(m,2H),7.51(m,J=8.3,6.3Hz,1H),7.44(t,J=7.5Hz,2H),7.08(m,J=9.6,2.3Hz,1H),7.01(m,J=8.4,5.9Hz,1H),6.91(m,J=8.4,2.5Hz,1H),6.43(s,2H),5.55(s,1H),3.84(s,3H)。13C NMR(101MHz,CDCl3)δ165.8,163.4(JCF=246.4Hz),157.1,141.3(JCF=9.1Hz),138.7,132.1,132.0,129.5,128.5,128.3,126.5(JCF=10.1Hz),118.8(JCF=3.0Hz),113.5(JCF=22.2Hz),112.2(JCF23.2Hz),73.6, 52.5. HRMS accurate mass calculation [ M + H]+(C18H15FNO3) m/z 311.0958, found m/z 312.1023.
Example 22
Characterization data for compound 2 u: yellow oil, 31.1mg,95% yield.1H NMR(400MHz,CDCl3)δ8.18–8.00(m,2H),7.57–7.48(m,1H),7.47–7.40(m,2H),7.35(d,J=2.2Hz,1H),7.21–7.13(m,1H),6.98(d,J=8.6Hz,1H),6.43(d,J=6.4Hz,2H),5.57(s,1H),3.83(s,3H)。13C NMR(101MHz,CDCl3) δ 165.8,157.2,140.8,138.7,135.0,132.2,132.0,129.5,128.5,128.3,126.6,126.3,125.3,121.5,73.6, 52.5. HRMS accurate mass calculation [ M + H]+(C18H15ClNO3) m/z 328.0735, found m/z 328.0730.
Example 23
Compound 2v characterization data: yellow oil, 34.7mg, 93% yield.1H NMR(400MHz,CDCl3)δ8.15–8.03(m,2H),7.57–7.48(m,2H),7.47–7.39(m,2H),7.32(m,J=8.1,2.0Hz,1H),6.92(d,J=8.1Hz,1H),6.42(d,J=13.4Hz,2H),5.58(s,1H),3.83(s,3H)。13C NMR(101MHz,CDCl3) δ 165.7,157.2,141.0,138.6,132.2,132.0,129.5,129.5,128.5,128.3,128.3,126.6,122.9,122.0,73.6, 52.5. HRMS accurate mass calculation [ M + H]+(C18H15BrNO3) m/z 372.0230, found m/z 372.0231.
Example 24
Compound 2w characterization data: yellow oil, 24.9mg, 81% yield.1H NMR(400MHz,CDCl3)δ8.15–7.93(m,2H),7.50–7.44(m,1H),7.44–7.38(m,2H),7.25(d,J=10.9Hz,2H),7.15(m,J=8.0,2.1Hz,1H),6.83(s,1H),6.41(d,J=7.7Hz,2H),5.53(s,1H),3.84(s,3H),2.34(s,3H)。13C NMR(101MHz,CDCl3) δ 166.1,156.3,139.5,139.3,139.1,132.7,131.56,129.3,128.4,128.1,127.5,125.9,125.1,120.2,73.7,52.3, 21.4. HRMS accurate mass calculation [ M + H]+(C19H18NO3) m/z 308.1281, found m/z 308.1277.
Example 25
Compound 2x characterization data: yellow oil, 27.8mg, 86% yield.1H NMR(400MHz,CDCl3)δ8.13–8.05(m,2H),7.39–7.29(m,2H),7.20(m,J=7.1,1.8Hz,1H),7.14–7.06(m,2H),7.05–7.00(m,1H),6.43(d,J=5.6Hz,2H),5.51(s,1H),4.29(q,J=7.1Hz,2H),1.30(t,J=7.1Hz,3H)。13C NMR(101MHz,CDCl3)δ165.5,165.1(JCF=252.9Hz),155.4,139.4,139.2,130.4(JCF=9.0Hz),129.6,129.4,128.8(JCF=3.1Hz),126.8,125.2,125.2,123.0,115.5(JCF22.0Hz),73.9,61.4, 14.3. HRMS accurate mass calculation [ M + H]+(C19H17FNO3) m/z 326.1187, found m/z 326.1181.
Example 26
Compound 2y characterization data: yellow oil, 29.8mg, 87% yield.1H NMR(400MHz,CDCl3)δ8.08–7.99(m,2H),7.41–7.36(m,2H),7.36–7.30(m,2H),7.20(m,J=7.2,1.9Hz,1H),7.02(m,J=7.6,1.3Hz,1H),6.43(d,J=6.6Hz,2H),5.51(s,1H),4.28(q,J=7.1Hz,2H),1.30(t,J=7.1Hz,3H)。13C NMR(101MHz,CDCl3) δ 165.4,155.3,139.3,139.2,137.8,131.2,129.6,129.5,129.4,128.7,126.9,125.3,125.3,123.1,74.0,61.4, 14.3. HRMS accurate mass calculation [ M + H]+(C19H17ClNO3) m/z 342.0891, found m/z 342.0887.
Example 27
Compound 2z characterization data: yellow oil, 35.4mg, 92% yield.1H NMR(400MHz,CDCl3)δ7.99–7.93(m,2H),7.58–7.52(m,2H),7.39–7.29(m,2H),7.20(m,J=7.1,2.0Hz,1H),7.05–6.98(m,1H),6.43(d,J=6.1Hz,2H),5.50(s,1H),4.28(q,J=7.1Hz,2H),1.30(t,J=7.1Hz,3H)。13C NMR(101MHz,CDCl3) δ 165.4,155.4,139.2,139.2,131.7,131.6,129.6,129.6,129.4,127.0,126.4,125.3,125.3,123.0,74.0,61.4, 14.3. HRMS accurate mass calculation [ M + H]+(C19H17ClNO3) m/z 386.0386, found m/z 386.0380.
Example 28
Chiral dihydroquinazolinones are structural units widely existing in bioactive molecules and natural products, and many asymmetric catalytic synthesis methods for synthesizing chiral dihydroquinazolinones exist at present, but all of the methods need to use a metal/ligand catalytic system. The invention successfully constructs the chiral 3, 4-dihydroquinazolin-2-one compound through the [4+2] cyclization reaction of a novel 4H-benzo [ d ] [1,3] oxazine compound and isocyanate under the organic catalysis condition, and the reaction has good yield and enantioselectivity.
Reaction of compound 2a with 4-methoxyphenyl isocyanate 4a in the presence of chiral phosphine P2 gave 3, 4-dihydroquinazolin-2-one 5aa in 43% yield and 39% ee. By screening the chiral phosphine organic catalyst, the yield and enantioselectivity are improved, and the yield of 44% ee and 85% ee can be obtained by adopting the optimal chiral phosphine P5 for reaction. Further optimization of the reaction conditions found that: in the usual organic solvents, CH2Cl2Is the best solvent; the effect of temperature on the reaction is observed to find that: when the reaction was carried out at-5 ℃ the product 5aa was obtained in 50% yield, 89% ee. By changing the proportion of reactants and the dosage of a catalyst, the yield can be improved to 61% under the condition of not influencing enantioselectivity; by screening the reaction concentration, the yield can be improved to 75%; adding Na2SO4With the additive, the results are not significantly improved. The final optimal reaction conditions are as follows: 4-methoxyphenyl isocyanate 4a (0.075mmol),4H-benzo [ d ]][1,3]Oxazine derivative 2a (0.05mmol), P5(20 mol%) CH2Cl2(3.0mL) the solution was stirred at-5 ℃ for 24 hours; the 3, 4-dihydroquinazolin-2 one was successfully obtained in 5aa, 75% yield, 90% ee.
TABLE 2
Reaction conditions are as follows: a mixture of 2a (0.05mmol), 4a (0.06mmol) and catalyst (10 mol%) was stirred in the indicated solvent (1.0mL) under Ar at the indicated temperature for 24 h. [ d ]]4a(0.075mmol),P5(20mol%);[e]CH2Cl2(2.0mL);[f]CH2Cl2(3.0mL);[g]CH2Cl2(4.0mL);[h]Na2SO4(20mg)。
Compound 5aa characterization data:
light viscous oil, 16.6mg, 75% yield.1H NMR(400Hz,CDCl3):δ7.93–7.82(m,2H),7.53(ddd,J=12.5,6.8,4.2Hz,2H),7.43(dd,J=10.5,4.6Hz,2H),7.37–7.27(m,2H),7.20–7.12(m,3H),6.93–6.76(m,2H),6.37(s,1H),5.81(s,1H),5.77(d,J=0.7Hz,1H),3.77(s,3H),3.73(s,3H)。13C NMR(101MHz,CDCl3) δ 171.7,165.9,158.4,152.2,139.4,136.2,135.7,133.7,132.7,129.2,128.9,128.6,127.8,126.7,126.7,124.5,123.3,118.6,114.3,63.5,55.5, 52.3. HRMS accurate mass calculation [ M + H]+(C26H23N2O5) m/z 443.1601, found m/z 433.1606. HPLC conditions are Daicel Chiralpak IF-3 column, n-hexane/2-propanol 60/40, flow rate 1.0mL/min, lambda 254nm, retention time tR(minor)=13.909min,tR(major)=20.523min,90%ee.[α]20 D=-75.0(c=1.00,CH2Cl2)。
To a solution of compound 2(0.05mmol,1.0 equiv.), aryl isocyanate 4(0.075mmol,1.5 equiv.) in DCM (1.5mL) under Ar protection was added a solution of catalyst P5(20 mol%) in DCM (1.5 mL). The mixture was stirred at-5 ℃ for 24 hours. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate 5/1) to give product 5.
The application range of the asymmetric reaction catalyzed by the organic phosphine is wide, the benzoxazine compound in the previous embodiment can be reacted to obtain the chiral 3, 4-dihydroquinazolin-2-one derivative 5 (embodiment 29-50), and the yield and the enantioselectivity are high. The benzoxazine with different ester groups and 4-methoxyphenyl isocyanate 4a smoothly react to obtain a 3, 4-dihydroquinazolin-2-one compound, wherein the yield is 74-80%, and 86-90% ee; aromatic R with different electron withdrawing groups (F, Cl, Br) and electron donating groups (Me, MeO)3Obtaining a product with the yield of 71-78% and the ee of 89-91%, and obtaining a product with benzoxazine with aliphatic groups with the yield of 61% and the ee of 84%; different substituents R2Can also be incorporated into the aromatic ring of benzoxazines in yields of 63-81% and ee of 90-92%. The isocyanate with different substituents (F, Cl, Br and Me) can obtain a product with 73-81% of yield and 75-89% of ee no matter how the electronic property and the position of the isocyanate are changed; the reaction of 2v benzoxazine with 4g isocyanate gave 5vg of 3, 4-dihydroquinazolin-2-one in 80% yield and 83% ee.
Example 29
Pale yellow oil, 16.8mg, 74% yield.1H NMR(400MHz,CDCl3)δ7.97–7.78(m,2H),7.61–7.48(m,2H),7.44(t,J=7.5Hz,2H),7.38–7.28(m,2H),7.22–7.11(m,3H),6.92–6.77(m,2H),6.37(s,1H),5.83(s,1H),5.74(d,J=0.6Hz,1H),4.35–4.05(m,2H),3.77(s,3H),1.24(t,J=7.1Hz,3H)。13C NMR(101MHz,CDCl3) δ 171.6,165.5,158.4,152.3,139.7,136.2,135.7,133.8,132.6,129.1,128.9,128.5,127.8,126.7,126.4,124.5,123.6,118.8,114.3,63.3,61.4,55.5, 14.1. HRMS accurate mass calculation [ M + H]+(C27H25N2O5) m/z 457.1758, found m/z 457.1759. HPLC conditions are Daicel Chiralpak IF-3 column, n-hexane/2-propanol 60/40, flow rate 1.0mL/min, lambda 254nm, retention time tR(minor)=12.23min,tR(major)=17.761min,87%ee.[α]20 D=-100.74(c=1.00,CH2Cl2)。
Example 30
Pale yellow oil, 19.1mg, 79% yield.1H NMR(400MHz,CDCl3)δ7.86(dd,J=5.2,3.3Hz,2H),7.53(ddd,J=8.0,6.7,4.7Hz,2H),7.43(dd,J=10.4,4.7Hz,2H),7.32(dt,J=9.5,4.1Hz,2H),7.22–7.09(m,3H),6.90–6.79(m,2H),6.35(s,1H),5.83(s,1H),5.74(d,J=0.8Hz,1H),4.25–4.04(m,2H),3.77(s,3H),1.65–1.49(m,2H),1.34(dq,J=14.6,7.3Hz,2H),0.93(t,J=7.4Hz,3H)。13C NMR(101MHz,CDCl3) δ 171.6,165.6,158.4,152.3,139.7,136.2,135.8,133.8,132.6,129.1,128.9,128.5,127.8,126.7,126.3,124.5,123.6,118.8,114.3,65.3,63.3,55.5,30.5,19.2, 13.8. HRMS accurate mass calculation [ M + H]+(C29H29N2O5) m/z 485.2071, found m/z 485.2074. HPLC conditions are Daicel Chiralpak IF-3 column, n-hexane/2-propanol 60/40, flow rate 1.0mL/min, lambda 254nm, retention time tR(minor)=11.729min,tR(major)=17.575min,86%ee.[α]20 D=-108.44(c=1.00,CH2Cl2)。
Example 31
Pale yellow oil, 19.3mg, 80% yield.1H NMR(400MHz,CDCl3)δ7.92–7.81(m,2H),7.61–7.48(m,2H),7.43(dd,J=10.5,4.6Hz,2H),7.38–7.27(m,2H),7.22–7.10(m,3H),6.91–6.77(m,2H),6.36(s,1H),5.84(s,1H),5.77(d,J=0.7Hz,1H),3.94(qd,J=10.6,6.7Hz,2H),3.77(s,3H),1.93(dp,J=13.4,6.7Hz,1H),0.92(dd,J=6.7,3.7Hz,6H)。13C NMR(101MHz,CDCl3) δ 171.6,165.5,158.4,152.3,139.7,136.1,135.7,133.8,132.6,129.1,128.9,128.5,127.8,126.7,126.2,124.5,123.6,118.8,114.3,77.4,71.4,63, 55.5,27.7,19.1, 19.1. HRMS accurate mass calculation [ M + H]+(C29H29N2O5) m/z 485.2071, found m/z 485.2076. HPLC conditions are Daicel Chiralpak IF-3 column, n-hexane/2-propanol 60/40, flow rate 1.0mL/min, lambda 254nm, retention time tR(minor)=11.377min,tR(major)=17min,86%ee.[α]20 D=-116.74(c=1.00,CH2Cl2)。
Example 32
Pale yellow oil, 19.9mg, 77% yield.1H NMR(400MHz,CDCl3)δ7.92–7.82(m,2H),7.64–7.48(m,2H),7.47–7.27(m,9H),7.21–7.06(m,3H),6.89–6.75(m,2H),6.40(s,1H),5.84(s,1H),5.77(d,J=0.8Hz,1H),5.25(d,J=12.2Hz,1H),5.12(d,J=12.2Hz,1H),3.76(s,3H)。13C NMR(101MHz,CDCl3) δ 171.6,165.3,158.4,152.2,139.5,136.2,135.7,135.4,133.7,132.6,129.1,128.9,128.7,128.5,128.4,127.8,126.9,126.7,124.5,123.4,118.7,114.3,67.1,63.5, 55.5. HRMS accurate mass calculation [ M + H]+(C32H27N2O5) m/z 519.1914, found m/z 519.1920. HPLC conditions are Daicel Chiralpak IF-3 column, n-hexane/2-propanol 60/40, flow rate 1.0mL/min, lambda 254nm, retention time tR(minor)=14.667min,tR(major)=22.623min,86%ee.[α]20 D=-103.70(c=1.00,CH2Cl2)。
Example 33
Light yellow oil, 17.9mg, 78% yield.1H NMR(400MHz,CDCl3)δ8.00–7.85(m,2H),7.43(dd,J=5.9,3.0Hz,1H),7.34–7.27(m,2H),7.22–7.02(m,5H),6.92–6.78(m,2H),6.33(s,1H),5.78(s,1H),5.72(d,J=0.7Hz,1H),3.77(s,3H),3.73(s,3H)。13C NMR(101MHz,CDCl3)δ170.8,165.8,165.6(JCF=262.6Hz),158.5,152.1,139.6,136.1,133.6,132.0(JCF=10.1Hz),129.0,128.0,126.8(JCF=10.1Hz),124.5,122.98,118.2,115.8(JCF20.2Hz),114.4,63.8,55.5, 52.3. HRMS accurate mass calculation [ M + H]+(C26H22FN2O5) m/z 461.1507, found m/z 461.1509. HPLC conditions are Daicel Chiralpak IF-3 column, n-hexane/2-propanol 60/40, flow rate 1.0mL/min, lambda 254nm, retention time tR(minor)=13.506min,tR(major)=17.901min,90%ee.[α]20 D=-105.48(c=1.00,CH2Cl2)。
Example 34
Pale yellow oil, 16.8mg, 71% yield.1H NMR(400MHz,CDCl3)δ7.86–7.77(m,2H),7.55(d,J=8.2Hz,1H),7.46–7.38(m,2H),7.36–7.28(m,2H),7.21–7.09(m,3H),6.89–6.81(m,2H),6.33(s,1H),5.77(s,1H),5.69(d,J=0.8Hz,1H),3.77(s,3H),3.72(s,3H)。13C NMR(101MHz,CDCl3) δ 170.9,165.8,158.5,152.2,139.5,138.9,136.0,134.4,133.6,130.5,129.0,128.9,127.9,126.8,126.7,124.7,123.4,118.8,114.4,63.8,55.5, 52.3. HRMS accurate mass calculation [ M + H]+(C26H22ClN2O5) m/z 477.1212, found m/z 477.1216. HPLC conditions are Daicel Chiralpak IF-3 column, n-hexane/2-propanol 60/40, flow rate 1.0mL/min, lambda 254nm, retention time tR(minor)=15.325min,tR(major)=20.078min,90%ee.[α]20 D=-81.77(c=1.00,CH2Cl2)。
Example 35
Light yellow oil, 18.9mg, 73% yield.1H NMR(400MHz,CDCl3)δ7.77–7.69(m,2H),7.58(t,J=5.4Hz,3H),7.37–7.29(m,2H),7.22–7.08(m,3H),6.92–6.79(m,2H),6.32(s,1H),5.77(s,1H),5.68(d,J=0.8Hz,1H),3.77(s,3H),3.72(s,3H).13C NMR(101MHz,CDCl3) δ 171.0,165.8,158.5,152.2,139.4,136.0,134.9,133.6,131.9,130.6,129.0,127.9,127.5,126.8,126.7,124.8,123.5,119.0,114.5, 63.8655.6, 52.4. HRMS accurate mass calculation [ M + H]+(C26H22BrN2O5) m/z 521.0707, found m/z 521.0710. HPLC conditions are Daicel Chiralpak IF-3 column, n-hexane/2-propanol 60/40, flow rate 1.0mL/min, lambda 254nm, retention time tR(minor)=16.685min,tR(major)=21.538min,91%ee.[α]20 D=-94.81(c=1.00,CH2Cl2)。
Example 36
Light yellow oil, 17.1mg, 75% yield.1H NMR(400MHz,CDCl3)δ7.81(d,J=8.2Hz,2H),7.39(d,J=7.8Hz,1H),7.35–7.27(m,2H),7.25(d,J=8.1Hz,2H),7.21–7.08(m,3H),6.90–6.80(m,2H),6.37(s,1H),5.82(s,1H),5.79(s,1H),3.78(s,3H),3.74(s,3H),2.40(s,3H)。13C NMR(101MHz,CDCl3)δ171.7,165.9,158.3,152.2,143.9,139.6,136.3,133.8,132.7,129.7,129.4,128.9,127.9,126.8,126.7,124.2,122.8,118.0,114.3,63.4,55.5,52.3,21.8. HRMS accurate mass calculation [ M + H]+(C27H25N2O5) m/z 457.1758, found m/z 457.1760. HPLC conditions are Daicel Chiralpak IF-3 column, n-hexane/2-propanol 60/40, flow rate 1.0mL/min, lambda 254nm, retention time tR(minor)=19.757min,tR(major)=25.389min,89%ee.[α]20 D=-67.55(c=1.00,CH2Cl2)。
Example 37
Light yellow oil, 17.7mg, 75% yield.1H NMR(400MHz,CDCl3)δ8.02–7.92(m,2H),7.29(dd,J=7.6,1.1Hz,1H),7.25–7.12(m,4H),7.08(td,J=7.5,1.1Hz,1H),6.96–6.89(m,2H),6.89–6.81(m,2H),6.35(s,1H),5.82(s,2H),3.85(s,3H),3.77(s,3H),3.74(s,3H)。13C NMR(101MHz,CDCl3) δ 171.1,165.8,164.1,158.3,152.0,139.8,136.3,133.7,132.5,128.9,128.0,127.4,126.9,126.8,123.7,121.9,116.9,114.3,114.1,63.5,55.6,55.5, 52.3. HRMS accurate mass calculation [ M + H]+(C27H25N2O6) m/z 473.1707, found m/z 473.1713. HPLC conditions are Daicel Chiralpak IB column, n-hexane/2-propanol 70/30, flow rate 1.0mL/min,. lambda.254 nm, retention time tR(minor)=18.373min,tR(major)=25.589min,90%ee.[α]20 D=-67.55(c=1.00,CH2Cl2)。
Example 38
Pale yellow oil, 17.2mg, 73% yield.1H NMR(400MHz,CDCl3)δ7.51(d,J=8.1Hz,1H),7.48–7.39(m,2H),7.38–7.28(m,3H),7.21–7.11(m,3H),7.11–7.03(m,1H),6.90–6.80(m,2H),6.37(s,1H),5.80(s,1H),5.77(s,1H),3.83(s,3H),3.77(s,3H),3.72(s,3H)。13C NMR(101MHz,CDCl3) δ 171.6,165.8,159.7,158.4,152.2,139.4,137.0,136.2,133.7,129.6,128.9,127.8,126.9,126.7,124.5,123.1,121.6,119.4,118.5,114.3,113.6,63.6,55.5, 52.3. HRMS accurate mass calculation [ M + H]+(C27H25N2O6) m/z 473.1707, found m/z 473.1710. HPLC conditions are Daicel Chiralpak IF-3 column, n-hexane/2-propanol 60/40, flow rate 1.0mL/min, lambda 254nm, retention time tR(minor)=17.166min,tR(major)=29.453min,90%ee.[α]20 D=-66.96(c=1.00,CH2Cl2)。
Example 39
Pale yellow oil, 13.0mg, 61% yield.1H NMR(400MHz,CDCl3)δ7.80(d,J=8.2Hz,1H),7.44(d,J=7.4Hz,1H),7.38(dd,J=11.3,4.4Hz,1H),7.25–7.15(m,3H),6.90(d,J=8.9Hz,2H),6.34(s,1H),5.82(d,J=1.0Hz,1H),5.62(s,1H),3.80(s,3H),3.70(s,3H),3.15(ddd,J=16.4,8.7,5.8Hz,1H),2.76–2.63(m,1H),1.81–1.65(m,2H),1.37(dt,J=14.3,7.1Hz,2H),0.93(t,J=7.3Hz,3H)。13C NMR(101MHz,CDCl3) δ 173.09,165.70,158.61,154.05,139.49,138.40,135.06,134.39,128.22,128.04,126.86,126.77,125.91,124.92,124.12,114.58,63.27,55.65,52.35,36.99,27.42,22.52, 14.07. HRMS accurate mass calculation [ M + H]+(C24H27N2O5) m/z 423.1914, found m/z 423.1909. HPLC conditions are Daicel Chiralpak IC-3 column, n-hexane/2-propanol 70/30, flow rate 1.0mL/min, lambda 254nm, retention time tR(minor)=9.841min,tR(major)=17.015min,84%ee.[α]20 D=-56.16(c=1.00,CH2Cl2)。
Example 40
Light yellow oil, 18.0mg, 79% yield.1H NMR(400MHz,CDCl3)δ7.87–7.75(m,2H),7.55–7.46(m,2H),7.42(t,J=7.5Hz,2H),7.18–7.06(m,4H),6.90–6.77(m,2H),6.36(s,1H),5.75(s,1H),5.73(s,1H),3.77(s,3H),3.72(s,3H),2.34(s,3H)。13C NMR(101MHz,CDCl3) δ 171.6,166.0,158.4,152.4,139.5,136.0,134.5,133.9,133.8,132.4,129.5,129.0,128.5,127.9,127.0,126.8,123.8,119.2,114.3,63.5,55.5,52.3, 20.9. HRMS accurate mass calculation [ M + H]+(C27H25N2O5) m/z 457.1758, found m/z 457.1759. HPLC conditions are Daicel Chiralpak IF-3 column, n-hexane/2-propanol 60/40, flow rate 1.0mL/min, lambda 254nm, retention time tR(minor)=13.958min,tR(major)=20.84min,91%ee.[α]20 D=-88.29(c=1.00,CH2Cl2)。
EXAMPLE 41
Pale yellow oil, 14.5mg, 63% yield.1H NMR(400MHz,CDCl3)δ7.89(dd,J=5.2,3.4Hz,2H),7.58–7.51(m,1H),7.45(dd,J=10.5,4.7Hz,2H),7.30(ddd,J=14.6,9.6,4.2Hz,2H),7.21–7.07(m,2H),6.95–6.69(m,3H),6.37(s,1H),5.77(d,J=1.4Hz,2H),3.77(s,3H),3.74(s,3H)。13C NMR(101MHz,CDCl3)δ171.8,165.7,162.6(JCF=242.4Hz),158.5,151.9,139.4,137.3(JCF=10.1Hz),135.5,133.5,133.0,129.2,128.7,128.1(JCF=10.1Hz),127.8,126.8,118.6(JCF=3.0Hz),114.4,111.2(JCF=30.3Hz),105.9(JCF20.2Hz),63.2,55.5, 52.4. HRMS accurate mass calculation [ M + H]+(C26H22FN2O5) m/z 461.1507, found m/z 461.1509. HPLC conditions are Daicel Chiralpak IF-3 column, n-hexane/2-propanol 60/40, flow rate 1.0mL/min, lambda 254nm, retention time tR(minor)=10.453min,tR(major)=14.976min,92%ee.[α]20 D=-81.77(c=1.00,CH2Cl2)。
Example 42
Light yellow oil, 18.5mg, 78% yield.1H NMR(400MHz,CDCl3)δ7.97–7.84(m,2H),7.55(dd,J=12.5,4.7Hz,2H),7.45(t,J=7.6Hz,2H),7.24(s,1H),7.20–7.05(m,3H),6.93–6.76(m,2H),6.37(s,1H),5.78(s,1H),5.76(s,1H),3.76(s,3H),3.74(s,3H)。13C NMR(101MHz,CDCl3) δ 171.8,165.6,158.5,151.8,139.2,137.1,135.4,134.8,133.4,133.1,129.3,128.7,127.9,127.8,127.1,124.4,121.2,118.1,114.4,63.3,55.5, 52.4. HRMS accurate mass calculation [ M + H]+(C26H22ClN2O5) m/z 477.1212, found m/z 477.1215. HPLC conditions are Daicel Chiralpak IF-3 column, n-hexane/2-propanol 60/40, flow rate 1.0mL/min, lambda 254nm, retention time tR(minor)=11.462min,tR(major)=16.349min,92%ee.[α]20 D=-58.66(c=1.00,CH2Cl2)。
Example 43
Light yellow oil, 21.0mg, 81% yield.1H NMR(400MHz,CDCl3)δ7.95–7.83(m,2H),7.68(d,J=1.8Hz,1H),7.61–7.52(m,1H),7.45(dd,J=10.6,4.7Hz,2H),7.27(dd,J=8.0,1.6Hz,1H),7.18(dd,J=8.7,5.3Hz,1H),7.16–7.09(m,2H),6.91–6.76(m,2H),6.38(s,1H),5.78(d,J=0.8Hz,1H),5.74(s,1H),3.76(s,3H),3.74(s,3H)。13C NMR(101MHz,CDCl3) δ 171.8,165.6,158.5,151.8,139.2,137.2,135.4,133.3,133.1,129.3,128.7,128.2,127.8,127.3,127.1,122.6,121.7,120.9,114.4,63.4,55.5, 52.4. HRMS accurate mass calculation [ M + H]+(C26H22BrN2O5) m/z 521.0707, found m/z 521.0712. HPLC conditions are Daicel Chiralpak IF-3 column, n-hexane/2-propanol 60/40, flow rate 1.0mL/min, lambda 254nm, retention time tR(minor)=12.087min,tR(major)=17.193min,92%ee.[α]20 D=-101.92(c=1.00,CH2Cl2)。
Example 44
Pale yellow oil, 16.4mg, 72% yield.1H NMR(400MHz,CDCl3)δ7.98–7.85(m,2H),7.53(dd,J=10.6,4.2Hz,1H),7.44(t,J=7.6Hz,2H),7.29(s,1H),7.20(d,J=7.8Hz,1H),7.18–7.12(m,2H),6.96(d,J=7.8Hz,1H),6.90–6.77(m,2H),6.34(s,1H),5.77(s,1H),5.76(s,1H),3.76(s,3H),3.73(s,3H),2.33(s,3H)。13C NMR(101MHz,CDCl3) δ 172.0,165.9,158.3,152.3,139.7,139.1,136.0,135.8,133.8,132.7,129.2,128.6,127.9,126.6,126.5,125.2,120.2,118.8,114.3,63.4,55.5,52.2, 21.6. HRMS accurate mass calculation [ M + H]+(C27H25N2O5) m/z 457.1758, found m/z 457.1760. HPLC conditions are Daicel Chiralpak IF-3 column, n-hexane/2-propanol 60/40, flow rate 1.0mL/min, lambda 254nm, retention time tR(minor)=13.245min,tR(major)=17.217min,90%ee.[α]20 D=-74.66(c=1.00,CH2Cl2)。
Example 45
The reaction temperature was 0 ℃.
Pale yellow oil, 18.0mg, 84% yield.1H NMR(400MHz,CDCl3)δ7.94–7.84(m,2H),7.59–7.51(m,1H),7.45(td,J=7.6,2.9Hz,3H),7.37–7.28(m,2H),7.26–7.20(m,2H),7.16(td,J=7.5,1.0Hz,1H),7.08–6.96(m,2H),6.38(s,1H),5.83(s,1H),5.76(d,J=0.9Hz,1H),3.74(s,3H)。13C NMR(101MHz,CDCl3)δ171.7,165.8,161.2(JCF=242.4Hz),152.1,139.3,136.9,136.8,136.1,135.5,133.0,129.3,129.1,128.7,128.3(JCF=10.1Hz),126.8(JCF=10.1Hz),124.6,122.9,118.4,116.0(JCF20.2Hz),63.3, 52.4. HRMS accurate mass calculation [ M + H]+(C25H20FN2O4) m/z 431.1402, found m/z 431.1406. HPLC conditions are Daicel Chiralpak IF-3 column, n-hexane/2-propanol 60/40, flow rate 1.0mL/min, lambda 254nm, retention time tR(minor)=7.9min,tR(major)=11.496min,89%ee.[α]20 D=-83.55(c=1.00,CH2Cl2)。
Example 46
The reaction temperature was room temperature.
Pale yellow oil, 16.9mg, 76% yield.1H NMR(400MHz,CDCl3)δ7.92–7.84(m,2H),7.60–7.52(m,1H),7.50–7.40(m,3H),7.32(ddt,J=9.3,4.7,1.9Hz,4H),7.24–7.12(m,3H),6.39(s,1H),5.84(s,1H),5.78(d,J=1.1Hz,1H),3.75(s,3H)。13C NMR(101MHz,CDCl3) δ 171.6,165.7,152.0,139.4,139.2,136.0,135.4,133.1,132.5,129.4,129.2,129.1,128.7,127.6,126.9,126.8,124.6,122.8,118.4,63.0, 52.4. HRMS accurate mass calculation [ M + H]+(C25H20ClN2O4) m/z 447.1106, found m/z 447.1110. HPLC conditions are Daicel Chiralpak IF-3 column, n-hexane/2-propanol 60/40, flow rate 1.0mL/min, lambda 254nm, retention time tR(minor)=9.257min,tR(major)=13.839min,75%ee.[α]20 D=-57.48(c=1.00,CH2Cl2)。
Example 47
The reaction temperature was room temperature.
Pale yellow oil, 17.8mg, 73% yield.1H NMR(400MHz,CDCl3)δ7.88(dd,J=5.2,3.3Hz,2H),7.60–7.51(m,1H),7.51–7.39(m,5H),7.39–7.28(m,2H),7.17(ddd,J=6.8,4.1,1.6Hz,3H),6.39(s,1H),5.85(s,1H),5.78(d,J=1.0Hz,1H),3.75(s,3H)。13C NMR(101MHz,CDCl3) δ 171.5,165.7,151.9,139.9,139.1,135.9,135.3,133.11,132.1,129.3,129.1,128.7,127.8,126.8,126.7,124.6,122.7,120.4,118.3,62.9, 52.4. HRMS accurate mass calculation [ M + H]+(C25H20BrN2O4) m/z 491.0601, found m/z 491.0605. HPLC conditions are Daicel Chiralpak IF-3 column, n-hexane/2-propanol 60/40, flow rate 1.0mL/min, lambda 254nm, retention time tR(minor)=9.925min,tR(major)=14.64min,78%ee.[α]20 D=-56.88(c=1.00,CH2Cl2)。
Example 48
Pale yellow oil, 17.4mg, 82% yield.1H NMR(400MHz,CDCl3)δ7.91–7.79(m,2H),7.55–7.49(m,2H),7.43(dd,J=10.4,4.7Hz,2H),7.38–7.28(m,2H),7.22–7.10(m,5H),6.38(s,1H),5.84(s,1H),5.79(d,J=1.1Hz,1H),3.73(s,3H),2.31(s,3H).13C NMR(101MHz,CDCl3) δ 171.7,165.9,152.2,139.4,138.4,136.9,136.2,135.7,132.7,129.7,129.2,128.9,128.6,126.8,126.5,126.1,124.5,123.4,118.8,63.2,52.3, 21.1. HRMS accurate mass calculation [ M + H]+(C26H23N2O4) m/z 427.1652, found m/z 427.1656. HPLC conditions are Daicel Chiralpak IF-3 column, n-hexane/2-propanol 60/40, flow rate 1.0mL/min, lambda 254nm, retention time tR(minor)=10.895min,tR(major)=17.625min,89%ee.[α]20 D=-82.96(c=1.00,CH2Cl2)。
Example 49
Pale yellow oil, 17.2mg, 81% yield.1H NMR(400MHz,CDCl3)δ7.88–7.81(m,2H),7.53(ddd,J=8.3,4.8,2.1Hz,2H),7.43(dd,J=10.4,4.7Hz,2H),7.37(d,J=7.6Hz,1H),7.34–7.27(m,1H),7.24–7.12(m,2H),7.05(dd,J=9.2,7.8Hz,3H),6.39(s,1H),5.85(s,1H),5.81(d,J=1.1Hz,1H),3.73(s,3H),2.31(s,3H)。13C NMR(101MHz,CDCl3) δ 171.7,165.9,152.3,140.9,139.4,139.1,136.1,135.7,132.7,129.2,129.0,128.9,128.6,127.9,126.9,126.4,124.6,123.4,123.1,118.8,63.0,52.3, 21.5. HRMS accurate mass calculation [ M + H]+(C26H23N2O4) m/z 427.1652, found m/z 427.1654. HPLC conditions are Daicel Chiralpak IF-3 column, n-hexane/2-propanol 60/40, flow rate 1.0mL/min, lambda 254nm, retention time tR(minor)=8.287min,tR(major)=14.593min,88%ee.[α]20 D=-84.14(c=1.00,CH2Cl2)。
Example 50
Pale yellow solid, mp 73.1-74.7 ℃,34.6mg, 80% yield.1H NMR(400MHz,CDCl3)δ7.94–7.86(m,2H),7.69–7.52(m,4H),7.46(t,J=7.7Hz,2H),7.28(dd,J=8.2,1.7Hz,1H),7.22(d,J=8.2Hz,1H),7.00(dd,J=9.2,2.3Hz,2H),6.39(s,1H),5.79(d,J=0.7Hz,1H),5.77(s,1H)。13C NMR(101MHz,CDCl3) δ 171.58,165.51,151.56,140.34,138.80,138.32,136.98,135.02,133.54,129.48,128.86,128.35,128.05,127.51,127.09,122.90,121.20,120.77,91.99,62.68, 52.55. HRMS accurate mass calculation [ M + H]+(C25H19BrIN2O4) m/z 616.9567, found m/z 616.9573. HPLC condition, Daicel ChiralpakIF-3 column, n-hexane/2-propanol 60/40, flow rate 1.0mL/min, lambda 254nm, retention time tR(minor)=8.989min,tR(major)=13.171min,83%ee.[α]20 D=-93.33(c=1.00,CH2Cl2)。
The absolute configuration of compound 5vg was confirmed by X-ray crystallography as S.
Example 51
The reaction was scaled up to 1.0mmol of starting material, and 1.0mmol of 4H-benzo [ d ] [1,3] oxazine 2u was reacted with 1.5mmol of 4-methoxyphenyl isocyanate 4a at room temperature to give 3, 4-dihydroquinazolin-2 one 5ua in 63% yield (0.3g) with an ee of 92%.
Example 52
The subsequent transformation of 3, 4-dihydroquinazolin-2-one was allowed and the compound 5ua was reduced with diisobutylaluminum hydride (DIBAL-H) at-70 ℃ to give the alcohol 6ua in 64% yield without loss of enantioselectivity.
DIBAL-H (1mL, 1M in THF) was added dropwise to a solution of 5ua (0.05mmol,1.0 eq.) in 1mL dry DCM under Ar protection at-70 ℃. The mixture was stirred for 30 min, then quenched with 1M dilute hydrochloric acid (1mL), and the resulting mixture was extracted with DCM (10 mL. times.3). The combined organic phases were washed successively with water (10mL) and brine (10mL) and then Na2SO4Drying, filtering, and concentrating under reduced pressureAnd (4) shrinking. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate 1/1) to give the product 6ua (11.0mg, 64% yield, 92% ee).
Product characterization data: pale yellow oil, 11.0mg, 64% yield.1H NMR(400MHz,CDCl3)δ8.55(s,1H),7.25(d,J=8.4Hz,3H),7.00(d,J=8.1Hz,1H),6.89(t,J=9.7Hz,3H),6.73(s,1H),5.32(s,1H),5.16(s,1H),5.07(s,1H),4.17(d,J=14.2Hz,1H),4.00(d,J=14.2Hz,1H),3.78(s,3H),2.25(s,1H)。13C NMR(101MHz,CDCl3) δ 158.37,153.92,147.03,137.44,134.36,133.84,128.33,127.34,122.35,118.44,114.47,113.72,66.09,62.00, 55.56. HRMS accurate mass calculation [ M + H]+(C18H18ClN2O3) m/z 345.1000, found m/z 345.1003. HPLC conditions are Daicel Chiralpak IF-3 column, n-hexane/2-propanol 70/30, flow rate 1.0mL/min, lambda 254nm, retention time tR(major)=10.481min,tR(minor)=12.466min,92%ee.[α]20 D=-48.25(c=1.00,CH2Cl2)。
Example 53
3, 4-dihydroquinazolin-2-one 5aa and Smi2And (3) reacting, removing benzoyl to obtain 3, 4-dihydroquinazolin-2-one 7aa with the yield of 85% and the ee of 86%.
To a solution of 5aa (0.05mmol,1.0 equiv.) in THF (1mL) at room temperature was added SmI2(3mL, 0.1M in THF, 6.0 equiv.). The mixture was stirred for 30 min and then concentrated to give the crude product which was purified by silica gel column chromatography (petroleum ether/ethyl acetate 1/1) to give the product 7aa (14.3mg, 85% yield, 86% ee).
Product characterization data: pale yellow solid, mp 90.1-93.7 ℃,14.3mg, 85% yield.1H NMR(400MHz,CDCl3)δ8.19(s,1H),7.32–7.26(m,3H),7.22(d,J=7.7Hz,1H),7.04–6.90(m,3H),6.80(d,J=7.9Hz,1H),6.34(s,1H),5.95(s,1H),5.83(s,1H),3.84(s,3H),3.75(s,3H)。13C NMR(101MHz,CDCl3) δ 165.94,158.24,154.24,139.78,136.05,134.08,128.81,128.08,126.44,126.14,122.38,120.03,114.44,63.12,55.57, 52.24. HRMS accurate mass calculation [ M + H]+(C19H19N2O4) m/z 339.1339, found m/z 339.1342. HPLC conditions are Daicel Chiralpak IF-3 column, n-hexane/2-propanol 80/20, flow rate 1.0mL/min, lambda 254nm, retention time tR(minor)=22.628min,tR(major)=28.374min,86%ee.[α]20 D=-45.0(c=1.00,CH2Cl2)。
Example 54
3, 4-dihydroquinazolin-2-one 5aa and N-hydroxybenzoyl chloride were subjected to a [3+2] cyclization reaction to give the product 8aa in 83% yield with an ee of 86%.
To a solution of N-hydroxybenzoyl chloride (0.1mmol, 2.0 equiv.) in DCM (1mL) at room temperature was added Et3N (0.1mmol, 2.0 equiv.). After stirring for 10 min, 5aa (0.05mmol,1.0 eq) in 1mL DCM was added to the solution. The mixture was stirred for 1 hour and then concentrated to give the crude product which was purified by silica gel column chromatography (petroleum ether/ethyl acetate 3/1) to give the product 8aa (23.2mg, 83% yield, 86% ee).
Product characterization data: pale yellow oil, 23.2mg, 83% yield.1H NMR(400MHz,CDCl3)δ8.14–8.05(m,2H),7.73(d,J=8.1Hz,1H),7.63–7.55(m,1H),7.54–7.46(m,4H),7.45–7.30(m,5H),7.24–7.14(m,3H),6.87–6.77(m,2H),5.67(s,1H),3.94(d,J=17.5Hz,1H),3.76(s,3H),3.61(d,J=17.5Hz,1H),3.44(s,3H)。13C NMR(101MHz,CDCl3) δ 171.64,170.93,158.51,157.07,152.40,137.23,135.52,134.18,132.87,130.84,129.89,129.37,128.91,128.68,128.61,128.20,127.93,126.91,124.73,120.37,119.14,114.28,91.81,65.58,55.65,53.17, 39.90. HRMS accurate mass calculation [ M + H]+(C33H28N3O6) m/z 562.1973, practiceM/z 562.1978 was measured. HPLC conditions are Daicel Chiralpak IF-3 column, n-hexane/2-propanol 60/40, flow rate 1.0mL/min, lambda 254nm, retention time tR(minor)=17.63min,tR(major)=22.014min,86%ee.[α]20 D=-60.12(c=1.00,CH2Cl2)。
The above description is only an embodiment of the present invention, but the scope of the present invention is not limited thereto, and any changes or substitutions that can be easily conceived by those skilled in the art within the technical scope of the present invention are included in the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.
Claims (10)
2. The benzoxazine compound of claim 1, wherein R is1Is (C1-C4) alkyl or benzyl.
3. The benzoxazine compound of claim 1, wherein R is2Hydrogen, (C1-C4) alkyl or halogen.
4. The benzoxazine compound of claim 1, wherein R is3Selected from phenyl, naphthyl, furyl, thienyl, alkyl substituted by halogen, alkyl or alkoxy.
5. The benzoxazine compound of claim 4, wherein R3Selected from the group consisting of fluorophenyl, chlorophenyl, bromophenyl, (C1-C4) alkyl-substituted phenyl, (C1-C4) alkoxy-substituted phenyl, naphthyl, furyl, thienyl, and (C1-C4) alkyl.
6. The benzoxazine compound of claim 5, wherein R is3Selected from naphthyl, furyl, thienyl and (C1-C4) alkyl.
8. a method for synthesizing a benzoxazine compound according to any one of claims 1 to 7, comprising the steps of: in the presence of di-tert-butyl dicarbonate and a catalyst, the compound M1 reacts as follows:
wherein R is1、R2、R3The method according to any one of claims 1 to 6; the catalyst is 1, 4-diazabicyclo [2.2.2]Octane or 4-dimethylaminopyridine.
9. The synthesis method according to claim 8, wherein the molar ratio of the compound M1 to di-tert-butyl dicarbonate is 1: (1-3); the dosage of the catalyst is more than 10 mol%; the reaction takes toluene, dichloromethane, chloroform, ethyl acetate or acetonitrile as solvents; the reaction temperature is above 20 ℃, and the reaction time is at least 24 h.
10. The use of a benzoxazine compound according to any one of claims 1 to 7 in the synthesis of a chiral quinazolinone, wherein a chiral phosphine catalyst is used, and compound i reacts with compound M2 to give the chiral quinazolinone compound:
wherein R is1、R2、R3The method according to any one of claims 1 to 6; ar is selected from phenyl substituted by halogen, alkyl or alkoxy; the chiral phosphine catalyst is one of the following:
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