CN109293700B - Chiral diphosphine ligand, preparation method, intermediate and application thereof - Google Patents
Chiral diphosphine ligand, preparation method, intermediate and application thereof Download PDFInfo
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- CN109293700B CN109293700B CN201811320212.2A CN201811320212A CN109293700B CN 109293700 B CN109293700 B CN 109293700B CN 201811320212 A CN201811320212 A CN 201811320212A CN 109293700 B CN109293700 B CN 109293700B
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- 239000003446 ligand Substances 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- -1 preparation method Substances 0.000 title claims description 22
- VURFVHCLMJOLKN-UHFFFAOYSA-N diphosphane Chemical compound PP VURFVHCLMJOLKN-UHFFFAOYSA-N 0.000 title abstract description 18
- 150000001875 compounds Chemical class 0.000 claims description 65
- 125000003118 aryl group Chemical group 0.000 claims description 26
- 125000000217 alkyl group Chemical group 0.000 claims description 21
- 239000003960 organic solvent Substances 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- 125000001072 heteroaryl group Chemical group 0.000 claims description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- 239000001257 hydrogen Substances 0.000 claims description 15
- 239000003638 chemical reducing agent Substances 0.000 claims description 14
- 229910052736 halogen Inorganic materials 0.000 claims description 13
- 150000002367 halogens Chemical class 0.000 claims description 13
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 12
- 238000006476 reductive cyclization reaction Methods 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 125000001424 substituent group Chemical group 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- 238000006722 reduction reaction Methods 0.000 claims description 8
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 6
- 150000002816 nickel compounds Chemical class 0.000 claims description 6
- 229940126062 Compound A Drugs 0.000 claims description 4
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 claims description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 229910052751 metal Inorganic materials 0.000 claims description 2
- 239000002184 metal Substances 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 125000006239 protecting group Chemical group 0.000 claims description 2
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 150000002431 hydrogen Chemical group 0.000 claims 3
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 claims 1
- 125000004437 phosphorous atom Chemical group 0.000 claims 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 1
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 abstract description 26
- 229910000073 phosphorus hydride Inorganic materials 0.000 abstract description 13
- 238000007363 ring formation reaction Methods 0.000 abstract description 6
- 229910052723 transition metal Inorganic materials 0.000 abstract description 6
- 150000003624 transition metals Chemical class 0.000 abstract description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 162
- 238000006243 chemical reaction Methods 0.000 description 41
- 238000005160 1H NMR spectroscopy Methods 0.000 description 39
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 38
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 38
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 38
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 28
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 27
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 27
- 239000007787 solid Substances 0.000 description 27
- 239000007791 liquid phase Substances 0.000 description 24
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 22
- 239000011734 sodium Substances 0.000 description 19
- 235000019439 ethyl acetate Nutrition 0.000 description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 15
- 125000004432 carbon atom Chemical group C* 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 239000003054 catalyst Substances 0.000 description 14
- 239000012230 colorless oil Substances 0.000 description 13
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 12
- 125000000623 heterocyclic group Chemical group 0.000 description 11
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 11
- 239000002585 base Substances 0.000 description 10
- 238000005859 coupling reaction Methods 0.000 description 10
- 229910052763 palladium Inorganic materials 0.000 description 10
- 239000007832 Na2SO4 Substances 0.000 description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 9
- 229910052938 sodium sulfate Inorganic materials 0.000 description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 8
- 238000006069 Suzuki reaction reaction Methods 0.000 description 8
- 238000006887 Ullmann reaction Methods 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 8
- 150000001924 cycloalkanes Chemical class 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 8
- 238000004679 31P NMR spectroscopy Methods 0.000 description 7
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 7
- 229910052731 fluorine Inorganic materials 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 229910052717 sulfur Inorganic materials 0.000 description 7
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 6
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 239000003480 eluent Substances 0.000 description 6
- 239000011737 fluorine Substances 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 125000002619 bicyclic group Chemical group 0.000 description 5
- 150000001721 carbon Chemical class 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 125000005842 heteroatom Chemical group 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 239000000758 substrate Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 150000002390 heteroarenes Chemical class 0.000 description 4
- 125000002950 monocyclic group Chemical group 0.000 description 4
- 229910052759 nickel Inorganic materials 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 125000003367 polycyclic group Chemical group 0.000 description 4
- 238000010791 quenching Methods 0.000 description 4
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 4
- DIOHEXPTUTVCNX-UHFFFAOYSA-N 1,1,1-trifluoro-n-phenyl-n-(trifluoromethylsulfonyl)methanesulfonamide Chemical compound FC(F)(F)S(=O)(=O)N(S(=O)(=O)C(F)(F)F)C1=CC=CC=C1 DIOHEXPTUTVCNX-UHFFFAOYSA-N 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
- 239000003513 alkali Substances 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 239000012024 dehydrating agents Substances 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 150000003053 piperidines Chemical class 0.000 description 3
- 229920001843 polymethylhydrosiloxane Polymers 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 150000003509 tertiary alcohols Chemical class 0.000 description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 2
- 238000004293 19F NMR spectroscopy Methods 0.000 description 2
- 125000002373 5 membered heterocyclic group Chemical group 0.000 description 2
- 125000004070 6 membered heterocyclic group Chemical group 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 238000010276 construction Methods 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 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 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 238000011161 development Methods 0.000 description 2
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- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 125000001188 haloalkyl group Chemical group 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 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 2
- 150000001282 organosilanes Chemical class 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 2
- 239000011698 potassium fluoride Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 150000003233 pyrroles Chemical class 0.000 description 2
- VNFWTIYUKDMAOP-UHFFFAOYSA-N sphos Chemical compound COC1=CC=CC(OC)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 VNFWTIYUKDMAOP-UHFFFAOYSA-N 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- BKWVXPCYDRURMK-UHFFFAOYSA-N (2,6-dimethoxyphenyl)boronic acid Chemical compound COC1=CC=CC(OC)=C1B(O)O BKWVXPCYDRURMK-UHFFFAOYSA-N 0.000 description 1
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 1
- BMIBJCFFZPYJHF-UHFFFAOYSA-N 2-methoxy-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine Chemical compound COC1=NC=C(C)C=C1B1OC(C)(C)C(C)(C)O1 BMIBJCFFZPYJHF-UHFFFAOYSA-N 0.000 description 1
- RKNCIBMWPVZEAJ-UHFFFAOYSA-N 3-bromoprop-1-ynylbenzene Chemical compound BrCC#CC1=CC=CC=C1 RKNCIBMWPVZEAJ-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 241000764238 Isis Species 0.000 description 1
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- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 1
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- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
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- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 description 1
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- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000003678 cyclohexadienyl group Chemical group C1(=CC=CCC1)* 0.000 description 1
- 125000006547 cyclononyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- VBXDEEVJTYBRJJ-UHFFFAOYSA-N diboronic acid Chemical compound OBOBO VBXDEEVJTYBRJJ-UHFFFAOYSA-N 0.000 description 1
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- 125000001041 indolyl group Chemical group 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229910052741 iridium Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 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
- 150000002576 ketones Chemical class 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 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
- 230000007935 neutral effect Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- LIGACIXOYTUXAW-UHFFFAOYSA-N phenacyl bromide Chemical compound BrCC(=O)C1=CC=CC=C1 LIGACIXOYTUXAW-UHFFFAOYSA-N 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- 235000003270 potassium fluoride Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- 229910052707 ruthenium Inorganic materials 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
- 239000007858 starting material Substances 0.000 description 1
- DUTLOVSBVBGNDM-UHFFFAOYSA-N tert-butyl n-(4-methylphenyl)sulfonylcarbamate Chemical compound CC1=CC=C(S(=O)(=O)NC(=O)OC(C)(C)C)C=C1 DUTLOVSBVBGNDM-UHFFFAOYSA-N 0.000 description 1
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- 229910052720 vanadium Inorganic materials 0.000 description 1
Images
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
- C07F9/657163—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms the ring phosphorus atom being bound to at least one carbon atom
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
- B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
- B01J31/2442—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems
- B01J31/2461—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems and phosphine-P atoms as ring members in the condensed ring system or in a further ring
- B01J31/2471—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems and phosphine-P atoms as ring members in the condensed ring system or in a further ring with more than one complexing phosphine-P atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/188—Preparation; Treatments not provided for in C07F7/20 by reactions involving the formation of Si-O linkages
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- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/60—Reduction reactions, e.g. hydrogenation
- B01J2231/64—Reductions in general of organic substrates, e.g. hydride reductions or hydrogenations
- B01J2231/641—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes
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- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
The invention discloses a chiral diphosphine ligand, a preparation method, an intermediate and application thereof. The chiral diphosphine ligand has a structure shown in formula I. Compared with the phosphine ligand in the prior art, the chiral diphosphine ligand is used for the enantioselective cyclization reaction of N-alkynone, and higher yield, better enantioselectivity or lower transition metal dosage are realized.
Description
Technical Field
The invention relates to a chiral diphosphine ligand, a preparation method, an intermediate and application thereof.
Background
Transition metal-catalyzed coupling of alkynal and alkynone has become an effective method for the efficient construction of allyl alcohol derivatives in current organic chemistry. Recent developments in such reactions have greatly expanded their scope and application by the use of various transition metal catalysts, such as Ti, Ni, Rh, Ir, Ru and Pd, in combination with various coupling components and reducing or alkylating agents. Of these, the nickel-catalyzed coupling reactions of the pi system, pioneered by Mori, Montgomery and Jamison, are particularly attractive because of the wide substrate range and good functional group compatibility of the reactions developed. However, enantioselective cyclisation of these substrates, in particular with regard to the construction of enantioselective cyclisation of chiral tertiary alcohols, has been poorly reported. The synthesis of chiral tertiary alcohols is more difficult because asymmetric addition of ketones (tetra-substituted carbon synthesis) is generally more challenging than addition of aldehydes. Furthermore, nickel catalytic reactions are typically at fairly high catalytic loadings (5 to 30 mol% Ni catalyst), which makes them less "green" for the utility of nickel catalytic synthesis. Thus, the development of efficient enantioselective nickel-catalyzed reactions remains one of the major challenges for synthetic chemists.
Pyrrole and piperidine are important components in organic synthesis, and polysubstituted pyrrole and piperidine derivatives are widely present in the structure of biologically active natural products and drugs. Generally, their optically active forms can enhance their biological activity. However, methods for the efficient synthesis of chirally substituted pyrroles and piperidines remain limited. Over the last two decades, scientists have developed a number of metal-catalyzed cyclizations to construct functionalized pyrrole and piperidine derivatives. However, the catalysts for the enantioselective cyclization reaction of N-alkynone in the prior art still have the technical problems of low yield, low enantioselectivity, low catalytic efficiency, large dosage of transition metal and the like.
Disclosure of Invention
The technical problems to be solved by the invention are that the catalyst for the enantioselective cyclization reaction of N-alkynone in the prior art has low yield, low enantioselectivity, low catalytic efficiency or large use amount of transition metal, and further, the invention provides a chiral diphosphine ligand, a preparation method, an intermediate and application thereof. Compared with the phosphine ligand in the prior art, the chiral diphosphine ligand is used for the enantioselective cyclization reaction of N-alkynone, and higher yield, better enantioselectivity or lower transition metal dosage are realized.
The invention provides a compound shown as a formula I:
wherein R is1And R1’Each independently is C1-C10An alkyl group;
R2、R3、R4、R5and R6Each independently is hydrogen, C1-C10Alkyl radical, C1-C10Alkoxy radical, C3-C10Cycloalkyl, halogen,Or C6-C20An aryl group; or, R2、R3、R4、R5And R6Any two adjacent groups together with the carbon atoms to which they are attached form C5-C10Cycloalkanes, 6-10 membered aromatic rings, 5-10 membered heterocycles or 5-10 membered heteroaromatics;
R2’、R3’、R4’、R5’and R6’Each independently is hydrogen, C1-C10Alkyl radical, C1-C10Alkoxy radical, C3-C10Cycloalkyl, halogen,Or C6-C20An aryl group; or, R2’、R3’、R4’、R5’And R6’Any two adjacent groups together with the carbon atoms to which they are attached form C5-C10Cycloalkanes, 6-10 membered aromatic rings, 5-10 membered heterocycles or 6-10 membered heteroaromatics;
each R10Independently is C1-C4An alkyl group; each R11Independently is C1-C4An alkyl group;
each heteroatom in the 5-10 membered heterocycle or 5-10 membered heteroaromatic ring is independently N, O or S, the number of heteroatoms being 1,2 or 3;
andrepresents the relative configuration of the P (i.e., phosphorus) atom whenIs composed ofWhen the temperature of the water is higher than the set temperature,is composed ofWhen in useIs composed ofWhen the temperature of the water is higher than the set temperature,is composed of
When said R is1And R1’Each independently is C1-C10When alkyl, said C1-C10The alkyl groups may independently be C1-C4Alkyl groups, such as tert-butyl.
When said R is2、R3、R4、R5、R6、R2’、R3’、R4’、R5’And R6’Each independently is C1-C10When alkyl, said C1-C10The alkyl groups may independently be C1-C4Alkyl groups such as methyl, ethyl, n-propyl, isopropyl or tert-butyl.
When said R is2、R3、R4、R5、R6、R2’、R3’、R4’、R5’And R6’Each independently is C1-C10At alkoxy, said C1-C10Alkoxy may independently be C1-C4Alkoxy, such as methoxy, ethoxy, n-propoxy, isopropoxy or tert-butoxy.
When said R is2、R3、R4、R5、R6、R2’、R3’、R4’、R5’And R6’Each independently is C3-C10When, C is said3-C10Cycloalkyl may independently be C3-C6Cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
When said R is2、R3、R4、R5、R6、R2’、R3’、R4’、R5’And R6’When each is independently halogen, the halogen may be independently fluorine, chlorine, bromine or iodine, for example fluorine.
When said R is2、R3、R4、R5、R6、R2’、R3’、R4’、R5’And R6’Each independently is C6-C20When aryl, said C6-C20Aryl may independently be C6-C12Aryl radicals, for example phenyl.
When said R is2、R3、R4、R5、R6、R2’、R3’、R4’、R5’And R6’Each independently isWhen it is used, theCan independently be
When each R is10Independently is C1-C4When alkyl, said C1-C4The alkyl groups may independently be methyl groups.
When each R is11Independently is C1-C4When alkyl, said C1-C4The alkyl groups may independently be methyl groups.
When said R is2、R3、R4、R5And R6Any two adjacent groups together with the carbon atoms to which they are attached form C5-C10In the case of cycloalkanes, said C5-C10The cycloalkane may be C5-C6A cycloalkane.
When said R is2、R3、R4、R5And R6When any two adjacent groups together with the carbon atoms to which they are attached form a 6-10 membered aromatic ring, the 6-10 membered aromatic ring may be a benzene ring.
When said R is2、R3、R4、R5And R6Any two adjacent groups together with the carbon atoms to which they are attached form a 5-to 10-membered heterocyclic ring, which 5-to 10-membered heterocyclic ring may be a 5-or 6-membered heterocyclic ring, for example
When said R is2、R3、R4、R5And R6When any two adjacent groups together with the carbon atoms to which they are attached form a 5-10 membered heteroaromatic ring, the 5-10 membered heteroaromatic ring may be a 5-or 6-membered heteroaromatic ring.
When said R is2’、R3’、R4’、R5’And R6’Any two adjacent groups together with the carbon atoms to which they are attached form C5-C10In the case of cycloalkanes, said C5-C10The cycloalkane may be C5-C6A cycloalkane.
When said R is2’、R3’、R4’、R5’And R6’When any two adjacent groups together with the carbon atoms to which they are attached form a 6-10 membered aromatic ring, the 6-10 membered aromatic ring may be a benzene ring.
When said R is2’、R3’、R4’、R5’And R6’Any two adjacent groups together with the carbon atoms to which they are attached form a 5-to 10-membered heterocyclic ring, which 5-to 10-membered heterocyclic ring may be a 5-or 6-membered heterocyclic ring, for example
When said R is2’、R3’、R4’、R5’And R6’Any two of them are adjacentWhen a group and the carbon atom to which it is attached together form a 5-10 membered heteroaromatic ring, the 5-10 membered heteroaromatic ring may be a 5-or 6-membered heteroaromatic ring.
In some embodiments of the invention, R is1And R1’Each independently is C1-C10An alkyl group;
said R4、R5、R6、R4’、R5’And R6’Each independently is hydrogen, C1-C10Alkyl radical, C1-C10Alkoxy radical, C3-C10Cycloalkyl, halogen,Or C6-C20An aryl group;
said R2And R3Each independently is hydrogen, C1-C10Alkyl radical, C1-C10Alkoxy radical, C3-C10Cycloalkyl, halogen,Or C6-C20An aryl group; or, said R2And R3Together with the carbon atom to which they are attached form C5-C10Cycloalkanes, 6-10 membered aromatic rings, 5-10 membered heterocycles or 5-10 membered heteroaromatics;
said R2’And R3’Each independently is hydrogen, C1-C10Alkyl radical, C1-C10Alkoxy radical, C3-C10Cycloalkyl, halogen,Or C6-C20An aryl group; or, said R2And R3Together with the carbon atom to which they are attached form C5-C10Cycloalkanes, 6-10 membered aromatic rings, 5-10 membered heterocycles or 5-10 membered heteroaromatics.
In some embodiments of the invention, R is1And R1’Each independentlyIs C1-C10An alkyl group;
said R4、R5、R6、R4’、R5’And R6’Each independently of the others is hydrogen, fluorine, methyl, ethyl, isopropyl, methoxy, isopropoxy or
Said R2And R3Each independently of the others is hydrogen, fluorine, methyl, ethyl, isopropyl, methoxy, isopropoxy orOr, said R2And R3Together with the carbon atoms to which they are attached form a benzene ring or
Said R2’And R3’Each independently of the others is hydrogen, fluorine, methyl, ethyl, isopropyl, methoxy, isopropoxy orOr, said R2’And R3’Together with the carbon atoms to which they are attached form a benzene ring or
In one embodiment of the present invention, in the compound represented by formula I, the compound isIs composed ofSaidIs composed of
In one embodiment of the present invention, said R is1And R1’The same is true.
In one embodiment of the present invention, said R is1And R1’Is a tert-butyl group.
In one embodiment of the invention, in the compound shown in the formula I,
R1and R1’The same;
R1and R1’Is C1-C10An alkyl group;
R3、R4、R5、R3’、R4’and R5’Are all hydrogen;
R2、R6、R2’and R6’Each independently is C1-C10An alkoxy group.
The compound shown in the formula I can be selected from any one of the following structures:
the invention also provides a preparation method of the compound shown in the formula I, which comprises the following steps: in an organic solvent, carrying out a reduction reaction shown as the following on a compound shown as a formula II in the presence of a reducing agent to obtain a compound shown as a formula I;
wherein R is1、R2、R3、R4、R5、R6、R1’、R2’、R3’、R4’、R5’、R6’、Andthe definitions of (A) and (B) are as described above.
In the reduction reaction, the organic solvent may be a solvent conventional in the art, such as an ethereal solvent (e.g., tetrahydrofuran).
In the reduction reaction, the amount of the organic solvent used is not particularly limited as long as the reaction is not affected.
In the reduction reaction, the reducing agent may be a reducing agent conventional in the art such as an organosilane reducing agent (e.g., polymethylhydrosiloxane). The reducing agent may be used in a conventional amount.
The reduction reaction can also be added with a dehydrating agent, and the dehydrating agent can be a titanate dehydrating agent, such as titanium tetraisopropoxide.
The reaction temperature of the reduction reaction may be 20 to 100 deg.C (e.g., 20 to 30 deg.C).
The reduction reaction is generally terminated when the compound represented by the formula II is no longer reacted.
The invention also provides a compound shown as the formula II:
wherein R is1、R2、R3、R4、R5、R6、R1’、R2’、R3’、R4’、R5’、R6’、Andthe definitions of (A) and (B) are as described above.
In one embodiment of the present invention, the compound represented by formula II is
The invention also provides a preparation method of the compound shown in the formula II, which comprises the following steps: in an organic solvent, carrying out the Suzuki coupling reaction shown in the specification on a compound shown in a formula III and a compound shown in a formula III-a in the presence of a palladium catalyst, a phosphine ligand and alkali to obtain a compound shown in a formula II;
wherein R is1、R2、R3、R4、R5、R6、R1’、R2’、R3’、R4’、R5’、R6’、Andthe definitions of (A) and (B) are as described above;
The conditions of the Suzuki coupling reaction may be conventional in the art, and the following conditions are preferred in the present invention.
In the Suzuki coupling reaction, the organic solvent can be an ether solvent, such as dioxane. The amount of the organic solvent to be used is not particularly limited as long as the reaction is not affected.
In the Suzuki coupling reaction, the palladium catalyst can be Pd2(dba)3. The palladium catalyst is used in an amount conventional in the art for such reactions.
In the Suzuki coupling reaction, the phosphine ligand can be BIDIME (namely). The phosphine ligand may be used in amounts conventional in the art for such reactions.
In the Suzuki coupling reaction, the base can be potassium fluoride. The base may be used in amounts conventional in the art for such reactions.
The reaction temperature of the Suzuki coupling reaction may be in the range of 80-120 ℃ (e.g. 100 ℃).
The Suzuki coupling reaction is generally terminated when the compound shown in formula III is no longer reacted.
The invention also provides a compound shown as the formula III:
In one embodiment of the present invention, the compound represented by formula III is
The invention also provides a preparation method of the compound shown in the formula III, which comprises the following steps: in an organic solvent, mixing a compound shown as a formula IV and PhNTf2(namely N-phenyl bis (trifluoromethanesulfonimide)) is subjected to coupling reaction in the presence of alkali to obtain a compound shown in a formula III;
The conditions of the coupling reaction may be conventional in the art for such reactions, and the following conditions are preferred in the present invention.
In the coupling reaction, the organic solvent may be a chlorinated hydrocarbon solvent, such as dichloromethane. The amount of the organic solvent to be used is not particularly limited as long as the reaction is not affected.
In the coupling reaction, the PhNTf2The molar ratio to the compound of formula IV may be 6-10:1 (e.g., 8: 1).
In the coupling reaction, the base may be a tertiary amine base, such as triethylamine. The molar ratio of the base to the compound of formula IV may be 10-20:1 (e.g., 12: 1).
The reaction temperature of the coupling reaction may be 20-30 ℃.
The coupling reaction is generally terminated when the compound of formula IV is no longer reacted.
The invention also provides a compound shown as the formula IV:
In one embodiment of the present invention, the compound represented by formula IV is
The invention also provides a preparation method of the compound shown in the formula IV, which comprises the following steps: in an organic solvent, a compound shown as a formula V is added in a palladium catalyst and H2Carrying out catalytic hydrogenation reaction as shown in the specification under the existing condition to obtain a compound as shown in a formula IV;
The conditions for the catalytic hydrogenation reaction may be conventional in the art for such reactions, and the following conditions are preferred in the present invention.
In the catalytic hydrogenation reaction, the organic solvent may be an alcohol solvent, such as methanol. The amount of the organic solvent to be used is not particularly limited as long as the reaction is not affected.
In the catalytic hydrogenation reaction, the palladium catalyst can be Pd/C. The palladium catalyst may be used in an amount conventional in the art for such reactions.
The reaction temperature of the catalytic hydrogenation reaction may be 20 to 30 ℃.
The catalytic hydrogenation reaction is generally terminated when the compound represented by the formula V is not reacted.
The invention also provides a compound shown as the formula V:
In one embodiment of the present invention, the compound represented by formula V is
The invention also provides a preparation method of the compound shown as the formula V, which comprises the following steps: in an organic solvent, carrying out Ullmann coupling reaction on a compound shown as a formula VI-a and a compound shown as a formula VI-b in the presence of a palladium catalyst, a phosphine ligand, diborate and alkali to obtain a compound shown as a formula V;
The conditions of the Ullmann coupling reaction may be conventional in the art for such reactions, and the following conditions are preferred in the present invention.
In the Ullmann coupling reaction, the organic solvent may be a mixed solvent of an ether solvent and water, for example, a mixed solvent of dioxane and water (the volume ratio of dioxane to water may be 3-5:1, for example, 4: 1). The amount of the organic solvent to be used is not particularly limited as long as the reaction is not affected.
The Ullmann coupling reactionIn addition, the palladium catalyst can be Pd (OAc)2. The palladium catalyst may be used in an amount conventional in the art for such reactions.
In the Ullmann coupling reaction, the phosphine ligand can be Sphos (namely 2-dicyclohexylphosphine-2 ',6' -dimethoxybiphenyl). The phosphine ligand may be used in amounts conventional in the art for such reactions.
In the Ullmann coupling reaction, the diboronate ester can be a diboronic acid pinacol ester. The diboronic acid ester may be used in amounts conventional in the art for such reactions.
In the Ullmann coupling reaction, the base may be KOAc. The base may be used in amounts conventional in the art for such reactions.
The reaction temperature of the Ullmann coupling reaction can be 20-30 ℃.
The above-mentioned production methods may be combined as desired to give a route for producing a compound represented by the formula I, II, III, IV or V (e.g., III → II → I, IV → III → II → I, V → IV → III → II, IV → III → II, etc.).
The invention also provides the application of the compound shown in the formula I as a metal ligand in the reductive cyclization reaction shown as the following steps:
the reductive cyclization reaction comprises the following steps: reacting a compound A in an organic solvent in the presence of a compound shown as a formula I, a nickel compound and a reducing agent to obtain a compound B;
wherein R is1、R2、R3、R4、R5、R6、R1’、R2’、R3’、R4’、R5’、R6’、Andthe definitions of (A) and (B) are as described above;
n is 1 or 2;
R7is substituted or unsubstituted C6-C20Aryl (e.g. C)6-C12Aryl, also for example phenyl), substituted or unsubstituted 5-20 membered heteroaryl (e.g. 5-12 membered heteroaryl, also for example phenyl)) Substituted or unsubstituted C1-C20Alkyl (e.g. C)1-C10Alkyl radicals, also as C1-C4Alkyl, e.g. tert-butyl) or substituted or unsubstituted C3-C20Cycloalkyl (e.g. C)3-C10Cycloalkyl groups);
R8is C1-C20Alkyl (e.g. C)1-C10Alkyl radicals, also as C1-C4Alkyl, again, methyl or ethyl) or substituted or unsubstituted C6-C20Aryl (e.g. C)6-C12Aryl radicals, such as phenyl radicals as well);
said substituted C6-C20Aryl, substituted 5-20 membered heteroaryl, substituted C1-C20Alkyl or substituted C3-C20The substituents in cycloalkyl are each independently halogen (e.g. fluorine or chlorine), C1-C5Haloalkyl (e.g. C)1-C5Fluoroalkyl, also as trifluoromethyl) or C1-C5Alkoxy (e.g., methoxy); the number of the substituent is one or more; when the number of the substituent is more than one, the substituent is the same or different;
R9is an amino protecting group (e.g. tert-butyloxycarbonyl, trifluoromethanesulfonyl, benzyl)Or p-toluenesulfonyl, preferably p-toluenesulfonyl).
The conditions for the reductive cyclization reaction may be conventional in the art, and the following conditions are preferred in the present invention.
In the reductive cyclization reaction, the organic solvent may be an ether solvent, such as dioxane. The amount of the organic solvent to be used is not particularly limited as long as the reaction is not affected.
In the reductive cyclization reaction, the molar ratio of the compound shown as the formula I to the compound A can be 0.001-0.2: 1.
In the reductive cyclization reaction, the nickel compound may be a nickel compound conventional in this type of reaction in the art. Preferred nickel compounds having a valence of 0 according to the invention, e.g. Ni (cod)2. The molar ratio of the nickel compound to the compound A may be 0.0005 to 0.2:1, preferably 0.005 to 0.1: 1.
In the reductive cyclization reaction, the reducing agent may be an organosilane reducing agent, such as triethylsilane. The molar ratio of the reducing agent to the compound a may be 2-4:1 (e.g., 3: 1).
The reaction temperature of the reductive cyclization reaction may be 20 to 100 ℃ (e.g., 60 ℃,80 ℃).
In some embodiments of the invention, compound a is selected from any of the following structures:
in the present invention, the term "alkyl" refers to a saturated, straight or branched chain, monovalent hydrocarbon radical having the specified number of carbon atoms, such as C1-C10Alkyl refers to alkyl groups having 1 to 10 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl, isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl, t-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl). Alkyl groups are optionally substituted with one or more substituents described herein.
In the present invention, the term "haloalkyl" means an alkyl group (as defined herein) in which one or more hydrogen atoms are replaced by halogen (as defined herein), the number of which may be one or more; when the number of the halogen is plural, the halogen may be the same or different. Examples of haloalkyl include, but are not limited to, trifluoromethyl and difluoromethyl.
In the present invention, the term "alkoxy" refers to an alkyl group (as defined herein) attached to the rest of the molecule through an oxygen bridge.
In the present invention, the term "cycloalkyl" or "cycloalkane" refers to a non-aromatic, saturated or unsaturated cyclic hydrocarbon group having the specified number of ring carbon atoms, and cycloalkyl groups may be monocyclic or polycyclic (e.g., bicyclic and tricyclic), may be bicyclic, spirocyclic and bridged. Cycloalkyl groups optionally contain one or more double or triple bonds therein. Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl. Cycloalkyl also includes polycyclic cycloalkyl structures, wherein the polycyclic structure optionally includes a saturated or partially unsaturated cycloalkyl fused to a saturated or partially unsaturated cycloalkyl or heterocyclyl or aryl or heteroaryl ring. Bicyclic carbocycles having 7 to 12 atoms may be arranged, for example, as bicyclo [ 4.5 ], [5,5], [5,6] or [6,6] systems or as bridged ring systems, for example, bis [2.2.1] heptane, bicyclo [2.2.2] octane and bicyclo [3.2.2] nonane.
In the present invention, the term "heterocycle" refers to a non-aromatic, saturated or partially unsaturated cyclic hydrocarbon group formed by replacing at least one ring carbon atom in a cycloalkane (as defined herein) with a heteroatom selected from N, O and S.
In the present invention, the term "aryl" or "aromatic ring" refers to any stable monocyclic or polycyclic (e.g., bicyclic or tricyclic) carbocycle of up to 7 atoms in each ring, wherein at least one ring is aromatic. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, 2, 3-indanyl, biphenyl, phenanthryl, anthryl, or acenaphthenyl (acenaphthyl). It will be understood that where the aryl substituent is a bicyclic substituent and one of the rings is non-aromatic, the attachment is through an aromatic ring.
In the present invention, the term "heteroaryl" or "heteroaromatic ring" refers to a stable monocyclic or polycyclic (e.g., bicyclic or tricyclic) carbocyclic ring of up to 7 atoms in each ring, wherein at least one ring is aromatic and contains at least one heteroatom selected from O, N and S. Heteroaryl groups may be attached to other parts of the molecule through heteroatoms or carbon atoms therein. Examples of heteroaryl groups include, but are not limited to, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furanyl.
In the present invention, the term "halogen" means F, Cl, Br, I unless otherwise specified.
In the present invention, room temperature means 20 to 30 ℃.
On the basis of the common knowledge in the field, the above preferred conditions can be combined randomly to obtain the preferred embodiments of the invention.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows: compared with the phosphine ligand in the prior art, the chiral diphosphine ligand is used for the enantioselective cyclization reaction of N-alkynone, and higher yield, better enantioselectivity or lower transition metal dosage are realized.
Drawings
FIG. 1 is an X-ray crystal diffraction pattern of Compound 3a in Effect example 2.
FIG. 2 is an X-ray crystal diffraction pattern of Compound 3o in Effect example 2.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
Example 1 preparation of (S, S) -DI-BI-DIME (L4)
To a solution of S1(2.00g, 8.84mmol, 1.0 equiv.) and imidazole (1.20g, 17.68mmol, 2.0 equiv.) in methylene chloride (25mL) under nitrogen at room temperature was added TBDPSCl (3.20g, 11.49mmol, 1.3 equiv.). After stirring at room temperature overnight, the reaction was quenched with water, extracted with DCM, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (eluent: DCM/MeOH 100/1) to give S2 as a white solid (4.11g, 99%). S2: [ alpha. ]]D 25=–8.2(c=1.0,CHCl3).1H NMR(500MHz,CDCl3)δ7.81(dd,J=7.7,1.5Hz,2H),7.81(dd,J=7.7,1.5Hz,2H),7.50–7.42(m,3H),7.39–7.35(m,1H),7.34–7.29(m,2H),6.90(t,J=8.2Hz,1H),6.39(dd,J=8.2,1.8Hz,1H),6.02(dd,J=8.1,3.5Hz,1H),4.56(d,J=13.7Hz,1H),4.38(dd,J=13.2,10.8Hz,1H),1.32(d,J=16.0Hz,9H),1.12(s,9H);13C NMR(126MHz,CDCl3)δ166.29(d,J=17.6Hz),157.97(d,J=1.5Hz),135.51(d,J=40.3Hz),135.44(d,J=0.8Hz),132.14(d,J=183.7Hz),130.14(d,J=1.9Hz),128.01(d,J=19.6Hz),113.03(d,J=5.8Hz),106.43(d,J=5.4Hz),104.70(d,J=92.8Hz),65.79(d,J=60.0Hz),34.22(d,J=73.2Hz),26.56,24.69(d,J=0.8Hz),19.62;31P NMR(162MHz,CDCl3) δ 63.13; HRMS (ESI) calculated value [ M + Na, C27H33NaO3PSi]+487.1829; found 487.1832.
Step 2
To a solution of S2(4.10g, 8.82mmol, 1.0 eq) in DCM (90mL) under nitrogen at room temperature was added NBS (1.65g, 9.27mmol, 1.05 eq). After stirring at room temperature for 4 hours, the reaction was quenched with water, extracted with DCM, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product (S3) was carried on to the next reaction without purification.
TBAF (13.3mL, 13.24mmol, 1.5 equiv., 1.0M in THF) was added to a solution of the above crude product (S3) in THF (20mL) at 0 deg.C and stirred at 0 deg.C for 5 min. Quenched with water, extracted with EtOAc, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was used without further purification.
At 0 ℃ to the above residue and K2CO3(3.66g, 26.47mmol, 3.0 equiv.) in DMF (50mL) was added dropwise benzyl bromide (1.26mL, 10.59mmol, 1.2 equiv.) under nitrogen and stirred at room temperature overnight. The reaction was then quenched with water, extracted with EtOAc, washed with saturated brine, and dried over Na2SO4Dried, filtered, and concentrated under vacuum. The residue was purified by column chromatography (eluent: DCM/MeOH 50/1) to give S4(3.3g, 95%) as a light yellow solid. S4: [ alpha ]]D 25=–41.9(c=1.0,MeOH).1H NMR(500MHz,CDCl3)δ7.50(d,J=8.6Hz,1H),7.44–7.38(m,2H),7.37–7.31(m,2H),7.31–7.26(m,1H),6.44(dd,J=8.7,4.5Hz,1H),5.13(q,J=12.0Hz,2H),4.60(dd,J=14.0,3.1Hz,1H),4.48(dd,J=14.0,10.6Hz,1H),1.21(d,J=16.6Hz,9H);13C NMR(126MHz,CDCl3)δ162.23(d,J=16.7Hz),159.61(d,J=2.1Hz),138.97(d,J=1.3Hz),135.48,128.65,128.25,127.41,106.54(d,J=6.2Hz),105.07(d,J=88.2Hz),98.19(d,J=6.9Hz),70.99,66.87(d,J=58.4Hz),34.00(d,J=73.6Hz),24.65(d,J=0.8Hz);31P NMR(162MHz,CDCl3) δ 65.18; HRMS (ESI) calculated value [ M + H, C18H21BrO3P]+395.0407; found 395.0406.
Step 3
S4(1.30g, 3.29mmol, 1.0 eq.), Pd (OAc) was added under nitrogen protection at room temperature2(148mg, 0.66mmol, 0.2 equiv.), Sphos (567mg, 1.38mmol, 0.42 equiv.), (BPin)2(585mg, 2.30mmol, 0.7 equiv.) and KOAc (968mg, 9.87mmol, 3.0 equiv.) were dissolved in dioxane/water (15mL, 4/1) and stirred at 80 ℃ for 24 h. The reaction was then quenched with water, extracted with EtOAc, washed with saturated brine, and dried over Na2SO4Dried, filtered, and concentrated under vacuum. The residue was purified by column chromatography (eluent: DCM/MeOH 20/1) to give S5(670mg, 65%) as a light yellow solid S5: [ alpha. ]]D 25=–32.7(c=1.0,MeOH).1H NMR(500MHz,CDCl3)δ7.48–7.41(m,4H),7.40–7.33(m,6H),7.33–7.27(m,2H),6.59–6.53(m,2H),5.24–5.14(m,4H),4.51–4.33(m,4H),1.24(d,J=16.4Hz,18H);13C NMR(126MHz,CDCl3)δ163.71(d,J=16.5Hz),159.85(d,J=2.0Hz),137.77,135.99,128.66,128.15,127.45,115.06(d,J=5.7Hz),104.77(d,J=6.2Hz),103.35(d,J=91.2Hz),70.78,66.31(d,J=59.3Hz),33.78(d,J=73.7Hz),24.79;31P NMR(162MHz,CDCl3) δ 64.88; HRMS (ESI) calculated value [ M + H, C36H41O6P2]+631.2373; found 631.2377.
Step 4
S5(825mg, 1.31mmol, 1.00 equiv.), Pd/C (800mg, 10%) was dissolved in MeOH (15mL), and the reaction was evacuated and filled with hydrogen (1 atmosphere). The reaction mixture was stirred under hydrogen overnight, then the reaction was filtered through celite (EtOAc eluent) to give S6 as a white solid (560mg, 95%). S6: [ alpha ]]D 25=+12.1(c=1.0,MeOH).1H NMR(500MHz,CD3OD)δ7.34(d,J=8.3Hz,2H),6.51(dd,J=8.2,4.6Hz,2H),4.69(dd,J=14.3,3.2Hz,2H),4.28(dd,J=14.2,10.7Hz,2H),1.30(d,J=16.6Hz,18H);13C NMR(126MHz,CD3OD)δ165.00(d,J=17.0Hz),160.58(d,J=2.3Hz),139.49,114.58(d,J=5.9Hz),108.90(d,J=6.8Hz),101.68(d,J=94.2Hz),66.76(d,J=60.7Hz),34.41(d,J=74.0Hz),24.82;31P NMR(162MHz,CD3OD) δ 69.13; HRMS (ESI) calculated value [ M + H, C22H29O6P2]+451.1434; found 451.1432.
Step 5
To a solution of S6(560mg, 1.31mmol, 1.0 equiv.) in DCM at room temperature were added triethylamine (2.2mL, 15.70mmol, 12.0 equiv.) and PhNTf2(3.74g, 10.47mmol, 8.0 equiv.) and stirred at room temperature overnight. The reaction was then quenched with water, extracted with DCM, washed with saturated brine, anhydrous Na2SO4Dried, filtered, and concentrated under vacuum. The residue was purified by column chromatography (eluent: DCM/MeOH 50/1) to give S7(735mg, 78%) as a white solid. S7: [ alpha ]]D 25=+15.6(c=1.0,CHCl3).1H NMR(500MHz,CDCl3)δ7.52(d,J=8.4Hz,2H),7.13(dd,J=8.4,3.6Hz,2H),4.58(dd,J=14.1,1.7Hz,2H),4.48(dd,J=13.9,10.9Hz,2H),1.26(d,J=16.9Hz,18H);13C NMR(126MHz,CDCl3)δ163.39(d,J=16.5Hz),149.76,137.48,121.04(d,J=5.1Hz),118.58(q,J=320.8Hz),113.75(d,J=4.7Hz),108.45(d,J=84.8Hz),66.54(d,J=59.1Hz),34.47(d,J=72.1Hz),24.08;31P NMR(162MHz,CDCl3) δ 63.67; HRMS (ESI) calculated value [ M + Na, C24H26F6NaO10P2S2]+737.0239; found 737.0240.
Step 6
To a nitrogen blanketed solution of S7(735mg, 1.03mmol, 1.0 equiv), (2, 6-dimethoxyphenyl) boronic acid (1.85g, 8.23mmol, 8.0 equiv) and KF (657mg, 11.3mmol, 11.0 equiv) in 10mL of ultra-dry dioxane was added Pd at room temperature2(dba)3(94mg, 0.10mmol, 0.1 equiv.) and BI-DIME (75mg, 0.23mmol, 0.22 equiv.), and stirred at 100 ℃ overnight. The reaction was then quenched with water, extracted with EtOAc, washed with saturated brine, and dried over Na2SO4Dried, filtered, and concentrated under vacuum. The residue was purified by column chromatography (eluent: DCM/MeOH 20/1) to give S8(700mg, 98%) as a gray solid. S8: [ alpha ]]D 25=+48.1(c=1.0,MeOH).1H NMR(500MHz,CDCl3)δ7.61(d,J=7.6Hz,2H),7.33(t,J=8.4Hz,2H),6.98(dd,J=7.6,3.6Hz,2H),6.69(d,J=8.4Hz,2H),6.60(d,J=8.3Hz,2H),4.46(dd,J=13.8,0.9Hz,2H),4.36(dd,J=13.6,10.4Hz,2H),3.82(s,6H),3.76(s,6H),0.93(d,J=15.9Hz,18H);13C NMR(126MHz,CDCl3)δ162.43(d,J=19.3Hz),158.81,157.61,137.91(d,J=5.8Hz),135.58,130.13,125.08(d,J=9.2Hz),121.37(d,J=6.4Hz),117.30(d,J=1.9Hz),114.63(d,J=91.6Hz),104.52,103.19,65.22(d,J=60.9Hz),56.08,55.52,33.80(d,J=71.6Hz),23.81;31P NMR(162MHz,CDCl3) δ 62.75; HRMS (ESI) calculated value [ M + H, C38H45O8P2]+691.2584; found 691.2583.
Step 9
To a solution of S8(680mg, 0.98mmol, 1.0 equiv.) in THF (20mL) was added polymethylhydrosiloxane PMHS (5.4g) and titanium tetraisopropoxide (2.3mL, 7.88mmol, 8.0 equiv.) at room temperature. The mixture was stirred under reflux under nitrogen for 12 hours, then most of the THF was distilled off under vacuum. Carefully add 30% degassed NaOH solution (30mL) to the residue. Gas is released during the addition. Extracting with degassed ether and extracting with anhydrous Na2SO4Dried, filtered, concentrated under vacuum, and passed through a neutral alumina column (Et)2O elution) to give the desired product (S, S) -DI-BI-DIME (L4) as a white solid (610mg, 90%). L4: [ alpha ]]D 25=+47.1(c=1.0,CHCl3).1H NMR(500MHz,CDCl3)δ7.54(d,J=7.7Hz,2H),7.31(t,J=8.3Hz,2H),6.96–6.90(m,2H),6.68(d,J=8.4Hz,2H),6.61(d,J=8.4Hz,2H),4.82(dd,J=12.6,1.4Hz,2H),4.51(dd,J=24.7,12.5Hz,2H),3.79(s,6H),3.73(s,6H),0.81(d,J=12.0Hz,18H);13C NMR(126MHz,CDCl3)δ160.63,158.04,157.37,137.40(d,J=18.4Hz),132.05,129.03,125.27(d,J=12.8Hz),123.66(d,J=4.5Hz),120.51,120.01,104.56,103.70,70.19(d,J=26.1Hz),55.96(d,J=1.7Hz),55.47,31.10(d,J=18.6Hz),26.74(d,J=14.5Hz);31P NMR(162MHz,CDCl3) Delta-6.93; HRMS (ESI) calculated value [ M + H, C38H45O6P2]+659.2686; found 659.2687.
EXAMPLE 2 preparation of chain N-alkynones
tert-Butyltosylcarbamate (17.7g, 65.3mmol, 1.0 eq.) and K2CO3(13.5g, 97.9mmol, 1.5 equiv.) is dissolved in 65mL of DMF and stirred at room temperature for 4 hours. (3-Bromopropynyl benzene (14.0g, 71.8mmol, 1.1 equiv.) is then added to the above solution and stirred at room temperature for 10 h, the reaction quenched with water, extracted with EtOAc, washed with saturated brine, anhydrous Na2SO4Dried, filtered, and concentrated under vacuum. The residue was dissolved in 60mL DCM and 20mL CF3COOH and stirred at room temperature overnight. Quench with water, EtOAc extraction, brine wash, anhydrous Na2SO4Dried, filtered, and concentrated under vacuum. The residue was recrystallized from hexanes/EtOAc to give S9 as a white solid (17.5g, 94%). S9:1H NMR(400MHz,CDCl3)δ7.85–7.78(m,2H),7.32–7.27(m,3H),7.26–7.20(m,2H),7.17–7.09(m,2H),4.63(t,J=5.8Hz,1H),4.08(d,J=6.1Hz,2H),2.36(s,3H);ESI-MS:m/z 286.2[M+H]+.
step 2
To S2(5.0g, 17.5mmol, 1.0 equiv.), 2-bromo-1-phenylethanone (3.7g, 18.4mmol, 1.05 equiv.), Bu at 0 deg.C4NI (647.2mg, 1.75mmol, 0.1 eq.) in DMF (35mL) was added K2CO3(3.6g, 26.3mmol, 1.5 equiv.) and stirred at 0 ℃ for 1 hour. The reaction was then quenched with water, extracted with EtOAc, washed with saturated brine, and dried over Na2SO4Dried, filtered, and concentrated under vacuum. The residue was recrystallized from hexanes/EtOAc to give 1a as a white solid (6.0g, 85%). 1a:1H NMR(500MHz,CDCl3)δ8.01–7.95(m,2H),7.84–7.79(m,2H),7.63–7.57(m,1H),7.51–7.45(m,2H),7.33–7.26(m,3H),7.25–7.19(m,2H),7.12–7.07(m,2H),4.81(s,2H),4.49(s,2H),2.39(s,3H);13C NMR(126MHz,CDCl3)δ193.46,143.90,136.12,135.00,133.92,131.69,129.79,128.92,128.64,128.24,128.22,127.80,122.07,86.33,81.67,51.99,38.41,21.60;ESI-MS:m/z 404.3[M+H]+.
preparation of chain N-alkynones 1b-1p according to the same procedure
1b white solid, 92% yield.1H NMR(500MHz,CDCl3)δ8.01–7.95(m,2H),7.84–7.78(m,2H),7.32–7.26(m,3H),7.25–7.20(m,2H),7.13–7.07(m,2H),6.97–6.91(m,2H),4.75(s,2H),4.47(s,2H),3.87(s,3H),2.38(s,3H);13C NMR(126MHz,CDCl3) δ 191.95,164.15,143.87,136.20,131.74,130.67,129.79,128.62,128.25,128.07,127.87,122.20,114.12,86.28,81.79,55.67,51.75,38.42, 21.63; HRMS (ESI) calculated value [ M + Na, C25H23NNaO4S]+456.1240; found 456.1244.
1c white solid, 80% yield.1H NMR(500MHz,CDCl3)δ8.08–8.01(m,2H),7.85–7.77(m,2H),7.33–7.21(m,5H),7.19–7.06(m,4H),4.76(s,2H),4.47(s,2H),2.39(s,3H);13C NMR(126MHz,CDCl3) δ 192.08,166.19(d, J-256.1 Hz),144.03,135.93,131.69,131.45(d, J-3.0 Hz),131.08(d, J-9.4 Hz),129.83,128.71,128.27,127.84,122.03,116.11(d, J-22.0 Hz),86.46,81.52,52.09,38.50, 21.61; HRMS (ESI) calculated value [ M + Na, C24H20FNNaO3S]+444.1040; found 444.1042.
1d white solid, 73% yield.1H NMR(500MHz,CDCl3)δ7.96–7.92(m,2H),7.82–7.78(m,2H),7.47–7.42(m,2H),7.33–7.26(m,3H),7.25–7.20(m,2H),7.13–7.06(m,2H),4.74(s,2H),4.45(s,2H),2.38(s,3H);13C NMR(126MHz,CDCl3) δ 192.57,144.07,140.45,135.88,133.33,131.71,129.86,129.77,129.28,128.74,128.29,127.85,122.01,86.52,81.48,52.19,38.53, 21.64; HRMS (ESI) calculated value [ M + Na, C24H20ClNNaO3S]+460.0745; found 460.0745.
1e white solid, 64% yield.1H NMR(500MHz,CDCl3)δ8.14–8.08(m,2H),7.84–7.79(m,2H),7.76–7.71(m,2H),7.35–7.21(m,5H),7.12–7.06(m,2H),4.79(s,2H),4.46(s,2H),2.40(s,3H);13C NMR(126MHz,CDCl3) δ 193.03,144.18,137.70,135.71,135.04(q, J ═ 32.6Hz),131.68,129.90,128.80,128.75,128.30,127.85,125.96(q, J ═ 3.6Hz),123.56(d, J ═ 272.8Hz),121.91,86.66,81.35,52.58,38.63, 21.61; HRMS (ESI) calculated value [ M + Na, C25H20F3NNaO3S]+494.1008; found 494.1009.
1f pale yellow solid, 92% yield.1H NMR(500MHz,CDCl3)δ7.85–7.77(m,2H),7.59–7.54(m,1H),7.54–7.48(m,1H),7.41–7.36(m,1H),7.33–7.26(m,3H),7.25–7.19(m,2H),7.17–7.07(m,3H),4.79(s,2H),4.48(s,2H),3.85(s,3H),2.39(s,3H);13C NMR(126MHz,CDCl3) δ 193.39,160.01,143.92,136.29,136.10,131.71,129.93,129.81,128.66,128.25,127.81,122.08,120.74,120.53,112.49,86.36,81.65,55.62,52.16,38.42, 21.62; HRMS (ESI) calculated value [ M + Na, C25H23NNaO4S]+456.1240; found 456.1242.
1g of pale yellow solid, 86% yield.1H NMR(500MHz,CDCl3)δ7.83–7.77(m,3H),7.54–7.47(m,1H),7.31–7.26(m,3H),7.25–7.20(m,2H),7.15–7.10(m,2H),7.04–6.95(m,2H),4.83(s,2H),4.51(s,2H),3.91(s,3H),2.38(s,3H);13C NMR(126MHz,CDCl3) δ 194.97,159.14,143.54,136.72,134.67,131.65,130.99,129.60,128.51,128.23,127.76,125.52,122.36,121.05,111.67,85.83,82.38,56.11,55.73,38.43, 21.60; HRMS (ESI) calculated value [ M + Na, C25H23NNaO4S]+456.1240; found 456.1243.
1h pale yellow solid, 79% yield.1H NMR(500MHz,CDCl3)δ8.27–8.21(m,1H),8.06(s,1H),7.72(d,J=8.2Hz,2H),7.27–7.20(m,3H),7.19–7.14(m,3H),7.13–7.07(m,2H),6.99–6.93(m,2H),4.42(s,2H),4.35(s,2H),3.74(s,3H),2.25(s,3H);13C NMR(126MHz,CDCl3) δ 188.54,143.99,137.30,136.83,135.72,131.72,129.78,128.52,128.17,127.96,126.72,123.74,123.06,122.63,122.26,113.99,109.86,86.41,81.51,53.34,38.55,33.83, 21.59; HRMS (ESI) calculated value [ M + H, C27H25N2O3S]+457.1580; found 457.1582.
1i white solid, 79% yield.1H NMR(500MHz,CDCl3)δ7.79–7.74(m,2H),7.32–7.24(m,5H),7.17–7.12(m,2H),4.45(s,2H),4.40(s,2H),2.39(s,3H),1.18(s,9H);13C NMR(126MHz,CDCl3) δ 208.92,143.74,136.42,131.68,129.73,128.70,128.34,127.68,122.16,86.11,81.88,49.72,43.64,37.85,26.48, 21.60; HRMS (ESI) calculated value [ M + Na, C20H25NNaO3S]+406.1447; found 406.1447.
1j white solid, 82% yield.1H NMR(500MHz,CDCl3)δ7.96(d,J=7.3Hz,2H),7.77(d,J=8.2Hz,2H),7.59(t,J=7.4Hz,1H),7.47(t,J=7.7Hz,2H),7.31(d,J=8.0Hz,2H),4.74(s,2H),4.21(s,2H),2.42(s,3H),1.94(tq,J=7.5,2.0Hz,2H),0.90(t,J=7.5Hz,3H);13C NMR(126MHz,CDCl3)δ193.62,143.67,136.29,135.10,133.82,129.61,128.88,128.18,127.81,88.45,71.81,51.80,38.04,21.64,13.56, 12.27; HRMS (ESI) calculated value [ M + Na, C20H21NNaO3S]+378.1134; found 378.1138.
1k white solid, 86% yield.1H NMR(500MHz,CDCl3)δ8.00–7.94(m,2H),7.69–7.62(m,1H),7.56–7.49(m,2H),7.42–7.27(m,5H),5.05(s,2H),4.67(s,2H);13C NMR(126MHz,CDCl3) δ 191.55,134.50,134.20,131.96,129.22,129.18,128.53,128.09,121.64,119.91(q, J ═ 322.3Hz),87.12,80.73,52.32, 39.89; HRMS (ESI) calculated value [ M + Na, C18H14F3NNaO3S]+404.0539; found 404.0541.
1l white solid, 77% yield.1H NMR(500MHz,CDCl3)δ7.96–7.89(m,2H),7.53–7.47(m,1H),7.42–7.31(m,6H),7.29–7.17(m,6H),4.01(s,2H),3.78(s,2H),3.66(s,2H);13C NMR(126MHz,CDCl3) δ 197.52,138.03,136.23,133.35,131.92,129.50,128.65,128.55,128.45,128.43,128.32,127.59,123.21,86.29,84.21,59.58,58.38, 43.46; HRMS (ESI) calculated value [ M + H, C24H22NO]+340.1696; found 340.1699.
1m white solid, 75% yield.1H NMR(500MHz,CDCl3)δ8.04–7.98(m,2H),7.60(t,J=7.4Hz,1H),7.49(t,J=7.6Hz,2H),7.31–7.22(m,5H),5.78(d,J=8.3Hz,1H),5.56–5.48(m,1H),3.04(dd,J=17.1,5.8Hz,1H),2.89(dd,J=17.0,5.1Hz,1H),1.47(s,9H);13C NMR(126MHz,CDCl3)δ197.35,155.27,134.88,133.84,131.71,128.93,128.75,128.22,128.07,123.16, 84.17, 84.12, 80.16, 53.93, 28.45, 24.75; HRMS (ESI) calculated value [ M + Na, C22H23NNaO3]+372.1570; found 372.1573.
1n white solid, 90% yield.1H NMR(500MHz,CDCl3)δ7.98–7.92(m,2H),7.85–7.77(m,2H),7.59–7.52(m,1H),7.48–7.40(m,2H),7.31–7.18(m,5H),7.11–7.05(m,2H),4.44(s,2H),3.71(t,J=7.1Hz,2H),3.45(t,J=7.1Hz,2H),2.33(s,3H);13C NMR(126MHz,CDCl3) δ 198.10,143.65,136.47,135.61,133.42,131.53,129.61,128.68,128.45,128.13,128.07,127.83,122.11,85.58,82.31,42.82,39.01,38.57, 21.44; HRMS (ESI) calculated value [ M + H, C25H24NO3S]+418.1471; found 418.1465.
White solid, 80% yield 1 o.1H NMR(500MHz,CDCl3)δ7.95(dd,J=8.3,1.1Hz,2H),7.76(d,J=8.3Hz,2H),7.59–7.54(m,1H),7.46(t,J=7.7Hz,2H),7.29(d,J=8.0Hz,2H),4.15(t,J=2.2Hz,2H),3.60(t,J=7.3Hz,2H),3.39(t,J=7.3Hz,2H),2.41(s,3H),1.92(qt,J=7.5,2.2Hz,2H),0.89(t,J=7.5Hz,3H);13C NMR(126MHz,CDCl3) δ 198.29,143.52,136.61,135.87,133.49,129.51,128.77,128.15,127.93,87.62,72.39,42.64,38.62,38.57,21.60,13.54, 12.24; HRMS (ESI) calculated value [ M + H, C21H23NO3S]+370.1471; found 370.1472.
1p white solid, 93% yield.1H NMR(500MHz,CDCl3)δ8.06–7.93(m,2H),7.81(d,J=8.2Hz,2H),7.33–7.20(m,5H),7.20–7.04(m,4H),4.42(s,2H),3.68(t,J=7.0Hz,2H),3.43(t,J=7.0Hz,2H),2.35(s,3H).13C NMR(126MHz,CDCl3)δ196.66,167.02,164.99,143.80,135.62,133.05(d,J=3.0Hz),131.61,130.86(d,J=9.4Hz),129.71,128.57,128.22,127.93,122.16,85.67,82.35,42.92,39.21,38.71,21.53;19F NMR(376MHz,CDCl3) Delta-104.62 (M), HRMS (ESI) calculated value [ M + Na, C25H22FNNaO3S]+458.1197; measured value 458.1204
1q white solid, 85% yield.1H NMR(400MHz,CDCl3)δ7.99(dd,J=8.7,5.4Hz,2H),7.75(d,J=8.2Hz,2H),7.29(d,J=8.0Hz,2H),7.14(t,J=8.5Hz,2H),4.14(s,2H),3.59(t,J=7.2Hz,2H),3.37(t,J=7.2Hz,2H),2.42(s,3H),1.93(dd,J=15.1,7.6Hz,2H),0.90(t,J=7.5Hz,3H);13C NMR(126MHz,CDCl3)δ196.79,167.07,165.04,143.61,135.84,133.14(d,J=2.9Hz),130.87(d,J=9.3Hz),129.57,128.65(d,J=267.4Hz),127.97,116.03,115.86,87.68,72.42,42.69,38.76,38.76,21.64,13.58,12.28;19F NMR(376MHz,CDCl3) Delta-104.69 (m); HRMS (ESI) calculated value [ M + Na, C21H22FNNaO3S]+410.1197; found 410.1201.
Effect example 1
The operation is as follows: in a glove box, under the protection of nitrogen, adding Ni (cod)2(2. mu. mol, 1 mol%), phosphine ligand (1. mu. mol/2. mu. mol, 0.5 mol%/1 mol%) and dioxane (0.5mL) were added to a 5mL vial with magnetic stirring. Substrate 1a (0.2mmol, 1.0 equiv.) was added to the solution in one portion, stirred for 5 minutes, and then triethylsilane (Et)3SiH,0.6mmol,3.0 equivalent). The vial was closed and the resulting mixture was stirred at 25 ℃ for 12 hours. With saturated sodium bicarbonate (NaHCO)3) Quench, extract with ethyl acetate (EtOAc), wash with saturated NaCl, dry over anhydrous sodium sulfate, filter, and concentrate under vacuum. The residue was purified by column chromatography (10% petroleum ether/EtOAc) to give compound 2 a.
By the above procedure, different phosphine ligands, amounts of phosphine ligands and Ni (cod)2The results of the reaction in amounts are shown in the following table:
TABLE 1 reaction results for different phosphine ligands
Effect example 2
Bisphosphine ligands L4 and Ni (cod) prepared in example 1, using Compound 1a as substrate for reductive cyclization2And (3) preparing an optically active chiral pyrrole tertiary alcohol compound 2a by using triethylsilane as a reducing agent and high ligand carrying capacity (s/c is 1000).
The operation is as follows: stirring in a glove box under the protection of nitrogen gas with Ni (cod)2N-alkynone 1a (1.0g, 2.48mmol, 1.0 equiv.) was added in one portion to a reaction flask (0.682mg, 2.48. mu. mol, 0.1 mol%) containing L4(0.816mg, 1.24. mu. mol, 0.05 mol%) as a yellow solution in dioxane (3 mL). The resulting brown solution was stirred for 15 minutes, then triethylsilane (Et) was added3SiH, 1.19mL, 7.44mmol, 3.0 equiv). The vial was sealed and the resulting mixture was stirred at 60 ℃ for 12 hours. With saturated sodium bicarbonate (NaHCO)3) Quench, extract with ethyl acetate (EtOAc), wash with saturated NaCl, over anhydrous sodium sulfate (Na)2SO4) Dried, filtered, and concentrated under vacuum. The residue was purified by column chromatography (10% petroleum ether/EtOAc) to give compound 2a as a colorless oil (1.26g, 98% yield, 99:1 er).
2a colorless oil, 98% yield, 99:1er, 0.05 mol% L4. The er value is determined by chiral high-pressure liquid phase; high-pressure liquid phase conditions: chiral AD-H column, flow rate of 1mL/min at 25 ℃, n-hexane/iso-hexanePropanol 98/2,254nm,6.8min (R),10.2min (S). The absolute configuration is determined by the X-ray single crystal structure of 3a (2a desilication-based product); [ alpha ] to]D 25=+23.6(c=1.0,CHCl3);1H NMR(500MHz,CDCl3)δ7.75(d,J=8.0Hz,2H),7.48(d,J=7.4Hz,2H),7.41–7.25(m,8H),7.16(d,J=7.6Hz,2H),6.45(s,1H),4.38(d,J=14.9Hz,1H),4.21(dd,J=14.9,1.8Hz,1H),3.68(d,J=9.6Hz,1H),3.44(d,J=9.6Hz,1H),2.44(s,3H),0.91(t,J=7.9Hz,9H),0.55(q,J=7.7Hz,6H);13C NMR(126MHz,CDCl3) δ 144.01,143.98,142.39,135.92,132.59,129.89,128.78,128.59,128.19,127.95,127.75,127.55,126.10,126.10,83.10,60.68,50.56,21.65,7.14, 6.25; HRMS (ESI) calculated value [ M + Na, C30H37NNaO3SSi]+542.2156; found 542.2159.
Compound 2a Synthesis of Compound 3a
TBAF (1.0M in THF, 1.5mL, 1.5 equiv.) was added to a solution of 2a (520mg, 1.0mmol, 1.0 equiv.) in THF (10mL) at 0 deg.C and stirred at 0 deg.C for 0.5 h. Quench with water, EtOAc extraction, brine wash, anhydrous Na2SO4Dried, filtered, and concentrated under vacuum. The residue was purified by column chromatography (20% petroleum ether/EtOAc) to give compound 3a as a white solid (390mg, 96%). 3a: [ alpha ]]D 25=+24.5(c=1.0,CHCl3);1H NMR(500MHz,CDCl3)δ7.63(d,J=8.2Hz,2H),7.39–7.32(m,2H),7.29–7.13(m,8H),7.03(d,J=7.4Hz,2H),6.19(t,J=2.3Hz,1H),4.40(dd,J=15.0,2.4Hz,1H),4.16(dd,J=15.0,2.5Hz,1H),3.47(q,J=10.4Hz,2H),2.42(s,1H),2.32(s,3H);13C NMR(126MHz,CDCl3)δ144.03,142.58,141.59,135.64,132.98,129.93,128.76,128.65,128.44,128.01,127.97,127.94,126.61,126.31,82.05,61.50,50.72, 21.68; HRMS (ESI) calculated value [ M + Na, C24H23NNaO3S]+428.1291; observed value 428.1292 the X-ray crystal diffraction pattern of Compound 3a is shown in FIG. 1.
Using the compound 1b-1p prepared in example 2 as a substrate for reductive cyclization, bisphosphine ligands L4 and Ni (cod)2The chiral pyrrole tertiary alcohol compound 2b-1q with optical activity is prepared by using the complex of (1) as a catalyst and triethylsilane as a reducing agent (the reaction operation is the same as that of the compound 1a in the embodiment 2).
2b colorless oil, 87% yield, 98:2er, 0.5 mol% L4. The er value is determined by chiral high-pressure liquid phase; high-pressure liquid phase conditions: chiral AD-H column, flow rate at 25 deg.C of 1mL/min, n-hexane/isopropanol of 98/2,254nm,15.4min (R),24.6min (S); [ alpha ] to]D 25=+19.1(c=1.0,CHCl3);1H NMR(500MHz,CDCl3)δ7.73(d,J=8.0Hz,2H),7.43–7.26(m,7H),7.15(d,J=7.5Hz,2H),6.84(d,J=8.6Hz,2H),6.47(s,1H),4.34(d,J=14.8Hz,1H),4.18(d,J=14.8Hz,1H),3.82(s,3H),3.68(d,J=9.5Hz,1H),3.39(d,J=9.5Hz,1H),2.43(s,3H),0.90(t,J=7.9Hz,9H),0.53(dd,J=15.6,7.7Hz,6H);13C NMR(126MHz,CDCl3) δ 159.01,143.91,142.39,135.96,135.70,132.73,129.87,128.76,128.60,127.89,127.68,127.47,125.53,113.49,82.70,60.30,55.35,50.33,21.64,7.14, 6.24; HRMS (ESI) calculated value [ M + H, C31H40NO4SSi]+550.2447; found 550.2431.
2c colorless oil, 90% yield, 99:1er, 0.5 mol% L4. The er value is determined by chiral high-pressure liquid phase; high-pressure liquid phase conditions: chiral AD-H column, flow rate at 25 deg.C 1mL/min, n-hexane/isopropanol 98/2,254nm,6.9min (R),10.6min (S); [ alpha ] to]D 25=+11.9(c=1.0,CHCl3);1H NMR(500MHz,CDCl3)δ7.74(d,J=8.2Hz,2H),7.48–7.42(m,2H),7.40–7.31(m,4H),7.28(t,J=7.4Hz,1H),7.15(d,J=7.4Hz,2H),7.02–6.96(m,2H),6.44(t,J=2.3Hz,1H),4.34(dd,J=14.9,2.3Hz,1H),4.21(dd,J=14.9,2.6Hz,1H),3.66(d,J=9.6Hz,1H),3.40(d,J=9.6Hz,1H),2.44(s,3H),0.89(t,J=7.9Hz,9H),0.58–0.49(m,6H);13C NMR(126MHz,CDCl3) δ 162.16(d, J ═ 246.4Hz),144.08,142.13,139.95(d, J ═ 3.1Hz),135.74,132.47,129.91,128.81,128.57,127.91,127.86(d, J ═ 2.0Hz),127.80,126.08,114.98(d, J ═ 21.4Hz),82.63,60.46,50.43,21.62,7.09, 6.23; HRMS (ESI) calculated value [ M + H, C30H37O3NFSSi]+538.2247; found 538.2234.
2d colorless oil, 74% yield, 99:1er, 0.5 mol% L4. The er value is determined by chiral high-pressure liquid phase; high-pressure liquid phase conditions: chiral AD-H column, flow rate at 25 deg.C of 1mL/min, n-hexane/isopropanol of 98/2,254nm,7.2min (R),9.4min (S); [ alpha ] to]D 25=+11.6(c=1.0,CHCl3);1H NMR(500MHz,CDCl3)δ7.73(d,J=8.2Hz,2H),7.43–7.32(m,6H),7.31–7.25(m,3H),7.14(d,J=7.4Hz,2H),6.41(t,J=2.2Hz,1H),4.35(dd,J=15.0,2.3Hz,1H),4.20(dd,J=15.0,2.6Hz,1H),3.63(d,J=9.7Hz,1H),3.40(d,J=9.7Hz,1H),2.44(s,3H),0.89(t,J=7.9Hz,9H),0.58–0.48(m,6H);13C NMR(126MHz,CDCl3) δ 144.14,142.91,141.98,135.70,133.42,132.43,129.94,128.84,128.59,128.36,127.93,127.51,126.34,110.10,82.69,60.50,50.50,21.67,7.11, 6.25; HRMS (ESI) calculated value [ M + H, C30H37O3NClSSi]+554.1952; found 554.1935.
2e colorless oil, 98% yieldThe ratio of the total weight of the particles,>99:1er, 0.25 mol% L4. The er value is determined by chiral high-pressure liquid phase; high-pressure liquid phase conditions: chiral AD-H column, flow rate at 25 deg.C 1mL/min, n-hexane/isopropanol 98/2,254nm,7.7min (R),9.0min (S); [ alpha ] to]D 25=+13.4(c=1.0,CHCl3);1H NMR(500MHz,CDCl3)δ7.76(d,J=8.1Hz,2H),7.59(dd,J=19.6,8.4Hz,4H),7.41–7.33(m,4H),7.32–7.27(m,1H),7.15(d,J=7.5Hz,2H),6.41(s,1H),4.38(dd,J=15.0,2.0Hz,1H),4.26(dd,J=15.0,2.3Hz,1H),3.65(d,J=9.8Hz,1H),3.44(d,J=9.8Hz,1H),2.45(s,3H),0.90(t,J=7.9Hz,9H),0.61–0.51(m,6H);13C NMR(126MHz,CDCl3) δ 148.77,144.26,141.87,135.57,132.20,129.96,129.70(q, J ═ 32.4Hz),128.86,128.57,128.04,127.98,126.91,126.27,125.21(q, J ═ 3.7Hz),124.21(q, J ═ 272.2Hz),82.87,60.73,50.69,21.61,7.07, 6.24; HRMS (ESI) calculated value [ M + H, C31H37O3NF3SSi]+588.2210; found 588.2216.
2f colorless oil, 98% yield, 99:1er, 0.25 mol% L4. The er value is determined by chiral high-pressure liquid phase; high-pressure liquid phase conditions: chiral AD-H column, flow rate at 25 deg.C of 1mL/min, n-hexane/isopropanol of 98/2,254nm,12.3min (S),22.3min (R); [ alpha ] to]D 25=+34.3(c=1.0,CHCl3);1H NMR(500MHz,CDCl3)δ7.75(d,J=8.2Hz,2H),7.41–7.31(m,4H),7.31–7.26(m,1H),7.22(t,J=8.0Hz,1H),7.18–7.13(m,2H),7.13–7.09(m,1H),7.02–6.97(m,1H),6.84–6.80(m,1H),6.44(t,J=2.3Hz,1H),4.40(dd,J=14.9,2.3Hz,1H),4.21(dd,J=14.9,2.6Hz,1H),3.81(s,3H),3.64(d,J=9.7Hz,1H),3.46(d,J=9.7Hz,1H),2.44(s,3H),0.91(t,J=7.9Hz,9H),0.56(q,J=7.6Hz,6H);13C NMR(126MHz,CDCl3) δ 159.46,145.83,143.98,142.23,135.91,132.57,129.88,129.19,128.77,128.58,127.93,127.76,126.33,118.47,112.71,112.19,83.14,60.96,55.29,50.63,21.63,7.15, 6.26; HRMS (ESI) calculated value [ M + H, C31H40NO4SSi]+550.2447; found 550.2432.
2g of a colorless oil, 98% yield, 99:1er, 0.5 mol% L4, 60 ℃. The er value is determined by chiral high-pressure liquid phase; high-pressure liquid phase conditions: chiral AD-H column, flow rate at 25 deg.C of 1mL/min, n-hexane/isopropanol of 98/2,254nm,12.2min (S),14.9min (R); [ alpha ] to]D 25=+27.0(c=1.0,CHCl3);1H NMR(500MHz,CDCl3)δ7.83(dd,J=7.7,1.7Hz,1H),7.79(d,J=8.2Hz,2H),7.38(d,J=8.0Hz,2H),7.33(t,J=7.6Hz,2H),7.26–7.20(m,2H),7.08(d,J=7.4Hz,2H),7.00(td,J=7.6,0.8Hz,1H),6.67(d,J=7.9Hz,1H),6.04(t,J=2.1Hz,1H),4.63(dd,J=14.1,2.0Hz,1H),4.03(dd,J=14.1,2.9Hz,1H),3.55(s,2H),3.10(s,3H),2.45(s,3H),0.98(t,J=7.9Hz,9H),0.79–0.63(m,6H);13C NMR(126MHz,CDCl3) δ 155.26,144.43,143.70,136.67,132.92,132.06,129.62,128.86,128.71,128.49,128.31,127.45,127.33,124.48,120.36,111.05,82.94,60.39,54.33,51.97,21.65,7.30, 6.16; HRMS (ESI) calculated value [ M + H, C31H40NO4SSi]+550.2447; found 550.2433.
2h colorless oil, 80% yield, 99:1er, 1 mol% L4, 80 ℃. The er value is determined by chiral high-pressure liquid phase; high-pressure liquid phase conditions: chiral OD-H column, flow rate at 25 deg.C of 1mL/min, n-hexane/isopropanol of 98/2,254nm,13.3min (S),20.5min (R); [ alpha ] to]D 25=+25.9(c=1.0,CHCl3);1H NMR(500MHz,CDCl3)δ7.79(d,J=8.3Hz,2H),7.61(d,J=8.0Hz,1H),7.41–7.27(m,7H),7.21(t,J=7.4Hz,1H),7.18–7.15(m,2H),7.13(d,J=7.7Hz,2H),7.09(s,1H),6.44(t,J=3.0Hz,1H),4.71(d,J=3.0Hz,2H),3.84(s,3H),2.42(s,3H),1.00(t,J=8.0Hz,9H),0.62(q,J=8.0Hz,6H);13C NMR(126MHz,CDCl3) δ 144.33,138.65,137.12,137.10,133.16,131.54,130.08,128.72,128.02,127.82,127.60,127.00,126.49,123.28,122.38,120.18,119.91,117.53,109.66,105.90,53.17,33.05,21.68,6.71, 5.92; HRMS (ESI) calculated value [ M-OTES, C27H25N2O2S]+441.1637; found 441.1619.
2i colorless oil, 94% yield,>99:1er, 1 mol% L4, 80 ℃. The er value is measured by a chiral high-pressure liquid phase to obtain a desiliconized base product 3 i; high-pressure liquid phase conditions: chiral AD-H column, flow rate at 25 deg.C 1mL/min, n-hexane/isopropanol 80/20,254nm,16.3min (R),21.8min (S); [ alpha ] to]D 25=–40.7(c=1.0,CHCl3);1H NMR(500MHz,CDCl3)δ7.74–7.69(m,2H),7.41–7.35(m,2H),7.33–7.26(m,3H),7.18–7.14(m,2H),6.45(t,J=2.4Hz,1H),4.26(dd,J=14.9,2.8Hz,1H),4.05(dd,J=14.9,2.2Hz,1H),3.82(d,J=10.0Hz,1H),2.89(d,J=10.0Hz,1H),2.40(s,3H),0.96(s,9H),0.81(t,J=7.9Hz,9H),0.46–0.28(m,6H);13C NMR(126MHz,CDCl3) δ 143.93,140.19,136.05,132.24,129.84,128.81,128.65,127.89,127.51,126.77,86.32,54.49,51.48,39.95,25.13,21.62,7.23, 6.46; HRMS (ESI) calculated value [ M + Na, C28H41NNaO3SSi]+522.2469; found 522.2465.
2j colorless oil, 83% yield, 92:8er, 1 mol% L4, 80 ℃. The er value is measured by a chiral high-pressure liquid phase to obtain a desiliconized base product 3 j; high-pressure liquid phase conditions: chiral OD-H column, flow rate at 25 deg.C of 1mL/min, n-hexane/isopropanol of 85/15,230nm,14.1min (R),17.8min (S); [ alpha ] to]D 25=+17.1(c=1.0,CHCl3);1H NMR(500MHz,CDCl3)δ7.72(d,J=8.2Hz,2H),7.39–7.33(m,4H),7.30–7.22(m,3H),5.35(tt,J=7.3,2.5Hz,1H),4.13–4.06(m,1H),3.85–3.79(m,1H),3.48–3.41(m,2H),2.46(s,3H),1.99–1.91(m,2H),0.93(t,J=7.5Hz,3H),0.89(t,J=7.9Hz,9H),0.53(q,J=7.7Hz,6H);13C NMR(126MHz,CDCl3) δ 144.24,143.87,140.76,132.58,129.80,129.08,128.05,127.95,127.24,126.15,82.18,62.86,49.59,22.77,21.68,13.23,7.15, 6.26; HRMS (ESI) calculated value [ M + H, C26H38NO3SSi]+472.2336; found 472.2338.
2n colorless oil, 95% yield, 90:10er, 2 mol% L4. The er value is determined by chiral high-pressure liquid phase; high-pressure liquid phase conditions: chiral AD-H column, flow rate at 25 deg.C of 1mL/min, n-hexane/isopropanol of 99/1,254nm,10.9min (R),15.5min (S); [ alpha ] to]D 25=–14.9(c=1.0,CHCl3);1H NMR(400MHz,CDCl3)δ7.52(d,J=7.8Hz,2H),7.41–7.32(m,4H),7.32–7.22(m,6H),7.20(d,J=7.8Hz,2H),6.85(s,1H),4.35(d,J=12.8Hz,1H),3.67–3.58(m,1H),3.18(d,J=12.8Hz,1H),3.03(t,J=10.1Hz,1H),2.67(d,J=13.5Hz,1H),2.36(s,3H),2.17–2.07(m,1H),0.74(t,J=7.9Hz,9H),0.39–0.18(m,6H);13C NMR(126MHz,CDCl3) δ 143.51,141.58,138.51,136.65,133.85,129.63,129.10,128.55,128.52,128.05,127.82,127.40,127.31,127.17,77.32,45.02,43.96,37.82,21.60,7.04, 6.38; HRMS (ESI) calculated value [ M + H, C31H40NO3SSi]+534.2493; found 534.2495.
2o colorless oil, 95% yield, 90:10er, 2 mol% L4. The er value is determined by chiral high-pressure liquid phase; high-pressure liquid phase conditions: a chiral AD-H column with the flow rate of 1mL/min at 25 ℃, 99/1,254nm of normal hexane/isopropanol, 6.2min (R),8.1min (S), and the absolute configuration of the chiral AD-H column is determined by the X-ray single crystal structure of 3o (2o desilication base product); [ alpha ] to]D 25=–18.9(c=1.0,CHCl3);1H NMR(500MHz,CDCl3)δ7.59(d,J=8.2Hz,2H),7.26–7.18(m,7H),5.58(t,J=7.4Hz,1H),3.99(d,J=12.7Hz,1H),3.43–3.37(m,1H),3.21(d,J=12.8Hz,1H),3.03(ddd,J=12.1,9.3,3.1Hz,1H),2.45(ddd,J=13.3,6.4,3.2Hz,1H),2.35(s,3H),2.11(dtd,J=14.8,7.4,3.5Hz,2H),1.92(ddd,J=13.2,9.1,3.9Hz,1H),0.95(t,J=7.5Hz,3H),0.67(t,J=7.9Hz,9H),0.29–0.13(m,6H);13C NMR(126MHz,CDCl3) δ 143.48,142.37,135.41,134.08,129.67,129.60,128.23,127.76,127.71,127.36,77.19,44.12,43.71,38.17,21.60,20.83,14.34,7.03, 6.41; HRMS (ESI) calculated value [ M + Na, C27H39NNaO3SSi]+508.2312; found 508.2320.
3o (2o desilication based product) preparation of 3o reference the synthetic procedure of 3a white solid; [ alpha ] to]D 25=–24.8(c=1.0,CHCl3);1H NMR(500MHz,CHCl3)δ7.68(d,J=8.1Hz,2H),7.36–7.28(m,6H),7.28–7.24(m,1H),5.14(t,J=7.3Hz,1H),4.16(d,J=13.1Hz,1H),3.58(d,J=13.1Hz,1H),3.52–3.44(m,1H),3.17(td,J=11.7,2.8Hz,1H),2.44(s,3H),2.39–2.31(m,1H),2.17–1.99(m,2H),1.84–1.79(m,1H),1.78(s,1H),0.90(t,J=7.5Hz,3H);13C NMR(126MHz,CHCl3) δ 143.74,143.62,135.52,134.02,131.74,129.78,128.22,127.78,127.47,126.35,77.41,77.16,76.91,75.34,43.84,42.90,38.79,21.63,20.78, 13.96; HRMS (ESI) calculated value [ M + H, C21H26NO3S]+372.1628; found 372.1629. The X-ray crystal diffraction pattern of compound 3o is shown in figure 2.
Claims (13)
1. A compound of formula I:
wherein R is1And R1’Is tert-butyl;
R2、R3、R4、R5and R6Each independently is hydrogen, C1-C10Alkyl or C1-C10An alkoxy group;
R2’、R3’、R4’、R5’and R6’Each independently is hydrogen, C1-C10Alkyl or C1-C10An alkoxy group;
2. A compound of formula I according to claim 1, wherein: said C1-C10Alkyl is independently C1-C4An alkyl group.
3. A compound of formula I according to claim 1, wherein: said C1-C10Alkoxy is independently C1-C4An alkoxy group.
4. A compound of formula I according to claim 1, wherein:
said C1-C10Alkyl is independently methyl, ethyl, n-propyl, isopropyl or tert-butyl.
5. A compound of formula I according to claim 1, wherein: said C1-C10Alkoxy is independently methoxy, ethoxy, n-propoxy, isopropoxy or tert-butoxy.
6. A compound of formula I according to claim 1, wherein:
said R4、R5、R6、R4’、R5’And R6’Each independently hydrogen, methyl, ethyl, isopropyl, methoxy or isopropoxy.
9. A compound of formula I according to claim 1, wherein:
R3、R4、R5、R3’、R4’and R5’Are all hydrogen;
R2、R6、R2’and R6’Each independently is C1-C10An alkoxy group.
11. a process for the preparation of a compound of formula I as claimed in any one of claims 1 to 10, comprising the steps of: in an organic solvent, carrying out a reduction reaction shown as the following on a compound shown as a formula II in the presence of a reducing agent to obtain a compound shown as a formula I;
13. Use of a compound of formula I according to any one of claims 1 to 10 as a metal ligand in a reductive cyclization reaction as follows:
the reductive cyclization reaction comprises the following steps: reacting a compound A in an organic solvent in the presence of a compound shown as a formula I, a nickel compound and a reducing agent to obtain a compound B;
n is 1 or 2;
R7is substituted or unsubstituted C6-C20Aryl, substituted or unsubstituted 5-20 membered heteroaryl, substituted or unsubstituted C1-C20Alkyl or substituted or unsubstituted C3-C20A cycloalkyl group;
R8is C1-C20Alkyl or substituted or unsubstituted C6-C20An aryl group;
said substituted C6-C20Aryl, substituted 5-20 membered heteroaryl, substituted C1-C20Alkyl or substituted C3-C20The substituents in the cycloalkyl group are each independently halogen, C1-C5Haloalkyl or C1-C5An alkoxy group; the number of the substituent is one or more; when the number of the substituent is more than one, the substituent is the same or different;
R9is an amino protecting group.
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