CN114920702A - Method for synthesizing optically active imidazolone compounds by asymmetric conjugate addition - Google Patents
Method for synthesizing optically active imidazolone compounds by asymmetric conjugate addition Download PDFInfo
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- CN114920702A CN114920702A CN202210591304.4A CN202210591304A CN114920702A CN 114920702 A CN114920702 A CN 114920702A CN 202210591304 A CN202210591304 A CN 202210591304A CN 114920702 A CN114920702 A CN 114920702A
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- optically active
- synthesizing
- catalyst
- conjugate addition
- imidazolone
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- 238000000034 method Methods 0.000 title claims abstract description 24
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 16
- WZELXJBMMZFDDU-UHFFFAOYSA-N Imidazol-2-one Chemical class O=C1N=CC=N1 WZELXJBMMZFDDU-UHFFFAOYSA-N 0.000 title claims description 16
- 239000003054 catalyst Substances 0.000 claims abstract description 41
- 239000002808 molecular sieve Substances 0.000 claims abstract description 31
- 238000006243 chemical reaction Methods 0.000 claims abstract description 29
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims abstract description 16
- -1 imidazolone compound Chemical class 0.000 claims abstract description 15
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000004327 boric acid Substances 0.000 claims abstract description 8
- PPTXVXKCQZKFBN-UHFFFAOYSA-N (S)-(-)-1,1'-Bi-2-naphthol Chemical compound C1=CC=C2C(C3=C4C=CC=CC4=CC=C3O)=C(O)C=CC2=C1 PPTXVXKCQZKFBN-UHFFFAOYSA-N 0.000 claims abstract description 7
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000002994 raw material Substances 0.000 claims abstract description 6
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- WKYGPLBOLUEBGZ-UHFFFAOYSA-N 1,2,3,4-tetraphenylcycloocta-1,3,5,7-tetraene Chemical compound C1(=CC=CC=C1)C1=C(C(=C(C=CC=C1)C1=CC=CC=C1)C1=CC=CC=C1)C1=CC=CC=C1 WKYGPLBOLUEBGZ-UHFFFAOYSA-N 0.000 claims abstract description 4
- 229940125904 compound 1 Drugs 0.000 claims abstract 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 64
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 42
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 39
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 25
- 229910052757 nitrogen Inorganic materials 0.000 claims description 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 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 6
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 4
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 claims description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical group CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 125000002541 furyl group Chemical group 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000001544 thienyl group Chemical group 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 125000004185 ester group Chemical group 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 125000005504 styryl group Chemical group 0.000 claims description 3
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- KTVKQTNGWVJHFL-UHFFFAOYSA-N 2-ethylchromen-4-one Chemical compound C1=CC=C2OC(CC)=CC(=O)C2=C1 KTVKQTNGWVJHFL-UHFFFAOYSA-N 0.000 claims description 2
- 229910052786 argon Inorganic materials 0.000 claims description 2
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 2
- 229940078552 o-xylene Drugs 0.000 claims description 2
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- KTQYWNARBMKMCX-UHFFFAOYSA-N tetraphenylene Chemical compound C1=CC=C2C3=CC=CC=C3C3=CC=CC=C3C3=CC=CC=C3C2=C1 KTQYWNARBMKMCX-UHFFFAOYSA-N 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- 238000007259 addition reaction Methods 0.000 abstract description 4
- 230000003197 catalytic effect Effects 0.000 abstract description 2
- CAAMSDWKXXPUJR-UHFFFAOYSA-N 3,5-dihydro-4H-imidazol-4-one Chemical compound O=C1CNC=N1 CAAMSDWKXXPUJR-UHFFFAOYSA-N 0.000 abstract 1
- 229940126214 compound 3 Drugs 0.000 abstract 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 63
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 54
- 238000004128 high performance liquid chromatography Methods 0.000 description 22
- 239000011777 magnesium Substances 0.000 description 21
- 239000002904 solvent Substances 0.000 description 21
- 239000002253 acid Substances 0.000 description 20
- 101150019148 Slc7a3 gene Proteins 0.000 description 19
- 230000008034 disappearance Effects 0.000 description 18
- 239000003208 petroleum Substances 0.000 description 18
- 238000003756 stirring Methods 0.000 description 17
- 239000007788 liquid Substances 0.000 description 16
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 14
- 239000000741 silica gel Substances 0.000 description 14
- 229910002027 silica gel Inorganic materials 0.000 description 14
- 238000003818 flash chromatography Methods 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-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](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 10
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen(.) Chemical compound [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 7
- 238000002390 rotary evaporation Methods 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 6
- 238000010898 silica gel chromatography Methods 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 5
- 150000002576 ketones Chemical class 0.000 description 4
- 238000010926 purge Methods 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- 230000000171 quenching effect Effects 0.000 description 3
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 2
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 2
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 231100000053 low toxicity Toxicity 0.000 description 2
- IVSZLXZYQVIEFR-UHFFFAOYSA-N m-xylene Chemical group CC1=CC=CC(C)=C1 IVSZLXZYQVIEFR-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000009738 saturating Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- HBENZIXOGRCSQN-VQWWACLZSA-N (1S,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-16-[(2S)-2-hydroxy-3,3-dimethylpentan-2-yl]-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-11-ol Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3[C@@]5(OC)CC[C@@]2([C@@]43CC1)C[C@@H]5[C@](C)(O)C(C)(C)CC)CC1CC1 HBENZIXOGRCSQN-VQWWACLZSA-N 0.000 description 1
- PHDIJLFSKNMCMI-ITGJKDDRSA-N (3R,4S,5R,6R)-6-(hydroxymethyl)-4-(8-quinolin-6-yloxyoctoxy)oxane-2,3,5-triol Chemical compound OC[C@@H]1[C@H]([C@@H]([C@H](C(O1)O)O)OCCCCCCCCOC=1C=C2C=CC=NC2=CC=1)O PHDIJLFSKNMCMI-ITGJKDDRSA-N 0.000 description 1
- JNPGUXGVLNJQSQ-BGGMYYEUSA-M (e,3r,5s)-7-[4-(4-fluorophenyl)-1,2-di(propan-2-yl)pyrrol-3-yl]-3,5-dihydroxyhept-6-enoate Chemical compound CC(C)N1C(C(C)C)=C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)C(C=2C=CC(F)=CC=2)=C1 JNPGUXGVLNJQSQ-BGGMYYEUSA-M 0.000 description 1
- VAVHMEQFYYBAPR-ITWZMISCSA-N (e,3r,5s)-7-[4-(4-fluorophenyl)-1-phenyl-2-propan-2-ylpyrrol-3-yl]-3,5-dihydroxyhept-6-enoic acid Chemical compound CC(C)C1=C(\C=C\[C@@H](O)C[C@@H](O)CC(O)=O)C(C=2C=CC(F)=CC=2)=CN1C1=CC=CC=C1 VAVHMEQFYYBAPR-ITWZMISCSA-N 0.000 description 1
- KJCVRFUGPWSIIH-UHFFFAOYSA-N 1-naphthol Chemical compound C1=CC=C2C(O)=CC=CC2=C1 KJCVRFUGPWSIIH-UHFFFAOYSA-N 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- 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
- JLBJTVDPSNHSKJ-UHFFFAOYSA-N 4-Methylstyrene Chemical compound CC1=CC=C(C=C)C=C1 JLBJTVDPSNHSKJ-UHFFFAOYSA-N 0.000 description 1
- HIHOEGPXVVKJPP-JTQLQIEISA-N 5-fluoro-2-[[(1s)-1-(5-fluoropyridin-2-yl)ethyl]amino]-6-[(5-methyl-1h-pyrazol-3-yl)amino]pyridine-3-carbonitrile Chemical compound N([C@@H](C)C=1N=CC(F)=CC=1)C(C(=CC=1F)C#N)=NC=1NC=1C=C(C)NN=1 HIHOEGPXVVKJPP-JTQLQIEISA-N 0.000 description 1
- FEJUGLKDZJDVFY-UHFFFAOYSA-N 9-borabicyclo[3.3.1]nonane Substances C1CCC2CCCC1B2 FEJUGLKDZJDVFY-UHFFFAOYSA-N 0.000 description 1
- DGJMHKMYSDYOFP-MRXNPFEDSA-N C=CC(N(CCC1)C[C@@H]1N1N=C(C2=CN(CC(C3=CC=CC=C3)(F)F)N=N2)C2=C(N)N=CN=C12)=O Chemical compound C=CC(N(CCC1)C[C@@H]1N1N=C(C2=CN(CC(C3=CC=CC=C3)(F)F)N=N2)C2=C(N)N=CN=C12)=O DGJMHKMYSDYOFP-MRXNPFEDSA-N 0.000 description 1
- 101150116295 CAT2 gene Proteins 0.000 description 1
- 101100326920 Caenorhabditis elegans ctl-1 gene Proteins 0.000 description 1
- 101100005280 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) cat-3 gene Proteins 0.000 description 1
- 101100126846 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) katG gene Proteins 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- HGDWHTASNMRJMP-UHFFFAOYSA-N [1-(hydroxyamino)-1-oxo-5-(3-phenoxyphenyl)pentan-2-yl]phosphonic acid Chemical compound ONC(=O)C(P(O)(O)=O)CCCC1=CC=CC(OC=2C=CC=CC=2)=C1 HGDWHTASNMRJMP-UHFFFAOYSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000001639 boron compounds Chemical class 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- PBIMIGNDTBRRPI-UHFFFAOYSA-N trifluoro borate Chemical compound FOB(OF)OF PBIMIGNDTBRRPI-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/10—Preparation of carboxylic acid amides from compounds not provided for in groups C07C231/02 - C07C231/08
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/673—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by change of size of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
-
- C—CHEMISTRY; METALLURGY
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
Abstract
The invention discloses a method for synthesizing an optically active imidazolone compound by asymmetric conjugate addition, belonging to the technical field of organic chemistry. The method comprises the steps of taking an alpha, beta-unsaturated 2-acyl imidazole compound 1 and organic boric acid 2 as raw materials, and carrying out asymmetric conjugate addition reaction in an organic solvent in the presence of a chiral binaphthol or tetraphenylcyclooctatetraene catalyst and a molecular sieve to obtain an optically active imidazolone compound 3. The method has the advantages of easily available reaction raw materials, simple catalyst structure, high catalytic efficiency, mild reaction conditions and simple post-treatment.
Description
Technical Field
The invention belongs to the technical field of asymmetric synthesis in organic chemistry, and particularly relates to a method for synthesizing an optically active ketone compound by asymmetric conjugate addition of an alpha, beta-unsaturated 2-acyl imidazole compound and organic boric acid.
Background
In recent years, the asymmetric conjugate addition reaction of alpha, beta-unsaturated ketone and organic boron compound catalyzed by small organic Molecules is an important synthesis method for constructing C-C bonds (Molecules 2018,23, 2317-containing organic ketone 2353), and the method has many advantages, such as low toxicity, easy preparation and good stability of the catalyst; the organic borides (alkyl boric acid, organic borate and organic borate) used in the method have the advantages of low toxicity, low price, easy obtaining, good functional group tolerance, simple reaction operation, no metal residue after reaction and the like, and play an important role in modern organic synthesis.
The alpha, beta-unsaturated 2-acyl imidazole compound is an important reaction substrate, and the 2-acyl imidazole group can be converted into various carboxyl functional groups. In 2012, Ohmiya et al reported that copper-N-heterocyclic carbene complexes catalyze enantioselective conjugate addition of alkylboranes (alkyl-9-BBN) to α, β -unsaturated 2-acylimidazole compounds to form imidazol-2-yl α, β -unsaturated ketone derivatives (j.am. chem. soc.2012,134, 11896-11899). In 2016, Meggers et al developed an imidazole-2-yl α, β -unsaturated ketone derivative synthesized by asymmetric conjugate addition of trifluoroborate and α, β -unsaturated 2-acylimidazole under photo-redox conditions (J.Am.chem.Soc.2016,138, 6936-6939).
So far, the number of chiral catalysts used in this reaction is relatively small. Therefore, it is still necessary to develop a catalytic system which has no transition metal participation, good reaction activity and simple operation, and realize the asymmetric conjugate addition reaction of the organic boric acid and the alpha, beta-unsaturated 2-acyl imidazole, which is simple, easy to obtain and relatively stable, so as to obtain the series of optically active acyl imidazolone derivatives.
Disclosure of Invention
In order to overcome the technical defects, the invention provides a method for synthesizing an optically active imidazolone derivative by asymmetric conjugate addition. Organic boric acid and alpha, beta-unsaturated 2-acyl imidazole are used as raw materials, chiral binaphthol compounds or tetraphenyl cyclooctatetraene compounds are used as catalysts, molecular sieves are used as additives, and the optically active imidazolone derivatives are synthesized in one step through asymmetric conjugate addition reaction with high yield and high enantioselectivity.
The method for synthesizing the optically active imidazolone derivative by asymmetric conjugate addition comprises the following steps: alpha, beta-unsaturated 2-acyl imidazole 1 and organic boric acid 2 are used as raw materials, and imidazolone compounds 3 are obtained by reaction in an organic solvent in the presence of chiral binaphthol or chiral tetraphenylcyclooctatetraene catalysts and molecular sieves. The reaction equation is as follows:
wherein: r 1 Selected from C1-C6 alkyl, benzyl, ester group; r 2 Is selected from substituted phenyl, naphthyl, furyl, thienyl, C1-C6 alkyl or substituted phenylethyl, wherein the substituent in the substituted phenyl is hydrogen, C1-C4 alkyl, C1-C4 alkoxy, halogen, trifluoromethyl, C1-C4 alkoxycarbonyl or nitro; r 3 Is selected from substituted styryl, furyl, phenylpropyl furyl, thienyl, benzothienyl or C1-C8 alkyl alkenyl, wherein the substituted phenyl is hydrogen, C1-C4 alkyl, C1-C4 alkoxy, halogen, trifluoromethyl, C1-C4 alkoxycarbonyl or nitro.
Further, in the above technical solution, R 1 Is methyl, isopropyl or benzyl; r 2 From alkyl, benzyl, ester groups; r is 2 Is substituted phenyl, 2-thienyl, 2-furyl, 1-naphthyl, 2-naphthyl, methyl or cyclohexyl; r is 3 Is styryl, p-methylstyrene, p-chlorostyreyl, p-bromostyryl, p-trifluoromethylstyryl, 2-furyl, 2-benzofuryl, 2-thienyl, 2-benzothienyl or dimethylvinyl.
Further, in the above technical solution, the chiral binariesThe naphthol catalyst is
R＝H、F、Cl、Br、I、Ph、3,5-Me 2 C 6 H 4 、3,5-(MeO) 2 C 6 H 4 、3,5-(CF 3 ) 2 C 6 H 4 (ii) a Under the preferable conditions, the chiral binaphthol catalysts are three types as follows:
further, in the above technical scheme, the chiral tetra-benzocyclooctatetraene phenol catalyst is
R＝H、F、Cl、Br、I、Ph、3,5-Me 2 C 6 H 4 、3,5-(MeO) 2 C 6 H 4 、3,5-(CF 3 ) 2 C 6 H 4 (ii) a Under the preferable conditions, the chiral tetra-benzocyclooctatetraenol catalyst comprises the following two types:
further, in the above technical scheme, the molar ratio of the α, β -unsaturated 2-acylimidazole 1, the organoboronic acid 2, and the catalyst is 1:2-4: 0.05-0.20.
Further, in the above technical solution, the organic solvent is selected from toluene, dichloromethane, tetrahydrofuran, trifluorotoluene, o-xylene, m-xylene, chlorobenzene, 1, 2-dichloroethane, diethyl ether, methyl tert-butyl ether, acetonitrile or 1, 4-dioxane.
Further, in the above technical scheme, the reaction temperature is 0-80 ℃, preferably 40-80 ℃.
Further, in the above technical scheme, magnesium tert-butoxide, methanol, isopropanol or tert-butanol is added in the reaction; the molecular sieve is selected from
Or
And (3) a molecular sieve.
Further, in the above technical scheme, the whole reaction process is carried out under nitrogen or argon, preferably nitrogen.
The invention has the beneficial effects that:
the invention has the advantages of easily obtained reaction raw materials, mild reaction conditions, simple post-treatment, recyclable and reusable catalyst, and good to excellent product yield and enantioselectivity.
Detailed Description
Example 1
a Alpha, beta-unsaturated 2-acylimidazole compound 1a (0.1mmol), trans-2-styrylboronic acid 2a (0.2mmol), catalyst (0.01mmol,10 mol%), Mg (O) t Bu) 2 (0.01mmol,10mol％)、
Molecular sieves (100mg), 1.0mL of anhydrous solvent, nitrogen atmosphere b Isolated yield c ee was analyzed by HPLC chiral column d Free of Mg (O) t Bu) 2 e HO t Bu(0.01mmol,10mol％) f Non-molecular sieve
Molecular sieve (100mg)
Molecular sieve (100mg) i 40℃ j 25℃ k Cat 3(0.005mmol,5mol％).
In the process of screening reaction conditions, the influence of different chiral catalysts on the reaction (1-10) is examined, and Cat 2 and Cat3 are determined to be the best catalysts. The influence of different solvents on the reaction was then examined (reference numerals 11-18), and finally toluene was used as the solvent. At the same time examine Mg (O) t Bu) 2 The influence of temperature, molecular sieve and catalyst amount on the reaction (reference numerals 19-25), the final reaction temperature was chosen to be 60 ℃ and the catalyst amount was 10 mol%.
Reaction conditions typical operation (reference number 1 as an example):
100mg of a Schlenk tube (anhydrous and anaerobic treatment, the same applies hereinafter) was charged under nitrogen atmosphere
Molecular sieve, catalyst Cat3(5.4Mg, 0.01mmol), Mg (O) t Bu) 2 (1.7mg, 0.01mmol), α, β -unsaturated 2-acylimidazole compound 1a (21.2mg, 0.1mmol) and organoboronic acid 2a (29.6mg, 0.2mmol, 2.0eq), and the reaction mixture was purged 3 times, followed by addition of dry toluene (1.0mL) and stirring at 60 ℃ for 48 hours. TLC showed disappearance of 1a, and flash column chromatography on silica gel (ethyl acetate/petroleum ether 1/5-1/2) separated and purified after removal of the solvent under reduced pressure to give 29.6mg of 3aa as yellow liquid in 94% yield. HPLC (Daicel Chiralcel OD-H, hexane/i-PrOH ═ 90:10, flow rate 1.0mL/min, λ ═ 254nm), t R (major)＝8.7min,t R (minor)＝9.6min,97.6:2.4e.r.,95％ee；[α] D 18 ＝+4.4(c 1.0,CHCl 3 )； 1 H NMR(600MHz,CDCl 3 )δ7.35-7.33(m,2H),7.31-7.28(m,4H),7.26-7.24(m,2H),7.21-7.14(m,3H),6.99(s,1H),6.45-6.37(m,2H),4.27(q,J＝7.2Hz,1H),3.92(s,3H)3.76(dd,J＝7.8,16.2Hz,1H),3.61(dd,J＝7.2,16.2Hz,1H)； 13 C NMR(100MHz,CDCl 3 )δ190.9,143.3,137.4,132.9,129.8,129.2,128.7,128.6,127.9,127.3,127.1,126.6,126.4,44.5,44.3,36.3；HRMS(ESI)m/z:[M+Na] + Calcd for C 21 H 20 N 2 ONa 339.1468；Found 339.1464.
Example 2
100mg were added to a Schlenk tube under nitrogen protection
Molecular sieve, catalyst Cat3(5.4Mg, 0.01mmol), Mg (O) t Bu) 2 (1.7mg, 0.01mmol), α, β -unsaturated 2-acylimidazole compound 1b (22.6mg, 0.1mmol) and organoboronic acid 2a (29.6mg, 0.2mmol, 2.0eq) were purged 3 times, then dry toluene (1.0mL) was added and stirred for 48h at 60 ℃. TLC showed disappearance of 1b, and flash column chromatography on silica gel (ethyl acetate/petroleum ether 1/5-1/2) separated and purified after removal of the solvent under reduced pressure to give 32.9mg of yellow liquid 3ba in 99% yield. HPLC (Daicel Chiralpak ID, hexane/i-PrOH 90:10, flow rate 1.0 mL/min. lambda. 254nm t R (minor)＝12.6min,t R (major)＝13.3min,2.2:97.8e.r.,96％ee；[α] D 18 ＝+3.2(c 1.0,CHCl 3 )； 1 H NMR(600MHz,CDCl 3 )δ7.29-7.22(m,6H),7.17-7.10(m,4H),6.97(s,1H),6.44-6.35(m,2H),4.24(q,J＝7.2Hz,1H),3.91(s,3H),3.75(dd,J＝7.8,16.2Hz,1H),3.58(dd,J＝7.2,16.2Hz,1H),2.30(s,3H)； 13 C NMR(150MHz,CDCl 3 )δ191.0,143.4,143.0,137.5,136.1,133.2,129.6,129.4,129.1,128.5,127.8,127.2,127.1,126.4,44.6,43.9,36.2,21.1；HRMS(ESI)m/z:[M+Na] + Calcd for C 22 H 22 N 2 ONa 353.1624；Found 353.1620.
Example 3
100mg of a Schlenk tube was charged under nitrogen
Molecular sieve, catalyst Cat3(5.4Mg, 0.01mmol), Mg (O) t Bu) 2 (1.7mg, 0.01mmol), α, β -unsaturated 2-acylimidazole compound 1c (24.2mg, 0.1mmol) and organoboronic acid 2a (29.6mg, 0.2mmol, 2.0eq), purged 3 times, followed by addition of dry toluene (1.0mL) and stirring at 60 ℃ for 48 h. TLC showed disappearance of 1c, removal of the solvent under reduced pressure and flash column chromatography on silica gel (ethyl acetate)Ester/petroleum ether 1/3-1/1) was isolated and purified to give 34.6mg of yellow liquid 3ca in 99% yield.
3ca:HPLC(Daicel Chiralcel OD-H,hexane/i-PrOH＝90:10,flow rate1.0mL/min,λ＝254nm)t R (major)＝11.8min,t R (minor)＝13.1min,97.1:2.9e.r.,94％ee；[α] D 18 ＝+7.6(c 1.0,CHCl 3 )； 1 H NMR(400MHz,CDCl 3 )δ7.30-7.23(m,6H),7.18-7.14(m,2H),6.98(s,1H),6.85-6.82(m,2H),6.44-6.33(m,2H),4.23(q,J＝7.2Hz,1H),3.91(s,3H),3.77(s,3H),3.72(dd,J＝7.6,16.4Hz,1H),3.58(dd,J＝7.2,16.4Hz,1H)； 13 C NMR(100MHz,CDCl 3 )δ191.1,158.3,143.4,137.5,135.4,133.3,129.5,129.2,128.9,128.5,127.2,127.1,126.4,114.1,55.4,44.6,43.5,36.3；HRMS(ESI)m/z:[M+Na] + Calcd for C 22 H 22 N 2 O 2 Na 369.1573；Found369.1573.
Example 4
100mg were added to a Schlenk tube under nitrogen protection
Molecular sieve, catalyst Cat3(5.4Mg, 0.01mmol), Mg (O) t Bu) 2 (1.7mg, 0.01mmol), α, β -unsaturated 2-acylimidazole compound 1d (23.0mg, 0.1mmol) and organoboronic acid 2a (29.6mg, 0.2mmol, 2.0eq), and the reaction mixture was purged 3 times, followed by addition of dry toluene (1.0mL) and stirring at 60 ℃ for 48 hours. TLC showed disappearance of 1d, and flash column chromatography on silica gel (ethyl acetate/petroleum ether 1/5-1/2) after removal of the solvent under reduced pressure gave 33.3mg of 3da as a yellow liquid with a yield of 99%. HPLC (Daicel Chiralcel OD-H, hexane/i-PrOH 90:10, flow rate 1.0mL/min, λ 254nm) t R (major)＝8.5min,t R (minor)＝9.7min,97.7:2.3e.r.,95％ee；[α] D 19 ＝+3.3(c 1.0,CHCl 3 )； 1 H NMR(400MHz,CDCl 3 )δ7.31-7.24(m,6H),7.20-7.14(m,2H),7.00-6.95(m,3H),6.44-6.32(m,2H),4.26(q,J＝7.2Hz,1H),3.92(s,3H),3.71(dd,J＝7.6,16.4Hz,1H),3.60(dd,J＝7.6,16.4Hz,1H)； 13 C NMR(100MHz,CDCl 3 )δ190.7,161.7(d,J＝243.0Hz),143.3,139.0(d,J＝3.0Hz),137.3,132.7,129.9,129.4(d,J＝8.0Hz),129.2,128.6,127.4,127.2,126.4,115.4(d,J＝21.0Hz),44.6,43.5,36.3； 19 F NMR(376MHz,CDCl 3 )δ-116.6；HRMS(ESI)m/z:[M+Na] + Calcd for C 21 H 19 FN 2 ONa 357.1374；Found 357.1374.
Example 5
100mg were added to a Schlenk tube under nitrogen protection
Molecular sieve, catalyst Cat3(5.4Mg, 0.01mmol), Mg (O) t Bu) 2 (1.7mg, 0.01mmol), α, β -unsaturated 2-acylimidazole compound 1e (31.1mg, 0.1mmol) and organoboronic acid 2a (29.6mg, 0.2mmol, 2.0eq), and the reaction mixture was purged 3 times, followed by addition of dry toluene (1.0mL) and stirring at 60 ℃ for 48 hours. TLC showed disappearance of 1e, and flash silica gel column chromatography (ethyl acetate/petroleum ether 1/5-1/2) isolated and purified by removing the solvent under reduced pressure to give 32.8mg of yellow liquid 3ea in 93% yield. HPLC (FLM Chiral MD, hexane/i-PrOH 90:10, flow rate 1.0mL/min,. lambda. 254nm) t R (major)＝7.6min,t R (minor)＝8.8min,97.2:2.8e.r.,94％ee；[α] D 18 ＝+1.2(c 1.0,CHCl 3 )； 1 H NMR(600MHz,CDCl 3 )δ7.30-7.24(m,8H),7.20-7.17(m,1H),7.14(s,1H),6.99(s,1H),6.44-6.32(m,2H),4.25(q,J＝7.2Hz,1H),3.92(s,3H),3.70(dd,J＝7.2,16.2Hz,1H),3.62(dd,J＝7.2,16.2Hz,1H)； 13 C NMR(150MHz,CDCl 3 )δ190.6,143.2,141.8,137.2,132.3,130.2,129.4,129.3,128.8,128.6,127.5,127.3,126.4,44.3,43.6,36.3；HRMS(ESI)m/z:[M+Na] + Calcd for C 21 H 19 ClN 2 ONa 373.1078；Found 373.1078.
Example 6
100mg were added to a Schlenk tube under nitrogen protection
Molecular sieve, catalyst Cat3(5.4Mg, 0.01mmol), Mg (O) t Bu) 2 (1.7mg, 0.01mmol), α, β -unsaturated 2-acylimidazole compound 1f (29.1mg, 0.1mmol) and organoboronic acid 2a (29.6mg, 0.2mmol, 2.0eq) were purged 3 times, then dry toluene (1.0mL) was added and stirred for 48h at 60 ℃. TLC showed disappearance of 1f, and flash column chromatography on silica gel (ethyl acetate/petroleum ether 1/5-1/2) separated and purified after removal of the solvent under reduced pressure to give 39.5mg of colorless liquid, 3fa, in 99% yield. HPLC (Daicel Chiralcel OD-H, hexane/i-PrOH ═ 90:10, flow rate 1.0mL/min, λ ═ 254nm) t R (major)＝9.1min,t R (minor)＝10.7min,97.4:2.6e.r.,95％ee；[α] D 19 ＝+2.3(c1.0,CHCl 3 )； 1 H NMR(400MHz,CDCl 3 )δ7.43-7.39(m,2H),7.30-7.16(m,7H),7.14-7.13(m,1H),6.99(s,1H),6.44-6.30(m,2H),4.23(q,J＝7.2Hz,1H),3.92(s,3H),3.70(dd,J＝7.2,16.4Hz,1H),3.62(dd,J＝7.6,16.4Hz,1H)； 13 C NMR(100MHz,CDCl 3 )δ190.5,143.2,142.3,137.2,132.2,131.8,130.2,129.8,129.3,128.6,127.5,127.3,126.4,120.4,44.3,43.6,36.3；HRMS(ESI)m/z:[M+Na] + Calcd for C 21 H 19 BrN 2 ONa 417.0573；Found 417.0571.
Example 7
100mg were added to a Schlenk tube under nitrogen protection
Molecular sieve, catalyst Cat3(5.4Mg, 0.01mmol), Mg (O) t Bu) 2 (1.7mg, 0.01mmol), 1g (26.2mg, 0.1mmol) of an α, β -unsaturated 2-acylimidazole compound and 2a (29.6mg, 0.2mmol, 2.0eq) of an organoboronic acid, purging 3 times, adding dry toluene (1.0mL), and stirring at 60 ℃ for 48 hours. TLC showed 1g disappearance, and flash column chromatography on silica gel (ethyl acetate/petroleum ether 1/5-1/2) separated and purified after removal of the solvent under reduced pressure to give 34.9mg of 3ga as a yellow solid in 95% yield. HPLC (Daicel Chiralcel OD-H, hexane/i-PrOH 90:10, flow rate 1.0mL/min, λ 254nm) t R (major)＝10.8min,t R (minor)＝11.9min,95.6:4.4e.r.,91％ee；[α] D 18 ＝+5.6(c 1.0,CHCl 3 )； 1 H NMR(600MHz,CDCl 3 )δ7.79-7.78(m,4H),7.50-7.48(m,1H),7.46-7.40(m,2H),7.31-7.30(m,2H),7.26-7.24(m,3H),7.18-7.16(m,2H),7.00(s,1H),6.50-6.44(m,2H),4.45(dd,J＝7.2,13.2Hz,1H),3.91(s,1H),3.84(dd,J＝7.8,16.8Hz,1H),3.75(dd,J＝7.2,16.2Hz,1H)； 13 C NMR(150MHz,CDCl 3 )δ190.9,143.3,140.8,137.4,133.7,132.8,132.5,130.1,129.2,128.6,128.4,127.9,127.7,127.3,127.2,126.7,126.4,126.2,126.1,125.6,44.4,44.3,36.3；HRMS(ESI)m/z:[M+Na] + Calcd for C 25 H 22 N 2 ONa 389.1624；Found 389.1624.
Example 8
100mg were added to a Schlenk tube under nitrogen protection
Molecular sieve, catalyst Cat3(5.4Mg, 0.01mmol), Mg (O) t Bu) 2 (1.7mg, 0.01mmol), α, β -unsaturated 2-acylimidazole compound 1h (21.8mg, 0.1mmol) and organoboronic acid 2a (29.6mg, 0.2mmol, 2.0eq), purged 3 times, then added dry toluene (1.0mL), stirred for 48h at 60 ℃. TLC showed 1h disappearance, and the solution was removed under reduced pressureThe preparation is separated and purified by flash silica gel column chromatography (ethyl acetate/petroleum ether 1/5-1/2) to obtain 28.8mg of yellow liquid 3ha with the yield of 89 percent. HPLC (Chiralcel OD-H, hexane/i-PrOH ═ 90:10, flow rate 1.0mL/min,. lambda.: 254nm) t R (major)＝8.4min,t R (minor)＝9.0min,95.0:5.0e.r.,90％ee；[α] D 20 ＝+16.4(c 0.5,CHCl 3 )； 1 H NMR(600MHz,CDCl 3 )δ7.32-7.30(m,1H),7.28-7.25(m,4H),7.20-7.15(m,2H),7.10-7.01(m,3H),6.45-6.33(m,2H),4.38(q,J＝7.2Hz,1H),3.95(s,3H),3.69(dd,J＝7.8,16.2Hz,1H),3.62(dd,J＝7.2,16.8Hz,1H)； 13 C NMR(100MHz,CDCl 3 )δ190.9,144.0,143.3,137.4,132.4,130.1,129.2,128.6,127.6,127.4,127.2,126.4,125.8,120.6,44.5,40.4,36.3；HRMS(ESI)m/z:[M+Na] + Calcd for C 19 H 18 N 2 SO Na 345.1032；Found 345.1032.
Example 9
100mg were added to a Schlenk tube under nitrogen protection
Molecular sieve, catalyst Cat3(5.4Mg, 0.01mmol), Mg (O) t Bu) 2 (1.7mg, 0.01mmol), α, β -unsaturated 2-acylimidazole compound 1i (16.4mg, 0.1mmol) and organoboronic acid 2a (29.6mg, 0.2mmol, 2.0eq), purged 3 times, followed by addition of dry toluene (1.0mL) and stirring at 60 ℃ for 48 h. TLC showed disappearance of 1i, and flash silica gel column chromatography (ethyl acetate/petroleum ether 1/5-1/2) isolated and purified by removing the solvent under reduced pressure to give 25.4mg of yellow liquid 3ia in 99% yield. HPLC (Daicel Chiralpak IA, hexane/i-PrOH ═ 90:10, flow rate 1.0mL/min, λ ═ 254nm) t R (minor)＝6.6min,t R (major)＝6.9min,5.2:94.8e.r.,90％ee；[α] D 18 ＝+46.8(c 1.0,CHCl 3 )； 1 H NMR(600MHz,CDCl 3 )δ7.31-7.30(m,2H),7.27-7.25(m,2H),7.18-7.16(m,1H),7.13(s,1H),7.00(s,1H),6.39(d,J＝15.6Hz,1H),6.21(dd,J＝7.2,15.6Hz,1H),3.30(dd,J＝7.2,15.6Hz,1H),3.15(dd,J＝7.2,15.6Hz,1H),3.08-3.06(m,1H),1.18(d,J＝6.6Hz,3H)； 13 C NMR(150MHz,CDCl 3 )δ192.1,143.4,137.7,135.2,129.1,128.6,128.5,127.1,126.2,45.9,36.3,33.6,20.7；HRMS(ESI)m/z:[M+Na] + Calcd for C 16 H 18 N 2 ONa 277.1311；Found 277.1300.
Example 10
100mg of a Schlenk tube was charged under nitrogen
Molecular sieve, catalyst Cat3(5.4Mg, 0.01mmol), Mg (O) t Bu) 2 (1.7mg, 0.01mmol), α, β -unsaturated 2-acylimidazole compound 1j (28.8mg, 0.1mmol) and organoboronic acid 2a (29.6mg, 0.2mmol, 2.0eq), purged 3 times, then added dry toluene (1.0mL), stirred for 48h at 60 ℃. TLC showed disappearance of 1j, and flash silica gel column chromatography (ethyl acetate/petroleum ether 1/5-1/2) isolated and purified by removing the solvent under reduced pressure to give 39.2mg of 3ja as a yellow liquid in 99% yield. HPLC (FLM Chiral MD, hexane/i-PrOH 90:10, flow rate 1.0mL/min,. lambda.254 nm) t R (major)＝10.4min,t R (minor)＝11.4min,97.3:2.7e.r.,94％ee；[α] D 18 ＝+12.3(c 1.0,CHCl 3 )； 1 H NMR(400MHz,CDCl 3 )δ7.34-7.15(m,14H),7.05-7.01(m,3H),6.44-6.34(m,2H),5.60-5.51(m,2H),4.29-4.24(m,1H),3.79(dd,J＝8.0,16.0Hz,1H)3.59(dd,J＝7.2,16.0Hz,1H)； 13 C NMR(150MHz,CDCl 3 )δ191.2,143.2,142.9,137.4,136.4,132.8,129.9,129.6,128.9,128.7,128.5,128.1,127.9,127.6,127.3,126.6,126.4,126.1,51.8,44.8,44.6；HRMS(ESI)m/z:[M+Na] + Calcd for C 27 H 24 N 2 ONa415.1781；Found 415.1782.
Example 11
100mg were added to a Schlenk tube under nitrogen protection
Molecular sieve, catalyst Cat3(5.4Mg, 0.01mmol), Mg (O) t Bu) 2 (1.7mg, 0.01mmol), α, β -unsaturated 2-acylimidazole compound 1k (19.4mg, 0.1mmol) and organoboronic acid 2a (29.6mg, 0.2mmol, 2.0eq), purged 3 times, followed by addition of dry toluene (1.0mL) and stirring at 60 ℃ for 48 h. TLC showed 1k disappearance, and flash column chromatography on silica gel (ethyl acetate/petroleum ether 1/5-1/3) separated and purified after removal of the solvent under reduced pressure to give 31.1mg of 3ka as a yellow liquid in 99% yield. HPLC (Daicel Chiralpak IA, hexane/i-PrOH ═ 90:10, flow rate 1.0mL/min,. lambda. 254nm) t R (minor)＝21.2min,t R (major)＝23.9min,4.7:95.3e.r.,91％ee；[α] D 18 ＝+31.6(c 1.0,CHCl 3 )； 1 H NMR(400MHz,CDCl 3 )δ7.36-7.22(m,5H),7.15(s,1H),7.02(s,1H),6.59(d,J＝15.6Hz,1H),6.28(dd,J＝7.6,16.0Hz,1H),4.19(q,J＝7.2Hz,2H),3.98(s,3H),3.84-3.76(m,2H),3.55-3.47(m,1H),1.26(t,J＝7.2Hz,3H)； 13 C NMR(100MHz,CDCl 3 )δ190.0,173.1,142.7,136.7,132.6,129.2,128.5,127.7,127.0,126.4,126.1,61.0,44.1,41.0,36.1,14.2；HRMS(ESI)m/z:[M+Na] + Calcd for C 18 H 20 N 2 O 3 Na 335.1366；Found335.1366.
Example 12
According to the reaction conditions of example 10, the reaction results of the alpha, beta-unsaturated 2-acylimidazole compound 1a and different organoboron acid compounds 2 are as follows:
example 13
100mg of a Schlenk tube was charged under nitrogen
Molecular sieve, catalyst Cat3(5.4Mg, 0.01mmol), Mg (O) t Bu) 2 (1.7mg, 0.01mmol), α, β -unsaturated 2-acylimidazole compound 1a (21.2mg, 0.1mmol) and organoboronic acid 2b (32.4mg, 0.2mmol, 2.0eq), purged 3 times, followed by addition of dry toluene (1.0mL) and stirring at 60 ℃ for 48 h. TLC showed disappearance of 1a, and flash column chromatography on silica gel (ethyl acetate/petroleum ether 1/5-1/2) separated and purified after removal of the solvent under reduced pressure to give 33.0mg of colorless liquid 3ab in 99% yield. HPLC (Daicel Chiralpak IA, hexane/i-PrOH ═ 90:10, flow rate 1.0mL/min,. lambda. 254nm) t R (major)＝11.6min,t R (minor)＝12.4min,96.6:3.4e.r.,93％ee；[α] D 18 ＝-3.5(c 1.0,CHCl 3 )； 1 H NMR(400MHz,CDCl 3 )δ7.35-7.25(m,4H),7.20-7.13(m,4H),7.06-7.04(m,2H),6.97(s,1H),6.41(d,J＝16.0,Hz,1H),6.32(dd,J＝7.2,16.0Hz,1H),4.25(q,J＝7.2,Hz,1H),3.90(s,1H),3.75(dd,J＝7.6,16.4Hz,1H),3.59(dd,J＝7.2,16.4Hz,1H),2.29(s,3H)； 13 C NMR(100MHz,CDCl 3 )δ191.0,143.5,143.3,137.0,134.6,131.9,129.7,129.23,129.15,128.7,127.9,127.1,126.6,126.3,44.6,44.3,36.2,21.3；HRMS(ESI)m/z:[M+Na] + Calcd for C 22 H 22 N 2 ONa 353.1624；Found 353.1620.
Example 14
100mg of a Schlenk tube was charged under nitrogen
Molecular sieve, catalyst Cat3(5.4Mg, 0.01mmol), Mg (O) t Bu) 2 (1.7mg, 0.01mmol), α, β -unsaturated 2-acylimidazole compound 1a (21.2mg, 0.1mmol) and organoboronic acid 2c (33.2mg, 0.2mmol,2.0eq), the gas was purged 3 times, then dry toluene (1.0mL) was added, and the mixture was stirred at 60 ℃ for 48 hours. TLC showed disappearance of 1a, and after removal of the solvent under reduced pressure, separation and purification by flash silica gel column chromatography (ethyl acetate/petroleum ether 1/5-1/2) gave 33.4mg of colorless liquid, 3ac, in 99% yield. HPLC (Daicel Chiralcel OD-H, hexane/i-PrOH ═ 90:10, flow rate 1.0mL/min, λ ═ 254nm) t R (major)＝8.7min,t R (minor)＝9.4min,98.0:2.0e.r.,96％ee；[α] D 18 ＝-4.0(c 1.0,CHCl 3 )； 1 H NMR(600MHz,CDCl 3 )δ7.34-7.29(m,4H),7.22-7.18(m,2H),7.14(s,1H),7.05-7.04(m,1H),6.99-6.98(m,2H),6.87-6.84(m,1H),6.403-6.397(m,2H),4.29-4.25(m,1H),3.92(s,3H),3.76(dd,J＝8.4,16.8Hz,1H),3.60(dd,J＝6.6,16.2Hz,1H)； 13 CNMR(150MHz,CDCl 3 )δ190.8,163.2(d,J＝243.0Hz),143.3,143.0,139.8(d,J＝7.5Hz),134.4,129.9(d,J＝9.0Hz),129.2,128.8(d,J＝3.0Hz),128.77,127.9,127.2,126.8,122.2(d,J＝3.0Hz),114.0(d,J＝21.0Hz),112.8(d,J＝21.0Hz),44.4,44.2,36.3； 19 F NMR(564MHz,CDCl 3 )δ-113.8；HRMS(ESI)m/z:[M+Na] + Calcd for C 21 H 19 FN 2 ONa357.1374；Found 357.1374.
Example 15
100mg of a Schlenk tube was charged under nitrogen
Molecular sieve, catalyst Cat3(5.4Mg, 0.01mmol), Mg (O) t Bu) 2 (1.7mg, 0.01mmol), α, β -unsaturated 2-acylimidazole compound 1a (21.2mg, 0.1mmol) and organoboronic acid 2e (36.5mg, 0.2mmol, 2.0eq), and the reaction mixture was purged 3 times, followed by addition of dry toluene (1.0mL) and stirring at 60 ℃ for 48 hours. TLC showed disappearance of 1a, removal of the solvent under reduced pressure and isolation and purification by flash column chromatography on silica gel (ethyl acetate/petroleum ether 1/5-1/2) gave 32.7mg of 3ae as a colorless liquid in 93% yield. HPLC (Daicel Chiralpak IC, hexane/i-PrOH ═ 90:10, flow rate 1.0mL/min,. lambda. -. 254nm)t R (minor)＝11.6min,t R (major)＝12.0min,3.6:96.4e.r.,93％ee；[α] D 18 ＝+2.0(c 1.0,CHCl 3 )； 1 H NMR(600MHz,CDCl 3 )δ7.33-7.30(m,4H),7.21-7.20(m,5H),7.14(s,1H),6.99(s,1H),6.40-6.34(m,2H),4.27-4.24(m,1H),3.92(s,3H),3.76(dd,J＝7.8,16.2Hz,1H),3.60(dd,J＝7.2,16.2Hz,1H)； 13 C NMR(150MHz,CDCl 3 )δ190.8,143.3,143.1,135.9,133.7,132.9,129.2,128.8,128.67,128.65,127.9,127.6,127.2,126.8,44.5,44.3,36.3；HRMS(ESI)m/z:[M+Na] + Calcd for C 21 H 19 ClN 2 ONa 373.1078；Found 373.1076.
Example 16
100mg of a Schlenk tube was charged under nitrogen
Molecular sieve, catalyst Cat3(5.4Mg, 0.01mmol), Mg (O) t Bu) 2 (1.7mg, 0.01mmol), α, β -unsaturated 2-acylimidazole compound 1a (21.2mg, 0.1mmol) and organoboronic acid 2f (45.4mg, 0.2mmol, 2.0eq), purged 3 times, then added dry toluene (1.0mL), stirred for 48h at 60 ℃. TLC showed disappearance of 1a, and after removal of the solvent under reduced pressure flash column chromatography (ethyl acetate/petroleum ether 1/5-1/2) isolated and purified to give 39.5mg of 3af as a colorless liquid in 99% yield. HPLC (FLM Chiral MD, hexane/i-PrOH 90:10, flow rate 1.0mL/min,. lambda.254 nm) t R (major)＝8.3min,t R (minor)＝8.8min,97.8:2.2e.r.,96％ee；[α] D 18 ＝+3.6(c 1.0,CHCl 3 )； 1 H NMR(600MHz,CDCl 3 )δ7.37-7.35(m,2H),7.33-7.29(m,4H),7.21-7.20(m,1H),7.15-7.14(m,3H),7.00(s,1H),6.41-6.34(m,2H),4.27-4.23(m,1H),3.92(s,3H),3.76(dd,J＝7.8,16.2Hz,1H),3.59(dd,J＝7.2,16.2Hz,1H)； 13 C NMR(150MHz,CDCl 3 )δ190.8,143.3,143.0,136.4,133.8,131.6,129.2,128.8,128.7,127.9,127.2,126.8,121.0,44.4,44.3,36.3；HRMS(ESI)m/z:[M+Na] + Calcd for C 21 H 19 BrN 2 ONa417.0573；Found417.0564.
Example 17
100mg of a Schlenk tube was charged under nitrogen
Molecular sieve, catalyst Cat3(5.4Mg, 0.01mmol), Mg (O) t Bu) 2 (1.7mg, 0.01mmol), α, β -unsaturated 2-acylimidazole compound 1a (21.2mg, 0.1mmol) and organoboronic acid 2j (25.5mg, 0.2mmol, 2.0eq), purging 3 times, adding dry toluene (1.0mL), and stirring at 60 ℃ for 48 h. TLC showed disappearance of 1a, and flash column chromatography on silica gel (ethyl acetate/petroleum ether 1/5-1/2) after removal of the solvent under reduced pressure isolated and purified to give 29.6mg of colorless liquid 3aj in 99% yield. HPLC (Daicel Chiralpak IE, hexane/i-PrOH 90:10, flow rate 1.0mL/min, λ 254nm) t R (major)＝13.8min,t R (minor)＝14.6min,95.0:5.0e.r.,90％ee；[α] D 18 ＝-24.0(c 1.0,CHCl 3 )； 1 H NMR(400MHz,CDCl 3 )δ7.36-7.34(m,2H),7.29-7.26(m,2H),7.20-7.16(m,1H),7.14(d,J＝0.8Hz,1H),7.11-7.10(m,1H),6.99(s,1H),6.89-6.86(m,2H),5.01(t,J＝7.6Hz,1H),4.00(dd,J＝7.2,16.8Hz,1H),3.91(s,3H),3.89(dd,J＝7.2,17.2Hz,1H)； 13 C NMR(100MHz,CDCl 3 )δ190.1,148.5,143.9,143.1,129.3,128.7,127.9,127.2,126.8,126.7,124.1,123.9,46.2,41.7,36.2；HRMS(ESI)m/z:[M+Na] + Calcd for C 17 H 16 N 2 OSNa 319.0876；Found 319.0878.
Example 18
100mg were added to a Schlenk tube under nitrogen protection
Molecular sieve, catalyst Cat3(5.4Mg, 0.01mmol), Mg (O) t Bu) 2 (1.7mg, 0.01mmol), α, β -unsaturated 2-acylimidazole compound 1a (21.2mg, 0.1mmol) and organoboronic acid 2j (35.6mg, 0.2mmol, 2.0eq), purging 3 times, adding dry toluene (1.0mL), and stirring at 60 ℃ for 48 h. TLC showed disappearance of 1a, and separation and purification by flash column chromatography on silica gel (ethyl acetate/petroleum ether 1/5-1/2) after removal of the solvent under reduced pressure gave 33.2mg of 3aj as a colorless liquid in 96% yield. HPLC (Daicel Chiralpak IA, hexane/i-PrOH ═ 90:10, flow rate 1.0mL/min,. lambda. 254nm) t R (major)＝16.7min,t R (minor)＝19.2min,92.8:7.2e.r.,86％ee；[α] D 18 ＝-16.6(c 1.0,CHCl 3 )； 1 H NMR(400MHz,CDCl 3 )δ7.69-7.62(m,2H),7.41-7.38(m,2H),7.31-7.18(m,5H),7.14(s,2H),6.98(s,1H),5.06(t,J＝7.2Hz,1H),4.13(dd,J＝8.0,17.2Hz,1H),3.94-3.88(m,4H)； 13 C NMR(150MHz,CDCl 3 )δ189.9,149.3,143.2,143.0,139.9,139.7,129.3,128.8,128.0,127.3,127.1,124.2,123.8,123.3,122.4,120.7,45.6,42.3,36.3；HRMS(ESI)m/z:[M+Na] + Calcd for C 21 H 18 N 2 OSNa 369.1032；Found 369.1030.
Example 19
100mg were added to a Schlenk tube under nitrogen protection
Molecular sieve, catalyst Cat3(5.4Mg, 0.01mmol), Mg (O) t Bu) 2 (1.7mg, 0.01mmol), α, β -unsaturated 2-acylimidazole compound 1a (21.2mg, 0.1mmol) and 2l (22.8mg, 0.2mmol, 2.0eq) of organoboronic acid, purging 3 times, adding dry toluene (1.0mL), and stirring for 48h at 60 ℃. TLC showed disappearance of 1a, and the solvent was removed under reduced pressure and purified by flash silica gel column chromatography (ethyl acetate/petroleum ether 1/3-1/2) to give 26.8mg of a colorless liquid3al in 99% yield. HPLC (Daicel Chiralpak IC, hexane/i-PrOH ═ 90:10, flow rate 1.0mL/min,. lambda. 254nm) t R (minor)＝9.4min,t R (major)＝11.0min,6.7:93.3e.r.,87％ee；[α] D 18 ＝+34.8(c 1.0,CHCl 3 )； 1 H NMR(400MHz,CDCl 3 )δ7.30-7.24(m,4H),7.17-7.12(m,2H),6.98(s,1H),5.34-5.31(m,1H),4.32-4.25(m,1H),3.92(s,3H),3.55-3.43(m,2H),1.66-1.65(m,6H)； 13 C NMR(100MHz,CDCl 3 )δ191.5,145.1,143.4,132.2,129.1,128.6,127.7,127.5,126.9,126.1,46.1,40.2,36.2,26.0,18.2；HRMS(ESI)m/z:[M+Na] + Calcd for C 17 H 20 N 2 ONa 291.1468；Found 291.1464.
Example 20
Heating at high temperature under vacuum, cooling to room temperature, evacuating, adding 3ja (0.1mmol,1.0eq) and NaBH under nitrogen charging 4 (0.25mmol,2.5eq) and 1mL of ultra-dry MeOH solution, stirring at room temperature for 2 hours, quenching with water, EA extraction, rotary evaporation to remove the solvent, adding MeI (1.0mmol,10.0eq) and 1mL of EA, heating at 50 ℃ for 12 hours, rotary evaporation at room temperature to remove MeI, adding 10% K to the reaction flask 2 CO 3 Aqueous solution (0.5mmol,5.0eq), 1mL toluene, stirring at 60 deg.C for 24h, EA extraction, anhydrous Na 2 SO 4 Drying, rotary evaporation to remove the solution, and quickly purifying the sample through a silica gel column to obtain a product 4. HPLC (FLM Chiral MD, hexane/i-PrOH 90:10, flow rate 1.0mL/min,. lambda.254 nm) t R (major)＝9.6min,t R (minor)＝11.1min,97.2:2.8e.r.,94％ee；[α] D 22 ＝-2.30(c 0.5,CHCl 3 )； 1 H NMR(400MHz,CDCl 3 )δ9.77(t,J＝4.0Hz,1H),7.36-7.19(m,11H),6.45-6.31(m,2H),4.13(q,J＝8.0Hz,1H),2.96-2.93(m,2H)； 13 C NMR(100MHz,CDCl 3 )δ201.3,142.5,137.0,131.9,130.6,129.0,128.7,127.7,127.6,127.1,126.4,49.2,43.0；HRMS(ESI)m/z:[M+Na] + Calcd for C 17 H 16 ONa 259.1093；Found 259.1093.
Example 21
Heating at high temperature under vacuum condition, cooling to room temperature, ventilating, adding 3ja (0.1mmol,1.0eq), MeI (1.0mmol,10.0eq) and 1mL of ultra-dry MeCN solution under the condition of filling nitrogen, heating for 24h under the condition of 60 ℃, removing MeI and MeCN by rotary evaporation, adding DBU (0.5mmol,5.0eq), DCM (1.0mmol,10.0eq) and methanol (1.0mmol,10.0eq) into a reaction bottle, stirring for 24h at room temperature, and saturating NH after stirring for 24h 4 Quenching with aqueous Cl solution, extracting with EA, and collecting anhydrous Na 2 SO 4 Drying, removing the solution by rotary evaporation, and purifying by a rapid silica gel column to obtain a product 5. HPLC (FLM Chiral MD, hexane/i-PrOH 90:10, flow rate 1.0mL/min, lambda 220nm) t R (major)＝5.5min,t R (minor)＝7.8min,97.1:2.9e.r.,94％ee；[α] D 18 ＝-11.1(c 0.25,CHCl 3 )； 1 H NMR(600MHz,CDCl 3 )δ7.34-7.31(m,4H),7.29-7.26(m,4H),7.24-7.20(m,2H),6.43(d,J＝15.6Hz,1H),6.34(dd,J＝7.2,15.6Hz,1H),4.04(q,J＝7.2Hz,1H),3.62(s,3H),2.88-2.79(m,2H)； 13 C NMR(150MHz,CDCl 3 )δ172.4,142.7,137.2,132.1,130.3,128.8,128.6,127.7,127.5,126.9,126.4,51.8,45.1,40.7；HRMS(ESI)m/z:[M+Na] + Calcd for C 18 H 18 O 2 Na 289.1192；Found 289.1199.
Example 22
Heating at high temperature under vacuum condition, cooling to room temperature, ventilating, adding 3ja (0.1mmol,1.0eq), MeI (1.0mmol,10.0eq) and 1mL of ultra-dry DMF solution under the condition of filling nitrogen, heating for 24h at 60 ℃, removing MeI and MeCN by rotary evaporation, adding DBU (0.5mmol,5.0eq) and isopropylamine (1.0mmol,10.0eq) into a reaction bottle, stirring for 24h at room temperature, and saturating NH 4 Quenching with aqueous Cl solution, EA extraction, anhydrous Na 2 SO 4 Drying, removing the solution by rotary evaporation, and purifying by a rapid silica gel column to obtain a product 6. HPLC (FLM Chiral MD, hexane/i-PrOH 90:10, flow rate 1.0mL/min, lambda 220nm) t R (major)＝10.0min,t R (minor)＝11.5min,97.0:3.0e.r.,94％ee；[α] D 18 ＝-10.8(c0.5,CHCl 3 )； 1 H NMR(600MHz,CDCl 3 )δ7.34-7.31(m,4H),7.29-7.26(m,4H),7.24-7.19(m,2H),6.43(d,J＝16.2Hz,1H),6.36(dd,J＝6.6,15.6Hz,1H),5.07-5.05(m,1H),4.05-4.02(m,1H),3.99-3.96(m,1H),2.64(dd,J＝7.8,13.8Hz,1H),2.56(dd,J＝7.8,13.8Hz,1H),1.01(d,J＝6.6Hz,3H),0.92(d,J＝6.6Hz,3H)； 13 C NMR(150MHz,CDCl 3 )δ170.2,143.0,137.3,132.3,130.4,128.9,128.6,127.8,127.5,126.9,126.4,45.8,44.0,41.4,22.9,22.7；HRMS(ESI)m/z:[M+Na] + Calcd for C 20 H 23 NONa 316.1672；Found 316.1672.
The foregoing embodiments have described the general principles, principal features and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are given by way of illustration of the principles of the present invention, and that various changes and modifications may be made without departing from the scope of the principles of the present invention, and such changes and modifications are within the scope of the present invention.
Claims (10)
1. The method for synthesizing the optically active imidazolone compound by asymmetric conjugate addition is characterized by comprising the following steps of: taking an alpha, beta-unsaturated 2-acyl imidazole compound 1 and organic boric acid 2 as raw materials, and reacting in an organic solvent in the presence of a chiral binaphthol or chiral tetraphenylcyclooctatetraene catalyst and a molecular sieve to obtain an imidazolone derivative 3; the reaction equation is expressed as:
wherein: r is 1 Selected from C1-C6 alkyl, benzyl, ester group; r 2 Selected from substituted phenyl,Naphthyl, furyl, thienyl, C1-C6 alkyl or substituted phenylethyl, wherein the substituent in the substituted phenyl is hydrogen, C1-C4 alkyl, C1-C4 alkoxy, halogen, trifluoromethyl, C1-C4 alkoxycarbonyl or nitro; r 3 Is selected from substituted styryl, furyl, phenylpropyl furyl, thienyl, benzothienyl or C1-C8 alkyl alkenyl, wherein the substituted phenyl is hydrogen, C1-C4 alkyl, C1-C4 alkoxy, halogen, trifluoromethyl, C1-C4 alkoxycarbonyl or nitro.
2. The method for synthesizing an optically active imidazolone derivative according to claim 1, wherein said method comprises the steps of: the chiral binaphthol catalyst and the chiral tetrabenzocyclooctatetraene catalyst are respectively
Wherein R is selected from H, F, Cl, Br, I, Ph and 3,5-Me 2 C 6 H 4 、3,5-(MeO) 2 C 6 H 4 Or 3,5- (CF) 3 ) 2 C 6 H 4 。
3. The method for synthesizing an optically active imidazolone derivative by asymmetric conjugate addition according to claim 2, wherein: in the chiral binaphthol catalyst, R is selected from Cl, Br, I or 3,5- (CF) 3 ) 2 C 6 H 4 。
4. The method for synthesizing an optically active imidazolone derivative by asymmetric conjugate addition according to claim 2, wherein: in the chiral tetra-benzocyclooctatetraenenol catalyst, R is selected from Cl or Br.
5. The method for synthesizing an optically active imidazolone derivative according to claim 1, wherein said method comprises the steps of: the mol ratio of the alpha, beta-unsaturated 2-acyl imidazole compound 1, the organic boric acid 2 and the catalyst is 1:2-4: 0.05-0.20.
6. The method for synthesizing an optically active imidazolone derivative by asymmetric conjugate addition according to claim 1, wherein: the organic solvent is selected from toluene, dichloromethane, tetrahydrofuran, trifluorotoluene, o-xylene, 1, 2-dichloroethane, diethyl ether, methyl tert-butyl ether, acetonitrile or 1, 4-dioxane.
7. The method for synthesizing an optically active imidazolone derivative by asymmetric conjugate addition according to claim 1, wherein: the reaction temperature is 0-80 ℃.
8. The method for synthesizing an optically active imidazolone derivative according to claim 1, wherein said method comprises the steps of: magnesium tert-butoxide, methanol, isopropanol or tert-butanol are added during the reaction.
9. The method for synthesizing an optically active imidazolone derivative by asymmetric conjugate addition according to claim 1, wherein: the molecular sieve is selected from
Or
And (3) a molecular sieve.
10. The method for synthesizing an optically active imidazolone derivative according to any one of claims 1 to 9, comprising the steps of: the whole reaction process is carried out under nitrogen or argon.
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|---|---|---|---|---|
| CN115286635A (en) * | 2022-08-22 | 2022-11-04 | 河南师范大学 | Synthesis method of chiral cyclo-pyrazolone compound |
| CN115286635B (en) * | 2022-08-22 | 2023-10-24 | 河南师范大学 | Synthesis method of chiral pyrazolone compound |
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