CN112724168B - Chiral pyridine derived N, B ligand, preparation method and application in iridium-catalyzed asymmetric boronation reaction - Google Patents
Chiral pyridine derived N, B ligand, preparation method and application in iridium-catalyzed asymmetric boronation reaction Download PDFInfo
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- CN112724168B CN112724168B CN202011602455.2A CN202011602455A CN112724168B CN 112724168 B CN112724168 B CN 112724168B CN 202011602455 A CN202011602455 A CN 202011602455A CN 112724168 B CN112724168 B CN 112724168B
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- 238000006243 chemical reaction Methods 0.000 title claims abstract description 99
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 title claims abstract description 75
- 239000003446 ligand Substances 0.000 title claims abstract description 71
- 229910052757 nitrogen Inorganic materials 0.000 title claims abstract description 67
- 229910052796 boron Inorganic materials 0.000 title claims abstract description 52
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 title claims abstract description 37
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 99
- 150000003222 pyridines Chemical class 0.000 claims abstract description 22
- 229910008423 Si—B Inorganic materials 0.000 claims abstract description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 93
- -1 3, 5-diisopropylbenzyl Chemical group 0.000 claims description 83
- 239000000243 solution Substances 0.000 claims description 65
- 150000002576 ketones Chemical class 0.000 claims description 42
- 150000005753 chloropyridines Chemical class 0.000 claims description 38
- 238000003756 stirring Methods 0.000 claims description 38
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 35
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 31
- 238000000746 purification Methods 0.000 claims description 29
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 27
- 238000002156 mixing Methods 0.000 claims description 25
- 238000000034 method Methods 0.000 claims description 24
- 150000002009 diols Chemical class 0.000 claims description 23
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 22
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 22
- 150000002923 oximes Chemical class 0.000 claims description 21
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 18
- JMXKSZRRTHPKDL-UHFFFAOYSA-N titanium ethoxide Chemical compound [Ti+4].CC[O-].CC[O-].CC[O-].CC[O-] JMXKSZRRTHPKDL-UHFFFAOYSA-N 0.000 claims description 16
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 14
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 claims description 14
- 125000005610 enamide group Chemical group 0.000 claims description 14
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 14
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 13
- 239000000203 mixture Substances 0.000 claims description 13
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 claims description 11
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical compound NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 claims description 11
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 11
- 229910021626 Tin(II) chloride Inorganic materials 0.000 claims description 11
- KTYAQHYBYRVCGD-UHFFFAOYSA-N [Ir].COC1=CC=CCCCC1 Chemical class [Ir].COC1=CC=CCCCC1 KTYAQHYBYRVCGD-UHFFFAOYSA-N 0.000 claims description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 11
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- 239000001119 stannous chloride Substances 0.000 claims description 11
- 235000011150 stannous chloride Nutrition 0.000 claims description 11
- WJZDXONSAPNKGB-UHFFFAOYSA-N 2-bromocyclopent-2-en-1-one Chemical compound BrC1=CCCC1=O WJZDXONSAPNKGB-UHFFFAOYSA-N 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 claims description 9
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 9
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 9
- 239000000843 powder Substances 0.000 claims description 9
- SYZCZDCAEVUSPM-UHFFFAOYSA-M tetrahexylazanium;bromide Chemical compound [Br-].CCCCCC[N+](CCCCCC)(CCCCCC)CCCCCC SYZCZDCAEVUSPM-UHFFFAOYSA-M 0.000 claims description 9
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 claims description 8
- CESUXLKAADQNTB-SSDOTTSWSA-N 2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)[S@](N)=O CESUXLKAADQNTB-SSDOTTSWSA-N 0.000 claims description 8
- 125000006186 3,5-dimethyl benzyl group Chemical group [H]C1=C(C([H])=C(C([H])=C1C([H])([H])[H])C([H])([H])*)C([H])([H])[H] 0.000 claims description 8
- 239000007864 aqueous solution Substances 0.000 claims description 7
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical group C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 claims description 7
- 239000002808 molecular sieve Substances 0.000 claims description 7
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 7
- 150000002081 enamines Chemical class 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- 239000012299 nitrogen atmosphere Substances 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 5
- 238000005888 cyclopropanation reaction Methods 0.000 claims description 4
- 150000005690 diesters Chemical class 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- BZKFMUIJRXWWQK-UHFFFAOYSA-N Cyclopentenone Chemical class O=C1CCC=C1 BZKFMUIJRXWWQK-UHFFFAOYSA-N 0.000 claims description 2
- 238000005859 coupling reaction Methods 0.000 claims description 2
- 125000004185 ester group Chemical group 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims 2
- BMQDAIUNAGXSKR-UHFFFAOYSA-N (3-hydroxy-2,3-dimethylbutan-2-yl)oxyboronic acid Chemical compound CC(C)(O)C(C)(C)OB(O)O BMQDAIUNAGXSKR-UHFFFAOYSA-N 0.000 claims 1
- 229910052741 iridium Inorganic materials 0.000 abstract description 10
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 abstract description 10
- 230000000694 effects Effects 0.000 abstract description 7
- 229910052751 metal Inorganic materials 0.000 abstract description 7
- 239000002184 metal Substances 0.000 abstract description 7
- 230000003197 catalytic effect Effects 0.000 abstract description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 90
- 239000012074 organic phase Substances 0.000 description 50
- 238000004440 column chromatography Methods 0.000 description 47
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 37
- 239000007787 solid Substances 0.000 description 33
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 24
- 238000001035 drying Methods 0.000 description 24
- 239000000706 filtrate Substances 0.000 description 21
- 238000000926 separation method Methods 0.000 description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 18
- 239000012065 filter cake Substances 0.000 description 17
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 16
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 16
- 238000010791 quenching Methods 0.000 description 14
- 230000000171 quenching effect Effects 0.000 description 14
- 238000010992 reflux Methods 0.000 description 13
- 239000008346 aqueous phase Substances 0.000 description 12
- 239000012071 phase Substances 0.000 description 12
- 239000000758 substrate Substances 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 11
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 10
- 238000000605 extraction Methods 0.000 description 10
- 238000005406 washing Methods 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 229910052786 argon Inorganic materials 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 8
- 125000001010 sulfinic acid amide group Chemical group 0.000 description 8
- 239000012043 crude product Substances 0.000 description 7
- 238000000967 suction filtration Methods 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 238000006555 catalytic reaction Methods 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 230000003647 oxidation Effects 0.000 description 6
- 238000007254 oxidation reaction Methods 0.000 description 6
- 238000007867 post-reaction treatment Methods 0.000 description 6
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 238000007865 diluting Methods 0.000 description 5
- 238000005086 pumping Methods 0.000 description 5
- HEWZVZIVELJPQZ-UHFFFAOYSA-N 2,2-dimethoxypropane Chemical compound COC(C)(C)OC HEWZVZIVELJPQZ-UHFFFAOYSA-N 0.000 description 4
- FNRMMDCDHWCQTH-UHFFFAOYSA-N 2-chloropyridine;3-chloropyridine;4-chloropyridine Chemical compound ClC1=CC=NC=C1.ClC1=CC=CN=C1.ClC1=CC=CC=N1 FNRMMDCDHWCQTH-UHFFFAOYSA-N 0.000 description 4
- CFOAUMXQOCBWNJ-UHFFFAOYSA-N [B].[Si] Chemical compound [B].[Si] CFOAUMXQOCBWNJ-UHFFFAOYSA-N 0.000 description 4
- 238000005903 acid hydrolysis reaction Methods 0.000 description 4
- PRKQVKDSMLBJBJ-UHFFFAOYSA-N ammonium carbonate Chemical class N.N.OC(O)=O PRKQVKDSMLBJBJ-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000010523 cascade reaction Methods 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000007810 chemical reaction solvent Substances 0.000 description 4
- 239000012418 sodium perborate tetrahydrate Substances 0.000 description 4
- IBDSNZLUHYKHQP-UHFFFAOYSA-N sodium;3-oxidodioxaborirane;tetrahydrate Chemical compound O.O.O.O.[Na+].[O-]B1OO1 IBDSNZLUHYKHQP-UHFFFAOYSA-N 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 229910001873 dinitrogen Inorganic materials 0.000 description 3
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical compound N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 description 1
- VMQMZMRVKUZKQL-UHFFFAOYSA-N Cu+ Chemical compound [Cu+] VMQMZMRVKUZKQL-UHFFFAOYSA-N 0.000 description 1
- IVDFJHOHABJVEH-UHFFFAOYSA-N HOCMe2CMe2OH Natural products CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 description 1
- BXEFQPCKQSTMKA-UHFFFAOYSA-N OC(=O)C=[N+]=[N-] Chemical compound OC(=O)C=[N+]=[N-] BXEFQPCKQSTMKA-UHFFFAOYSA-N 0.000 description 1
- 235000008331 Pinus X rigitaeda Nutrition 0.000 description 1
- 235000011613 Pinus brutia Nutrition 0.000 description 1
- 241000018646 Pinus brutia Species 0.000 description 1
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 1
- 125000000746 allylic group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- ZDVHQYVXWOYBEH-UHFFFAOYSA-N bis(2-methylpropyl)alumane hexane Chemical compound CCCCCC.[H][Al](CC(C)C)CC(C)C ZDVHQYVXWOYBEH-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000003889 chemical engineering Methods 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 206010013781 dry mouth Diseases 0.000 description 1
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical group [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229930003658 monoterpene Natural products 0.000 description 1
- 150000002773 monoterpene derivatives Chemical class 0.000 description 1
- 235000002577 monoterpenes Nutrition 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
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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
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
- C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
-
- 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
- B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
- B01J31/1805—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms the ligands containing nitrogen
- B01J31/181—Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine
- B01J31/184—Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine mixed aromatic/aliphatic ring systems, e.g. indoline
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/30—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
- C07D221/06—Ring systems of three rings
- C07D221/16—Ring systems of three rings containing carbocyclic rings other than six-membered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/113—Spiro-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
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Abstract
Chiral pyridine derived N, B ligand, preparation method and application in iridium-catalyzed asymmetric boronization reaction, namely chiral pyridine derivative and PhMe2Si‑B(NiPr2)2Reacting in toluene at 125-135 ℃ to obtain chiral pyridine derived N, B ligand; the ligand is used in iridium catalytic asymmetric boronization, as the ligand is an N and B bidentate ligand, the catalytic activity of central metal iridium can be obviously improved, the chiral pyridine part is a rigid fused ring structure framework, the whole ligand has a relatively rigid and stable chiral space, a complex is formed after coordination with the metal iridium and is stable, the chiral environment cannot be changed in the reaction process, and meanwhile, the steric hindrance of the ortho position of the pyridine cannot be obviously increased due to the introduction of a five-membered ring and a three-membered ring, so that the catalytic activity of the metal iridium is influenced. The ligand of the invention shows excellent reaction activity and enantioselectivity in the iridium-catalyzed asymmetric boronation reaction.
Description
Technical Field
The invention belongs to the technical field of fine chemical engineering, and relates to a chiral pyridine derived N, B ligand, a preparation method and application thereof in iridium-catalyzed asymmetric boronization.
Background
The chiral ligand is a key part for regulating and controlling the activity and reaction stereoselectivity of the catalyst in asymmetric metal catalysis and realizing the synthesis of a single enantiomer of a product. Pyridine is a ligand structural unit which is most widely applied in catalysis, but a chiral pyridine skeleton which is lack of universality so far restricts the development of a plurality of asymmetric catalytic reactions. For example,
chiral Bipyridine Ligand PINDY is synthesized from natural monoterpene Pinene and applied to the reactions of cyclopropanation, Allylic Oxidation and the like (PINDY: A Novel, pine-depleted dipyridine Ligand and Its Application in asymmetry Copper (I) -Catalyzed Allyllic Oxidation, Malkov, A.V.; Bella, M.J.; Langer, V.;
leg.2000, 2,3047. (p.org). Because of the difficulty of structural modification of PINDY, the structure cannot be further optimized, and the reactions are only moderate to goodEnantioselectivity. The Fu topic group skillfully designs Planar Chiral pyridine ligand BPY containing ferrocene skeleton, and obtains higher selectivity in copper-catalyzed cyclopropanation reaction using bulky steric diazoacetate (Applications of Planar-Chiral Heterocycles as Ligands in asymmetry Catalysis, Fu, G.C. Acc.chem.Res.2006,39,853.). The introduction of chiral elements on a planar structure is difficult, the contradiction between activity and selectivity caused by steric hindrance is difficult, the structure has poor modifiability, and the modular synthesis is difficult, which is a main challenge facing the design of chiral pyridine.
Disclosure of Invention
Aiming at the problems existing in the design and synthesis aspects of the prior chiral pyridine, the invention aims to provide a chiral pyridine derived N, B ligand, a preparation method and application in iridium-catalyzed asymmetric boronation reaction.
The invention is realized by the following technical scheme:
the structural general formula of the chiral pyridine derived N, B ligand is shown as formula (1):
r is methyl, ethyl, isopropyl, benzyl, 3, 5-dimethylbenzyl, 3, 5-diisopropylbenzyl, 3, 5-di-tert-butylbenzyl, 3, 5-diphenylbenzyl, phenyl, 3, 5-dimethylphenyl, 3, 5-dimethoxyphenyl, 3, 5-diisopropylphenyl, 3, 5-di-tert-butylphenyl or 3, 5-diphenylphenyl.
A process for preparing chiral pyridine-derived N, B ligand by reacting chiral pyridine derivative shown in formula (9) with PhMe2Si-B(NiPr2)2Reacting in toluene at 125-135 ℃ to obtain chiral pyridine-derived N, B ligand shown in formula (1);
wherein R is methyl, ethyl, isopropyl, benzyl, 3, 5-dimethylbenzyl, 3, 5-diisopropylbenzyl, 3, 5-di-tert-butylbenzyl, 3, 5-diphenylbenzyl, phenyl, 3, 5-dimethylphenyl, 3, 5-dimethoxyphenyl, 3, 5-diisopropylphenyl, 3, 5-di-tert-butylphenyl or 3, 5-diphenylphenyl.
The invention has the further improvement that the concrete process is as follows: under nitrogen atmosphere, 1mmol of chiral pyridine derivative shown as formula (9) and 1.1-1.3 mmol of PhMe2Si-B(NiPr2)2And mixing the chiral pyridine and anhydrous toluene, and then reacting for 24-36 h at 125-135 ℃ to obtain the chiral pyridine derived N, B ligand.
In a further improvement of the present invention, the chiral pyridine derivative represented by formula (9) is prepared by the following process:
mixing chiral diol, ketal, p-toluenesulfonic acid, stannous chloride and dichloroethane shown in formula (7), and reacting under reflux to obtain chiral chloropyridine derivative shown in formula (8);
the ketal formula is as follows:
wherein R is methyl, ethyl, isopropyl, benzyl, 3, 5-dimethylbenzyl, 3, 5-diisopropylbenzyl, 3, 5-di-tert-butylbenzyl, 3, 5-diphenylbenzyl, phenyl, 3, 5-dimethylphenyl, 3, 5-dimethoxyphenyl, 3, 5-diisopropylphenyl, 3, 5-di-tert-butylphenyl or 3, 5-diphenylphenyl;
mixing a chiral chloropyridine derivative shown in a formula (8) and phenylenediamine in palladium acetate, 2 '-bis- (diphenylphosphino) -1,1' -binaphthyl and toluene, and then carrying out C-N bond coupling reaction to obtain a chiral pyridine derivative shown in a formula (9);
the further improvement of the invention is that chiral diol, ketal, p-toluenesulfonic acid, stannous chloride, 4A molecular sieve and anhydrous dichloroethane are mixed and stirred for 6-8 h at 80-100 ℃ to obtain the chiral chloropyridine derivative shown in formula (8); wherein the ratio of the amounts of the chiral diol, the ketal, the p-toluenesulfonic acid and the stannous chloride is 1: (1.5-2): (0.02-0.05): (0.02-0.05);
mixing the chiral chloropyridine derivative shown in the formula (8), o-phenylenediamine, palladium acetate, 2,2 '-bis- (diphenylphosphino) -1,1' -binaphthyl, cesium carbonate and anhydrous toluene under a nitrogen atmosphere, and stirring at 90-100 ℃ for 10-16 h to obtain the chiral pyridine derivative shown in the formula (9); wherein the ratio of the amounts of the chiral chloropyridine derivative, o-phenylenediamine, palladium acetate, 2 '-bis- (diphenylphosphino) -1,1' -binaphthyl and cesium carbonate is 1: (1.2-2): (0.02-0.05): (0.04-0.1): (1.5-2).
In a further development of the invention, the chiral diol is prepared by the following process:
(1) performing cyclopropanation reaction on bromo-cyclopentenone and malonic diester to generate ketone shown in a formula (2);
wherein R is1Is methyl, ethyl, isopropyl, tert-butyl or benzyl;
(2) reacting ketone shown in a formula (2) with (R) -tert-butyl sulfinamide and tetraethyl titanate to obtain sulfinyl imine, and hydrolyzing to obtain chiral ketone shown in a formula (3) or a formula (3');
(3) placing chiral ketone shown in a formula (3) or a formula (3') and hydroxylamine into ethanol for reaction to obtain oxime shown in a formula (4);
(4) adding oxime shown in a formula (4) into toluene, adding iron powder, acetic anhydride and acetic acid, and reacting to obtain enamide shown in a formula (5);
(5) dissolving the enamine shown in the formula (5) in N, N-dimethylformamide, then dropwise adding phosphorus oxychloride, and reacting to obtain the chiral chloropyridine derivative shown in the formula (6);
(6) the chiral chloropyridine derivative shown in the formula (6) is dissolved in dichloromethane, and an ester group is reduced to a hydroxyl group by diisobutylaluminum hydride to obtain a chiral diol.
The invention has the further improvement that the specific process of the step (1) is as follows: mixing bromo-cyclopentenone, diethyl malonate, tetrahexylammonium bromide, potassium carbonate and 1, 2-dichloroethane, and stirring at 80-90 ℃ for 8-12 hours to obtain racemic ketone shown in formula (2); wherein the mass ratio of the brominated cyclopentenone, diethyl malonate, tetrahexylammonium bromide and potassium carbonate is 1: (1.0-1.5): (0.1-0.2): (4-6);
the specific process of the step (2) is as follows: mixing racemic ketone (R) -tert-butyl sulfenamide shown in formula (2), tetraethoxytitanate and anhydrous 1, 2-dichloroethane, and stirring at 80-90 ℃ for 12-18 h to obtain a pair of enantiomeric ketone shown in formula (3) and formula (3'); wherein the ratio of the amounts of racemic ketone, tetraethyl (R) -tert-butylsulfinamide UI titanate is 1: (1.0-1.5): (2-3);
the specific process of the step (3) is as follows: dissolving chiral ketone and hydroxylamine aqueous solution shown in formula (3) or formula (3') in ethanol, and stirring for 2-4 h at 60-80 ℃; obtaining oxime represented by a formula (4); wherein the ratio of the amount of substance of chiral ketone to hydroxylamine is 1: (3-5).
The invention has the further improvement that the specific process of the step (4) is as follows: dissolving oxime shown in a formula (4) in toluene, then adding reduced iron powder, dropwise adding a mixture of acetic acid and acetic anhydride at 0 ℃, and stirring for 2-4 h to obtain enamide shown in a formula (5); wherein the mass ratio of the oxime, the reduced iron powder, the acetic acid and the acetic anhydride is 1: (8-10): (3-5): (3-5);
the specific process of the step (5) is as follows: dissolving enamine shown in a formula (5) in anhydrous N, N-dimethylformamide, dropwise adding phosphorus oxychloride at 0 ℃, heating to 60-80 ℃ after dropwise adding, and reacting for 6-10 h to obtain chiral chloropyridine derivatives shown in a formula (6); wherein the mass ratio of the enamine to the phosphorus oxychloride is 1: (7-10);
the specific process of the step (6) is as follows: dissolving the chiral chloropyridine derivative shown in the formula (6) in anhydrous dichloromethane, dropwise adding n-hexane solution of diisobutyl aluminum hydride at 0 ℃, and stirring at room temperature for 4-6 hours after dropwise adding to obtain chiral diol shown in the formula (7); wherein the ratio of the amount of the chiral chloropyridine derivative to the amount of the diisobutylaluminum hydride is 1 mmol: 6-8 mL.
The application of the chiral pyridine-derived N, B ligand in iridium-catalyzed asymmetric boronation reaction is provided.
The further improvement of the invention is that in an argon glove box, the chiral N, B ligand, methoxy (cyclooctadiene) iridium dimer and bis pinacol boric acid ester are pre-stirred in N-hexane for 5-30 min, diaryl pyridine is added, stirring is carried out at 60-80 ℃ for 2-8 h, and purification is carried out to obtain a chiral aryl boron compound; wherein the ratio of the amounts of the chiral N, B ligand, methoxy (cyclooctadiene) iridium dimer and bis (pinacolato) borate is (0.04-0.1): (0.02-0.05): (1.2-2): 1.
compared with the prior art, the invention has the following beneficial effects:
the ligand is used in iridium catalytic asymmetric boronization, as the ligand is an N and B bidentate ligand, the catalytic activity of central metal iridium can be obviously improved, the chiral pyridine part is a rigid fused ring structure framework, the whole ligand has a relatively rigid and stable chiral space, a complex is formed after coordination with the metal iridium and is stable, the chiral environment cannot be changed in the reaction process, and meanwhile, the steric hindrance of the ortho position of the pyridine cannot be obviously increased due to the introduction of a five-membered ring and a three-membered ring, so that the catalytic activity of the metal iridium is influenced. In addition, the chiral ligand has a hydroxyl functional group with adjustable structure height, can conveniently derive a series of chiral N and B ligands, and can improve the enantioselectivity of chiral aryl boronization products while obtaining high yield. The ligand of the invention has excellent reaction activity and enantioselectivity in the iridium-catalyzed asymmetric boronization reaction, and the obtained chiral aryl boron product has good enantioselectivity and high yield. The raw materials for synthesizing the ligand have low cost, are simple and easy to obtain, and are convenient to synthesize.
The chiral ligand of the invention shows excellent reaction activity and enantioselectivity in the asymmetric boronization reaction catalyzed by iridium. Therefore, the invention provides a new framework chiral ligand for the development of asymmetric catalysis, and provides a new method for preparing the chiral aryl boron compound.
Furthermore, the chiral chloropyridine compound with rigid fused ring structure skeleton and adjustable structure height is designed and synthesized, and is further derived into chiral N and B ligands.
Drawings
FIG. 1 shows chiral pyridine-derived N, B ligands of formula (1) in an embodiment of the present invention1H NMR spectrum, wherein the R group is benzyl.
Detailed Description
The present invention will now be described in further detail with reference to specific examples, which are intended to be illustrative, but not limiting, of the invention.
A chiral chloropyridine compound with a rigid fused ring structure skeleton and a height-adjustable structure is further derivatized into a chiral N, B ligand, and the chiral ligand shows excellent reaction activity and enantioselectivity in an iridium-catalyzed asymmetric boronization reaction.
The structural general formula of the chiral pyridine derived N, B ligand provided by the invention is shown as formula (1):
a process for preparing chiral pyridine-derived N, B ligands comprising the steps of:
the first step is as follows: mixing bromo-cyclopentenone (1mmol), malonic diester (1.0-1.5 mmol), tetrahexylammonium bromide (0.1-0.2 mmol), potassium carbonate (4-6 mmol) and 1, 2-dichloroethane (the concentration of bromo-cyclopentenone is 0.5-1 mol/L), and stirring at 80-90 ℃ for 8-12 hours. And (3) post-reaction treatment: filtering, collecting filtrate, concentrating, and purifying by column chromatography to obtain racemic ketone represented by formula (2).
Wherein R is1Methyl, ethyl, isopropyl, tert-butyl, benzyl or the like.
The second step is that: mixing 1mmol of racemic ketone (shown in formula (2), (1.0-1.5 mmol of R) -tert-butyl sulfenamide, 2-3 mmol of tetraethyl titanate and anhydrous 1, 2-dichloroethane (the concentration of the racemic ketone is 0.5-1 mol/L), and stirring at 80-90 ℃ for 12-18 h. And (3) post-reaction treatment: quenching reaction with saturated ammonium chloride solution at 0 deg.C, vacuum filtering, collecting filtrate, extracting with dichloromethane, drying organic phase, concentrating, and purifying by column chromatography to obtain diastereoisomer sulfinylimine. And then, respectively carrying out hydrochloric acid (2mol/L) hydrolysis on the pair of diastereoisomer sulfinylimines obtained by purification, and using methanol (the concentration of the pair of diastereoisomer sulfinylimines obtained by purification is 0.2-0.4 mol/L) as a solvent. After the reaction is finished, ethyl acetate is used for extraction, an organic phase is dried, concentrated, and separated and purified by column chromatography to obtain a pair of enantiomer ketones shown in formula (3) and formula (3').
The third step: dissolving 1mmol of chiral ketone (shown in formula (3)) and 3-5 mmol of hydroxylamine (50% aqueous solution) in ethanol (the concentration of the chiral ketone is 0.5-1 mol/L), and stirring at 60-80 ℃ for 2-4 h. After the reaction, extraction was performed with ethyl acetate, and the organic phase was dried and concentrated to obtain an oxime represented by the formula (4).
The fourth step: dissolving oxime (1mmol) shown in formula (4) in toluene (the concentration of the oxime is 0.5-1 mol/L), adding reduced iron powder (8-10 mmol), dropwise adding a mixture of acetic acid (3-5 mmol) and acetic anhydride (3-5 mmol) at 0 ℃, and vigorously stirring at room temperature for 2-4 h. And (3) after the reaction is finished, performing suction filtration, washing a filter cake with ethyl acetate, collecting filtrate, adjusting the pH value to 6-7 with a saturated sodium carbonate solution, extracting with ethyl acetate, drying an organic phase, concentrating, and performing column chromatography separation and purification to obtain the enamide shown in the formula (5).
The fifth step: dissolving 1mmol of enamide shown in a formula (5) in anhydrous N, N-dimethylformamide (3-5 mmol), dropwise adding 7-10 mmol of phosphorus oxychloride at 0 ℃, heating the system to 60-80 ℃ after dropwise adding, and reacting for 6-10 h. After the reaction is finished, diluting the reaction solution with a proper amount of ethyl acetate at low temperature, slowly pouring the diluted reaction solution into a proper amount of saturated sodium bicarbonate solution, adjusting the pH value to 7-8, extracting with ethyl acetate, drying an organic phase, concentrating, and carrying out column chromatography separation and purification to obtain the chiral chloropyridine derivative shown in the formula (6).
And a sixth step: dissolving 1mmol of chiral chloropyridine derivative shown in formula (6) in anhydrous dichloromethane (the concentration of the chiral chloropyridine derivative is 0.5-1 mol/L), dropwise adding 1mol/L diisobutylaluminum hydride normal hexane solution (6-8 mL of diisobutylaluminum hydride) at 0 ℃, and stirring at room temperature for 4-6 h after dropwise adding. After the reaction is finished, slowly quenching the reaction by using a saturated ammonium chloride solution at a low temperature, adding a proper amount of methanol, stirring for 30 minutes, extracting by using dichloromethane, drying an organic phase, concentrating, and carrying out column chromatography separation and purification to obtain the chiral diol shown in the formula (7).
The seventh step: mixing chiral diol (1mmol) shown in formula (7), ketal (1.5-2 mmol), p-toluenesulfonic acid (0.02-0.05 mmol), stannous chloride (0.02-0.05 mmol) and a proper amount of 4A molecular sieve with anhydrous dichloroethane (the concentration of the chiral diol is 0.5-1 mol/L), and stirring at 80-100 ℃ for 4-8 h. And (3) post-treatment: and (3) carrying out suction filtration, collecting the filtrate, concentrating, and carrying out column chromatography separation and purification to obtain the chiral chloropyridine derivative shown in the formula (8).
Wherein R is methyl, ethyl, isopropyl, benzyl (including benzyl with substituent on benzene ring: 3, 5-dimethylbenzyl, 3, 5-diisopropylbenzyl, 3, 5-di-tert-butylbenzyl, 3, 5-diphenylbenzyl) or phenyl (including phenyl with substituent on benzene ring: 3, 5-dimethylphenyl, 3, 5-dimethoxyphenyl, 3, 5-diisopropylphenyl, 3, 5-di-tert-butylphenyl or 3, 5-diphenylphenyl), etc.
Eighth step: mixing 1mmol of chiral chloropyridine derivative represented by formula (8), 1.2 to 2mmol of o-phenylenediamine, 0.02 to 0.05mmol of palladium acetate, 0.04 to 0.1mmol of 2,2 '-bis- (diphenylphosphino) -1,1' -binaphthyl, 1.5 to 2mmol of cesium carbonate and anhydrous toluene (the concentration of the chiral chloropyridine derivative is 0.3 to 0.5mol/L) in a nitrogen atmosphere, and stirring at 90 to 100 ℃ for 10 to 16 hours.
And (3) post-treatment: and (3) carrying out suction filtration, collecting the filtrate, concentrating, and carrying out column chromatography separation and purification to obtain the chiral pyridine derivative shown in the formula (9).
The ninth step: under nitrogen atmosphere, chiral pyridine derivative (1mmol) shown in formula (9) and silicon boron reagentPhMe2Si-B(NiPr2)2(1.1-1.3 mmol) and anhydrous toluene (the concentration of the chiral pyridine derivative is 0.5-1 mol/L), and reacting for 24-36 h at 125-135 ℃. And (3) post-treatment: and (3) pumping the toluene under anhydrous and anaerobic conditions, and washing the obtained yellow solid for 3-5 times by using anhydrous N-hexane to obtain a white or light yellow product, namely the target N, B ligand shown in the formula (1).
Wherein R is methyl, ethyl, isopropyl, benzyl, 3, 5-dimethylbenzyl, 3, 5-diisopropylbenzyl, 3, 5-di-tert-butylbenzyl, 3, 5-diphenylbenzyl, phenyl, 3, 5-dimethylphenyl, 3, 5-dimethoxyphenyl, 3, 5-diisopropylphenyl, 3, 5-di-tert-butylphenyl or 3, 5-diphenylphenyl, etc.
The application of the chiral pyridine derived N, B ligand in iridium-catalyzed asymmetric boronization comprises the following steps:
in an argon glove box, pre-stirring chiral N, B ligand (0.04-0.1 mmol), methoxy (cyclooctadiene) iridium dimer (0.02-0.05 mmol) and bis (pinacolato) borate (1.2-2 mmol) in N-hexane (0.1-0.2 mol/L) for 5-30 min, adding substrate diaryl pyridine (1mmol), stirring at 60-80 ℃ for 2-8 h, and separating and purifying the obtained crude product by column chromatography to obtain the corresponding chiral aryl boron compound.
The structure of the chiral aryl boron compound is shown as the formula (10):
wherein R is1，R2Represents different functional group substituents connected with the ortho, meta and para positions of the aromatic ring.
The following are specific examples.
Example 1
Synthesis of chiral pyridine-derived N, B ligands:
1.1)
in a 250mL single-necked flask, bromocyclopentenone (17.71g,110mmol), diethyl malonate (25.05mL,165mmol), tetrahexylammonium bromide (4.78g,11mmol), potassium carbonate (91.21g,660mmol), and 60mL 1, 2-dichloroethane were added, and heated at 90 ℃ under reflux for 8 hours. And (3) post-treatment: the reaction solution was filtered through a buchner funnel, and the filter cake was washed with dichloromethane, collected, concentrated, and subjected to column chromatography to separate and purify the racemic ketone represented by formula (2) (colorless oily liquid, 86% yield).
1.2)
Racemic ketone (9.6g,40mmol) represented by the formula (2), (R) -t-butylsulfinamide (5.33g,44mmol), tetraethyltitanate (18.25g,80mmol), 40mL of anhydrous 1, 2-dichloroethane were mixed, and heated at 90 ℃ under reflux for 12 hours. And (3) post-reaction treatment: quenching reaction with saturated ammonium chloride solution at 0 deg.C, vacuum filtering, collecting filtrate, extracting water phase with dichloromethane for 3 times, mixing organic phases, back-extracting with saturated saline solution, drying organic phase with anhydrous sodium sulfate, concentrating, and purifying by column chromatography to obtain a pair of diastereoisomer sulfinylimines (1: 1, each with 40% yield). The pair of diastereoisomeric sulfinamides obtained after purification is subsequently subjected to a respective hydrochloric acid hydrolysis, here for example a three-membered ring-up sulfinamide, which is dissolved in 30mL of methanol at 0 ℃ and stirred at room temperature for 6h with the addition of 2mol/L hydrochloric acid solution (20 mL). And (3) post-treatment: quenching the reaction with saturated ammonium carbonate solution at 0 deg.C, extracting the water phase with ethyl acetate for 3 times, mixing the organic phases, back-extracting with saturated saline, drying the organic phase with anhydrous sodium sulfate, concentrating, and purifying by column chromatography to obtain chiral ketone (colorless oily liquid, 95% yield) represented by formula (3).
1.3)
The chiral ketone (3.65g,15.2mmol) and hydroxylamine (3.01g,45.6mmol) (50% aqueous solution) obtained in the previous step were dissolved in 30mL of ethanol and heated under reflux for 4 hours. And (3) post-treatment: to the reaction solution was added saturated brine, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, the organic phase was dried over anhydrous sodium sulfate, and concentrated to give the oxime represented by formula (4) (pale yellow solid, 100% yield).
1.4)
The oxime obtained in the previous step was dissolved in 15mL of toluene, and reduced iron powder (8.51g,152mmol) was added, and a mixture of acetic acid (2.74g,45.6mmol) and acetic anhydride (4.66g,45.6mmol) was added dropwise at 0 ℃ and stirred vigorously at room temperature for 4 hours. And (3) post-treatment: and (2) carrying out suction filtration, washing a filter cake with ethyl acetate, collecting filtrate, adjusting the pH value to 6-7 with a saturated sodium carbonate solution, extracting the water phase with ethyl acetate for 3 times, combining organic phases, carrying out back extraction with saturated saline solution, drying the organic phase with anhydrous sodium sulfate, concentrating, and carrying out column chromatography separation and purification to obtain the enamide (light yellow solid, 80% yield) shown in the formula (5).
1.5)
Into a 25mL dry Schlenk tube, enamide (3.40g,12.0mmol) obtained in the previous step was added, the system was purged with nitrogen 3 times, a mixture of N, N-dimethylformamide (2.77mL) and phosphorus oxychloride (7.81mL,84.0mmol) was added dropwise at 0 ℃ and, after completion of the addition, the system was heated to 80 ℃ for 6 hours. And (3) post-treatment: diluting the reaction solution with 20mL of ethyl acetate at 0 ℃, slowly pouring the diluted solution into a proper amount of saturated sodium bicarbonate solution, adjusting the pH to 7-8, extracting the aqueous phase with ethyl acetate for 3 times, combining the organic phases, carrying out back extraction with saturated saline, drying the organic phase with anhydrous sodium sulfate, concentrating, and carrying out column chromatography separation and purification to obtain the chiral chloropyridine derivative (white solid, 86% yield) shown in the formula (6).
1.6)
Chiral chloropyridine (2.8g,9mmol) obtained in the previous step and 18mL of anhydrous dichloromethane were added to a 100mL dry mouth piece under anhydrous and oxygen-free conditions, diisobutylaluminum hydride (54mL of a 1M n-hexane solution) was added dropwise at 0 ℃ from a constant pressure dropping funnel, and after completion of the addition, the mixture was stirred at room temperature for 6 hours. And (3) post-treatment: slowly quenching the reaction with a saturated ammonium chloride solution at 0 ℃, adding 30mL of methanol, stirring for 30 minutes, extracting the aqueous phase with dichloromethane for 5-6 times, combining the organic phases, drying with anhydrous sodium sulfate, concentrating, and carrying out column chromatography separation and purification to obtain the chiral diol (white solid, 90% yield) shown in the formula (7).
1.7)
In a dry Schlenk tube, the chiral diol (34mg,0.15mmol) obtained in the previous step, 2, 2-dimethoxypropane (31.2mg,0.3mmol), p-toluenesulfonic acid monohydrate (1.5mg,0.0075mmol), stannous chloride (1.5mg,0.0075mmol), an appropriate amount of 4A molecular sieve, and 1mL of anhydrous 1, 2-dichloroethane were added and reacted at 100 ℃ for 4 hours. And (3) post-treatment: the reaction solution was filtered with a buchner funnel, and the filter cake was washed with dichloromethane, and the filtrate was collected, concentrated, and subjected to column chromatography separation and purification to obtain a chiral chloropyridine derivative represented by formula (8) (white solid, 93% yield).
1.8)
To a dry Schlenk tube, the chiral chloropyridine derivative (34.5mg,0.13mmol) obtained in the previous step, o-phenylenediamine (17.3mg,0.16mmol), palladium acetate (1.5mg,0.0065mmol), 2,2 '-bis- (diphenylphosphino) -1,1' -binaphthyl (4mg,0.0065mmol), cesium carbonate (85mg,0.26mmol) were added, the reaction tube was purged with nitrogen three times, 1mL of anhydrous toluene was added under a nitrogen stream, and the reaction was carried out at 100 ℃ for 12 hours. And (3) post-treatment: the reaction solution was filtered through a suction filter funnel, and the filter cake was washed with dichloromethane, and the filtrate was collected, concentrated, and purified by column chromatography to obtain a chiral pyridine derivative represented by formula (9) (white solid, 88% yield).
1.9)
In a dry Schlenk tube, the chiral pyridine derivative (33.7mg,0.1mmol) obtained in the previous step, the reagent Si-B PhMe, were added2Si-B(NiPr2)2(45mg,0.13mmol), the nitrogen gas was purged into the reaction tube three times, and 1mL of anhydrous toluene was added under nitrogen flow to conduct reaction at 135 ℃ for 36 hours. And (3) post-treatment: and (3) pumping the toluene under anhydrous and anaerobic conditions, and washing the obtained yellow solid with anhydrous N-hexane for 3 times (1 mL each time) to obtain a white solid, namely the chiral N, B ligand L shown in the formula (1).
Example 1 preparation of the chiral N, B ligand1The H NMR spectrum is shown in FIG. 1.1H NMR(400MHz,CDCl3)δ7.21-7.11(m,2H),7.09-7.05(m,1H),6.81(dd,J＝8.0,1.2Hz,1H),6.78-6.74(m,1H),6.13(d,J＝8.3Hz,1H),6.02(s,1H),4.02(d,J＝11.8Hz,1H),3.87(s,2H),3.68(d,J＝12.4Hz,1H),3.36(dd,J＝11.8,1.1Hz,1H),3.27-3.23(m,1H),3.06(dd,J＝17.3,7.1Hz,1H),2.85(d,J＝17.3Hz,1H),2.33(dd,J＝6.3,1.6Hz,1H),1.97(t,J＝6.7Hz,1H),1.46(s,3H),1.44(s,3H).
Example 2
1.1) in a 10mL single-necked flask, bromocyclopentenone (1mmol), diethyl malonate (1.0mmol), tetrahexylammonium bromide (0.15mmol), potassium carbonate (4mmol), and 2mL of 1, 2-dichloroethane were added, and heated at 84 ℃ under reflux for 10 hours. And (3) post-treatment: the reaction solution was filtered through a buchner funnel, and the filter cake was washed with dichloromethane, collected, concentrated, and subjected to column chromatography to separate and purify the racemic ketone represented by formula (2) (colorless oily liquid, 86% yield).
1.2) racemic ketone (1mmol), (R) -t-butylsulfinamide (1.2mmol) represented by formula (2), tetraethyltitanate (3mmol), 2mL anhydrous 1, 2-dichloroethane were mixed, and heated under reflux at 80 ℃ for 18 hours. And (3) post-reaction treatment: quenching reaction with saturated ammonium chloride solution at 0 deg.C, vacuum filtering, collecting filtrate, extracting water phase with dichloromethane for 3 times, mixing organic phases, back-extracting with saturated saline solution, drying organic phase with anhydrous sodium sulfate, concentrating, and purifying by column chromatography to obtain a pair of diastereoisomer sulfinylimines (1: 1, each with 40% yield). The pair of diastereoisomeric sulfinamides obtained after purification is subsequently subjected to a respective hydrochloric acid hydrolysis, here for example a three-membered ring-up sulfinamide, which is dissolved in 5mL of methanol at 0 ℃ and stirred at room temperature for 6 hours with the addition of 2mol/L hydrochloric acid solution (2 mL). And (3) post-treatment: quenching the reaction with saturated ammonium carbonate solution at 0 deg.C, extracting the water phase with ethyl acetate for 3 times, mixing the organic phases, back-extracting with saturated saline, drying the organic phase with anhydrous sodium sulfate, concentrating, and purifying by column chromatography to obtain chiral ketone (colorless oily liquid, 95% yield) represented by formula (3).
1.3) the chiral ketone (1mmol) obtained in the previous step, a 50% strength by mass aqueous solution of hydroxylamine (the amount of hydroxylamine substance is 4mmol) was dissolved in 2mL of ethanol and heated under reflux at 70 ℃ for 3 hours. And (3) post-treatment: to the reaction solution was added saturated brine, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, the organic phase was dried over anhydrous sodium sulfate, and concentrated to give the oxime represented by formula (4) (pale yellow solid, 100% yield).
1.4) the oxime (1mmol) obtained in the previous step was dissolved in toluene, reduced iron powder (8mmol) was added, a mixture of acetic acid (3mmol) and acetic anhydride (3mmol) was added dropwise at 0 ℃ and stirred vigorously at room temperature for 2 hours. And (3) post-treatment: and (2) carrying out suction filtration, washing a filter cake with ethyl acetate, collecting filtrate, adjusting the pH value to 6-7 with a saturated sodium carbonate solution, extracting the water phase with ethyl acetate for 3 times, combining organic phases, carrying out back extraction with saturated saline solution, drying the organic phase with anhydrous sodium sulfate, concentrating, and carrying out column chromatography separation and purification to obtain the enamide (light yellow solid, 80% yield) shown in the formula (5).
1.5) in a 25mL dry Schlenk tube, adding the enamide (1mmol) obtained in the previous step, replacing nitrogen for 3 times, dropwise adding a mixture of N, N-dimethylformamide (4mL) and phosphorus oxychloride (10mmol) at 0 ℃, heating the system to 75 ℃ after dropwise adding, and reacting for 7 hours. And (3) post-treatment: diluting the reaction solution with 20mL of ethyl acetate at 0 ℃, slowly pouring the diluted solution into a proper amount of saturated sodium bicarbonate solution, adjusting the pH to 7-8, extracting the aqueous phase with ethyl acetate for 3 times, combining the organic phases, carrying out back extraction with saturated saline, drying the organic phase with anhydrous sodium sulfate, concentrating, and carrying out column chromatography separation and purification to obtain the chiral chloropyridine derivative (white solid, 86% yield) shown in the formula (6).
1.6) adding the chiral chloropyridine (1mmol) obtained in the previous step and anhydrous dichloromethane (2mL) into a 25mL dry branch mouth tube under anhydrous and oxygen-free conditions, dropwise adding a 1mol/L diisobutylaluminum hydride n-hexane solution (6 mL diisobutylaluminum hydride) at 0 ℃ by using a constant pressure dropping funnel, and after the dropwise addition is finished, stirring at room temperature for 4 hours. And (3) post-treatment: slowly quenching the reaction with a saturated ammonium chloride solution at 0 ℃, adding 10mL of methanol, stirring for 30 minutes, extracting the aqueous phase with dichloromethane for 5-6 times, combining the organic phases, drying with anhydrous sodium sulfate, concentrating, and carrying out column chromatography separation and purification to obtain the chiral diol (white solid, 90% yield) shown in the formula (7).
1.7) in a dry Schlenk tube, the chiral diol (1mmol) obtained in the previous step, 2, 2-dimethoxypropane (1.7mmol), p-toluenesulfonic acid monohydrate (0.03mmol), stannous chloride (0.05mmol), an appropriate amount of 4A molecular sieve and 1mL of anhydrous 1, 2-dichloroethane are added and reacted for 8 hours at 80 ℃. And (3) post-treatment: the reaction solution was filtered with a buchner funnel, and the filter cake was washed with dichloromethane, and the filtrate was collected, concentrated, and subjected to column chromatography separation and purification to obtain a chiral chloropyridine derivative represented by formula (8) (white solid, 93% yield).
1.8) in a dry Schlenk tube, the chiral chloropyridine derivative (1mmol) obtained in the previous step, o-phenylenediamine (1.2mmol), palladium acetate (0.02mmol), 2,2 '-bis- (diphenylphosphino) -1,1' -binaphthyl (0.04mmol), and cesium carbonate (1.5mmol) were added, the nitrogen gas was replaced three times in the reaction tube, and anhydrous toluene was added under a nitrogen stream to react at 100 ℃ for 10 hours. And (3) post-treatment: the reaction solution was filtered through a suction filter funnel, and the filter cake was washed with dichloromethane, and the filtrate was collected, concentrated, and purified by column chromatography to obtain a chiral pyridine derivative represented by formula (9) (white solid, 88% yield).
1.9) inAdding the chiral pyridine derivative (1mmol) obtained in the previous step and a silicon boron reagent PhMe into a dried Schlenk tube2Si-B(NiPr2)2(1.1mmol), the nitrogen gas was purged three times through the reaction tube, and anhydrous toluene was added under nitrogen flow to conduct a reaction at 130 ℃ for 30 hours. And (3) post-treatment: and (3) pumping the toluene under anhydrous and anaerobic conditions, and washing the obtained yellow solid with anhydrous N-hexane for 3 times (1 mL each time) to obtain a white solid, namely the chiral N, B ligand L shown in the formula (1).
Example 3
1.1) in a 10mL single-necked flask, bromocyclopentenone (1mmol), diethyl malonate (1.5mmol), tetrahexylammonium bromide (0.2mmol), potassium carbonate (5mmol), and 2mL of 1, 2-dichloroethane were added, and heated at 80 ℃ under reflux for 12 hours. And (3) post-treatment: the reaction solution was filtered through a buchner funnel, and the filter cake was washed with dichloromethane, collected, concentrated, and subjected to column chromatography to separate and purify the racemic ketone represented by formula (2) (colorless oily liquid, 86% yield).
1.2) racemic ketone (1mmol), (R) -t-butylsulfinamide (1.5mmol) represented by formula (2), tetraethyl titanate (2.5mmol), 2mL anhydrous 1, 2-dichloroethane were mixed, and heated at 85 ℃ under reflux for 15 hours. And (3) post-reaction treatment: quenching reaction with saturated ammonium chloride solution at 0 deg.C, vacuum filtering, collecting filtrate, extracting water phase with dichloromethane for 3 times, mixing organic phases, back-extracting with saturated saline solution, drying organic phase with anhydrous sodium sulfate, concentrating, and purifying by column chromatography to obtain a pair of diastereoisomer sulfinylimines (1: 1, each with 40% yield). The pair of diastereoisomeric sulfinamides obtained after purification is subsequently subjected to a respective hydrochloric acid hydrolysis, here for example a three-membered ring-up sulfinamide, which is dissolved in 5mL of methanol at 0 ℃ and stirred at room temperature for 6 hours with the addition of 2mol/L hydrochloric acid solution (2 mL). And (3) post-treatment: quenching the reaction with saturated ammonium carbonate solution at 0 deg.C, extracting the water phase with ethyl acetate for 3 times, mixing the organic phases, back-extracting with saturated saline, drying the organic phase with anhydrous sodium sulfate, concentrating, and purifying by column chromatography to obtain chiral ketone (colorless oily liquid, 95% yield) represented by formula (3).
1.3) the chiral ketone (1mmol) obtained in the previous step, a 50% strength by mass aqueous solution of hydroxylamine (5mmol of the substance of hydroxylamine) was dissolved in 2mL of ethanol and heated under reflux at 80 ℃ for 2 hours. And (3) post-treatment: to the reaction solution was added saturated brine, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, the organic phase was dried over anhydrous sodium sulfate, and concentrated to give the oxime represented by formula (4) (pale yellow solid, 100% yield).
1.4) the oxime (1mmol) obtained in the previous step was dissolved in toluene, reduced iron powder (9mmol) was added, a mixture of acetic acid (5mmol) and acetic anhydride (5mmol) was added dropwise at 0 ℃ and stirred vigorously at room temperature for 3 hours. And (3) post-treatment: and (2) carrying out suction filtration, washing a filter cake with ethyl acetate, collecting filtrate, adjusting the pH value to 6-7 with a saturated sodium carbonate solution, extracting the water phase with ethyl acetate for 3 times, combining organic phases, carrying out back extraction with saturated saline solution, drying the organic phase with anhydrous sodium sulfate, concentrating, and carrying out column chromatography separation and purification to obtain the enamide (light yellow solid, 80% yield) shown in the formula (5).
1.5) in a 25mL dry Schlenk tube, adding the enamide (1mmol) obtained in the previous step, replacing nitrogen for 3 times, dropwise adding a mixture of N, N-dimethylformamide (5mL) and phosphorus oxychloride (8mmol) at 0 ℃, heating the system to 70 ℃ after dropwise adding, and reacting for 8 hours. And (3) post-treatment: diluting the reaction solution with 20mL of ethyl acetate at 0 ℃, slowly pouring the diluted solution into a proper amount of saturated sodium bicarbonate solution, adjusting the pH to 7-8, extracting the aqueous phase with ethyl acetate for 3 times, combining the organic phases, carrying out back extraction with saturated saline, drying the organic phase with anhydrous sodium sulfate, concentrating, and carrying out column chromatography separation and purification to obtain the chiral chloropyridine derivative (white solid, 86% yield) shown in the formula (6).
1.6) adding the chiral chloropyridine (1mmol) obtained in the previous step and 2mL of anhydrous dichloromethane into a 25mL dry branch mouth tube under anhydrous and oxygen-free conditions, dropwise adding a 1mol/L diisobutylaluminum hydride normal hexane solution (7 mL of diisobutylaluminum hydride) at 0 ℃ by using a constant pressure dropping funnel, and after the dropwise addition is finished, stirring at room temperature for 5 hours. And (3) post-treatment: slowly quenching the reaction with a saturated ammonium chloride solution at 0 ℃, adding 10mL of methanol, stirring for 30 minutes, extracting the aqueous phase with dichloromethane for 5-6 times, combining the organic phases, drying with anhydrous sodium sulfate, concentrating, and carrying out column chromatography separation and purification to obtain the chiral diol (white solid, 90% yield) shown in the formula (7).
1.7) in a dry Schlenk tube, the chiral diol (1mmol) obtained in the previous step, 2, 2-dimethoxypropane (2mmol), p-toluenesulfonic acid monohydrate (0.05mmol), stannous chloride (0.02mmol), an appropriate amount of 4A molecular sieve and 2mL of anhydrous 1, 2-dichloroethane are added and reacted for 7 hours at 90 ℃. And (3) post-treatment: the reaction solution was filtered with a buchner funnel, and the filter cake was washed with dichloromethane, and the filtrate was collected, concentrated, and subjected to column chromatography separation and purification to obtain a chiral chloropyridine derivative represented by formula (8) (white solid, 93% yield).
1.8) in a dry Schlenk tube, the chiral chloropyridine derivative (1mmol) obtained in the previous step, o-phenylenediamine (1.5mmol), palladium acetate (0.05mmol), 2,2 '-bis- (diphenylphosphino) -1,1' -binaphthyl (0.07mmol), and cesium carbonate (2mmol) were added, the reaction tube was purged with nitrogen three times, 1mL of anhydrous toluene was added under nitrogen flow, and the reaction was carried out at 90 ℃ for 12 hours. And (3) post-treatment: the reaction solution was filtered through a suction filter funnel, and the filter cake was washed with dichloromethane, and the filtrate was collected, concentrated, and purified by column chromatography to obtain a chiral pyridine derivative represented by formula (9) (white solid, 88% yield).
1.9) in a dry Schlenk tube, the chiral pyridine derivative (1mmol) obtained in the previous step and a silicon boron reagent PhMe are added2Si-B(NiPr2)2(1.2mmol), the reaction tube was purged with nitrogen three times, and 1mL of anhydrous toluene was added under nitrogen flow to conduct reaction at 135 ℃ for 24 hours. And (3) post-treatment: and (3) pumping the toluene under anhydrous and anaerobic conditions, and washing the obtained yellow solid with anhydrous N-hexane for 3 times (1 mL each time) to obtain a white solid, namely the chiral N, B ligand L shown in the formula (1).
Example 4
1.1) in a 10mL single-necked flask, bromocyclopentenone (1mmol), diethyl malonate (1.2mmol), tetrahexylammonium bromide (0.1mmol), potassium carbonate (6mmol), and 2mL of 1, 2-dichloroethane were added, and heated at 90 ℃ under reflux for 8 hours. And (3) post-treatment: the reaction solution was filtered through a buchner funnel, and the filter cake was washed with dichloromethane, collected, concentrated, and subjected to column chromatography to separate and purify the racemic ketone represented by formula (2) (colorless oily liquid, 86% yield).
1.2) racemic ketone (1mmol), (R) -t-butylsulfinamide (1mmol) represented by formula (2), tetraethyltitanate (2mmol), 2mL anhydrous 1, 2-dichloroethane were mixed and heated under reflux at 90 ℃ for 12 hours. And (3) post-reaction treatment: quenching reaction with saturated ammonium chloride solution at 0 deg.C, vacuum filtering, collecting filtrate, extracting water phase with dichloromethane for 3 times, mixing organic phases, back-extracting with saturated saline solution, drying organic phase with anhydrous sodium sulfate, concentrating, and purifying by column chromatography to obtain a pair of diastereoisomer sulfinylimines (1: 1, each with 40% yield). The pair of diastereoisomeric sulfinamides obtained after purification is subsequently subjected to a respective hydrochloric acid hydrolysis, here for example a three-membered ring-up sulfinamide, which is dissolved in 5mL of methanol at 0 ℃ and stirred at room temperature for 6 hours with the addition of 2mol/L hydrochloric acid solution (2 mL). And (3) post-treatment: quenching the reaction with saturated ammonium carbonate solution at 0 deg.C, extracting the water phase with ethyl acetate for 3 times, mixing the organic phases, back-extracting with saturated saline, drying the organic phase with anhydrous sodium sulfate, concentrating, and purifying by column chromatography to obtain chiral ketone (colorless oily liquid, 95% yield) represented by formula (3).
1.3) the chiral ketone (1mmol) obtained in the previous step, a 50% strength by mass aqueous solution of hydroxylamine (the amount of hydroxylamine substance is 3mmol) was dissolved in 2mL of ethanol and heated under reflux at 60 ℃ for 4 hours. And (3) post-treatment: to the reaction solution was added saturated brine, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, the organic phase was dried over anhydrous sodium sulfate, and concentrated to give the oxime represented by formula (4) (pale yellow solid, 100% yield).
1.4) the oxime (1mmol) obtained in the previous step was dissolved in toluene, reduced iron powder (10mmol) was added, a mixture of acetic acid (4mmol) and acetic anhydride (5mmol) was added dropwise at 0 ℃ and stirred vigorously at room temperature for 4 hours. And (3) treatment: and (2) carrying out suction filtration, washing a filter cake with ethyl acetate, collecting filtrate, adjusting the pH value to 6-7 with a saturated sodium carbonate solution, extracting the water phase with ethyl acetate for 3 times, combining organic phases, carrying out back extraction with saturated saline solution, drying the organic phase with anhydrous sodium sulfate, concentrating, and carrying out column chromatography separation and purification to obtain the enamide (light yellow solid, 80% yield) shown in the formula (5).
1.5) in a 25mL dry Schlenk tube, adding the enamide (1mmol) obtained in the previous step, replacing nitrogen for 3 times, dropwise adding a mixture of N, N-dimethylformamide (3mL) and phosphorus oxychloride (7mmol) at 0 ℃, heating the system to 60 ℃ after dropwise adding, and reacting for 10 hours. And (3) post-treatment: diluting the reaction solution with 20mL of ethyl acetate at 0 ℃, slowly pouring the diluted solution into a proper amount of saturated sodium bicarbonate solution, adjusting the pH to 7-8, extracting the aqueous phase with ethyl acetate for 3 times, combining the organic phases, carrying out back extraction with saturated saline, drying the organic phase with anhydrous sodium sulfate, concentrating, and carrying out column chromatography separation and purification to obtain the chiral chloropyridine derivative (white solid, 86% yield) shown in the formula (6).
1.6) adding the chiral chloropyridine (1mmol) obtained in the previous step and 2mL of anhydrous dichloromethane into a 25mL dry branch mouth tube under anhydrous and oxygen-free conditions, dropwise adding a 1mol/L diisobutylaluminum hydride normal hexane solution (8 mL of diisobutylaluminum hydride) at 0 ℃ by using a constant pressure dropping funnel, and after the dropwise addition is finished, stirring at room temperature for 6 hours. And (3) post-treatment: slowly quenching the reaction with a saturated ammonium chloride solution at 0 ℃, adding 10mL of methanol, stirring for 30 minutes, extracting the aqueous phase with dichloromethane for 5-6 times, combining the organic phases, drying with anhydrous sodium sulfate, concentrating, and carrying out column chromatography separation and purification to obtain the chiral diol (white solid, 90% yield) shown in the formula (7).
1.7) in a dry Schlenk tube, the chiral diol (1mmol) obtained in the previous step, 2, 2-dimethoxypropane (1.5mmol), p-toluenesulfonic acid monohydrate (0.02mmol), stannous chloride (0.03mmol), an appropriate amount of 4A molecular sieve and 2mL of anhydrous 1, 2-dichloroethane are added and reacted for 6 hours at 100 ℃. And (3) post-treatment: the reaction solution was filtered with a buchner funnel, and the filter cake was washed with dichloromethane, and the filtrate was collected, concentrated, and subjected to column chromatography separation and purification to obtain a chiral chloropyridine derivative represented by formula (8) (white solid, 93% yield).
1.8) in a dry Schlenk tube, the chiral chloropyridine derivative (1mmol) obtained in the previous step, o-phenylenediamine (2mmol), palladium acetate (0.04mmol), 2,2 '-bis- (diphenylphosphino) -1,1' -binaphthyl (0.1mmol), and cesium carbonate (1.8mmol) were added, the reaction tube was purged with nitrogen three times, 1mL of anhydrous toluene was added under nitrogen flow, and the reaction was carried out at 90 ℃ for 16 hours. And (3) post-treatment: the reaction solution was filtered through a suction filter funnel, and the filter cake was washed with dichloromethane, and the filtrate was collected, concentrated, and purified by column chromatography to obtain a chiral pyridine derivative represented by formula (9) (white solid, 88% yield).
1.9) in a dry Schlenk tube, the chiral pyridine derivative (1mmol) obtained in the previous step and a silicon boron reagent PhMe are added2Si-B(NiPr2)2(1.3mmol), the reaction tube was purged with nitrogen three times, and 1mL of anhydrous toluene was added under a nitrogen stream to conduct a reaction at 125 ℃ for 36 hours. And (3) post-treatment: and (3) pumping the toluene under anhydrous and anaerobic conditions, and washing the obtained yellow solid with anhydrous N-hexane for 3 times (1 mL each time) to obtain a white solid, namely the chiral N, B ligand L shown in the formula (1).
The following examples further illustrate the use of the invention and do not therefore limit the scope of the invention described.
The application of pyridine derived chiral N, B ligand in iridium catalyzed asymmetric boronization reaction:
in an argon glove box, adding chiral N, B ligand L (3.9mg,0.008mmol), methoxy (cyclooctadiene) iridium dimer (2.7mg,0.004mmol) and bis (pinacolato) borate (76.2mg,0.3mmol, 1.5 times of the amount of a substrate triarylmethane substance) into a 10mL Schlenk tube, adding 1mL (0.2-0.4 mol/L) of N-hexane, stirring at room temperature for 30 minutes to 1 hour, then adding a substrate triarylmethane (49mg,0.2mmol), and continuing to react at 60-80 ℃ for 3-6 hours. The crude product obtained by the reaction was separated and purified by column chromatography to obtain a chiral boronated product represented by formula (11) (82% yield, 95% ee).
Application example 1: preparation of chiral arylboronic acid esters of formula (11).
The specific operation is as follows: in an argon glove box, chiral N, B ligand L (3.9mg,0.008mmol), methoxy (cyclooctadiene) iridium dimer (2.7mg,0.004mmol) and bis-pinacolato borate (76.2mg,0.3mmol) were added to a 10mL schlenk tube, 1mL N-hexane was added, stirring was carried out at room temperature for 30 minutes, then substrate S1(49mg,0.2mmol) was added, and the reaction was continued at 80 ℃ for 3 hours. The crude product obtained by the reaction was separated and purified by column chromatography to obtain a chiral boronated product represented by formula (11) (82% yield,95% ee). The nuclear magnetic data are as follows:1H NMR(400MHz,CDCl3)δ9.19(d,J＝5.4Hz,1H),7.82–7.75(m,1H),7.72(td,J＝7.8,1.7Hz,1H),7.48–7.33(m,6H),7.19(dd,J＝14.4,7.5Hz,2H),7.08(td,J＝7.6,1.3Hz,1H),6.78(d,J＝7.7Hz,1H),6.02(s,1H),1.28(s,6H),1.20(s,6H)。13C NMR(100MHz,CDCl3)δ161.66,144.08,143.15,139.23,131.53,131.15,128.89,127.54,127.01,126.32,126.03,124.88,121.89,81.13,53.09,26.37,25.79。
application example 2: the substrate S2 is an asymmetric boronization/oxidation tandem reaction.
The specific operation is as follows: chiral N, B ligand L (3.9mg,0.008mmol), methoxy (cyclooctadiene) iridium dimer (2.7mg,0.004mmol) and bis-pinacolato borate (76.2mg,0.3mmol) were added to a 10mL schlenk tube in an argon glove box, 1mL N-hexane was added, stirring was carried out at room temperature for 30 minutes, then substrate S2(79.5mg,0.2mmol) was added and reaction was continued at 80 ℃ for 4 hours. After the reaction, the reaction solvent was concentrated off, 1mL of tetrahydrofuran was added again to dissolve the obtained crude boronated product, sodium perborate tetrahydrate (92.3mg,0.6mmol) was added and stirred at room temperature for 10 hours, and after the reaction was completed, the reaction solution was concentrated and the obtained crude product was separated and purified by column chromatography to obtain the chiral alcohol represented by formula (12) (92% yield, 96% ee). The nuclear magnetic data are as follows:1H NMR(400MHz,CDCl3)δ12.32(s,1H),8.59(d,J＝4.4Hz,1H),7.85(td,J＝7.7,1.6Hz,1H),7.61(d,J＝7.4Hz,2H),7.57-7.52(m,3H),7.49–7.37(m,6H),7.36-7.27(m,5H),7.14(dd,J＝7.8,1.7Hz,1H),7.08(d,J＝8.1Hz,2H),5.39(s,1H)；13C NMR(100MHz,CDCl3)δ162.53,156.87,148.32,142.65,140.94,140.77,140.45,139.57,138.75,132.45,128.80,128.22,127.39,127.25,127.16,127.13,126.83,124.77,122.77,118.68,118.41,58.64。
application example 3: the substrate S3 is an asymmetric boronization/oxidation tandem reaction.
The specific operation is as follows: chiral N, B ligand L (3.9mg,0.008mmol), methoxy (cyclooctadiene) iridium dimer (2.7mg,0.004mmol) and bis-pinacolato borate (76.2mg,0.3mmol) were added to a 10mL schlenk tube in an argon glove box, 1mL N-hexane was added, stirring was carried out at room temperature for 30 minutes, then substrate S3(69.1mg,0.2mmol) was added and reaction was continued at 80 ℃ for 4 hours. After the reaction was completed, the reaction solvent was concentrated off, 1mL of tetrahydrofuran was added again to dissolve the obtained crude boronated product, sodium perborate tetrahydrate (92.3mg,0.6mmol) was added and stirred at room temperature for 10 hours, and after the reaction was completed, the reaction solution was concentrated and the obtained crude product was separated and purified by column chromatography to obtain chiral alcohol represented by formula (13) (92% yield, 90% ee). The nuclear magnetic data are as follows:1H NMR(400MHz,DMSO)δ10.09(s,1H),8.55(dd,J＝5.6,1.6Hz,1H),7.88–7.84(m,2H),7.80–7.74(m,2H),7.66(d,J＝8.2Hz,1H),7.62–7.55(m,2H),7.47–7.45(m,2H),7.38–7.34(m,3H),7.28(dd,J＝7.6,4.3Hz,2H),7.22-7.16(m,2H),6.18(s,1H)；13C NMR(100MHz,DMSO)δ162.27,153.77,149.05,140.23,136.86,133.48,132.97,132.48,131.75,129.15,128.02,127.64,127.51,127.48,127.43,127.23,126.09,125.82,125.66,125.45,123.81,122.80,121.72,108.99,52.78。
application example 4: the substrate S4 is an asymmetric boronization/oxidation tandem reaction.
The specific operation is as follows: chiral N, B ligand L (3.9mg,0.008mmol), methoxy (cyclooctadiene) iridium dimer (2.7mg,0.004mmol) and bis-pinacolato borate (76.2mg,0.3mmol) were added to a 10mL schlenk tube in an argon glove box, 1mL N-hexane was added, stirring was carried out at room temperature for 30 minutes, then substrate S4(62.8mg,0.2mmol) was added and reaction was continued at 80 ℃ for 3 hours. After the reaction is finished, the reaction solvent is concentrated, 1mL of tetrahydrofuran is added again to dissolve the obtained crude boronized product, sodium perborate tetrahydrate (92.3mg,0.6mmol) is added, the mixture is stirred for 10 hours at room temperature, after the reaction is finished,the reaction solution was concentrated, and the obtained crude product was separated and purified by column chromatography to give a chiral alcohol represented by formula (14) (87% yield, 94% ee). The nuclear magnetic data are as follows:1H NMR(400MHz,CDCl3)δ12.16(s,1H),8.56(d,J＝4.6Hz,1H),7.85(td,J＝7.7,1.4Hz,1H),7.48(d,J＝7.7Hz,1H),7.35(dd,J＝7.3,5.2Hz,1H),7.23(d,J＝2.4Hz,1H),7.20–7.11(m,3H),6.91-6.84(m,3H),5.20(s,1H)；13C NMR(100MHz,CDCl3)δ161.28,155.22,148.38,142.72,138.97,134.37,131.24,129.62,129.35,128.89,127.97,127.09,125.99,124.77,124.27,123.16,121.05,57.84。
application example 5: the substrate S5 is an asymmetric boronization/oxidation tandem reaction.
The specific operation is as follows: chiral N, B ligand L (3.9mg,0.008mmol), methoxy (cyclooctadiene) iridium dimer (2.7mg,0.004mmol) and bis-pinacolato borate (76.2mg,0.3mmol) were added to a 10mL schlenk tube in an argon glove box, 1mL N-hexane was added, stirring was carried out at room temperature for 30 minutes, then substrate S5(76.3mg,0.2mmol) was added and reaction was continued at 80 ℃ for 3 hours. After the reaction was completed, the reaction solvent was concentrated off, 1mL of tetrahydrofuran was added again to dissolve the obtained crude boronated product, sodium perborate tetrahydrate (92.3mg,0.6mmol) was added and stirred at room temperature for 10 hours, and after the reaction was completed, the reaction solution was concentrated and the obtained crude product was separated and purified by column chromatography to obtain chiral alcohol represented by formula (14) (80% yield, 91% ee). The nuclear magnetic data are as follows:1H NMR(400MHz,CDCl3)δ12.76(s,1H),8.58(d,J＝4.6Hz,1H),7.90(td,J＝7.7,1.5Hz,1H),7.59–7.51(m,2H),7.51–7.43(m,2H),7.42–7.31(m,2H),7.20–7.08(m,2H),7.03(dd,J＝8.3,2.5Hz,1H),5.38(s,1H)；13C NMR(100MHz,CDCl3)δ161.07,159.73,148.37,141.48,139.34,131.09,130.81(q,JCF＝32.0Hz),129.02,127.34,127.14(q,JCF＝3.7Hz),124.64(q,JCF＝269.4Hz),124.12(q,JCF＝270.7Hz),124.91,124.48(q,JCF＝3.8Hz),123.94(q,JCF＝3.7Hz),123.45,122.05(q,JCF＝32.4Hz),120.20,58.41。
the invention designs and synthesizes the chiral N and B ligands with rigid condensed ring structural frameworks and adjustable structural height, and the chiral ligands show excellent reaction activity and enantioselectivity in the iridium-catalyzed asymmetric boronization reaction. The invention provides a new framework chiral ligand for the development of asymmetric catalysis, and provides a new method for preparing the chiral aryl boron compound. The obtained chiral aryl boron product can be used for synthesizing functional material molecules and has potential industrial application value.
Claims (10)
1. The chiral pyridine derived N, B ligand is characterized by having a structural general formula shown as formula (1):
r is methyl, ethyl, isopropyl, benzyl, 3, 5-dimethylbenzyl, 3, 5-diisopropylbenzyl, 3, 5-di-tert-butylbenzyl, 3, 5-diphenylbenzyl, phenyl, 3, 5-dimethylphenyl, 3, 5-dimethoxyphenyl, 3, 5-diisopropylphenyl, 3, 5-di-tert-butylphenyl or 3, 5-diphenylphenyl.
2. The preparation method of the N, B ligand derived from chiral pyridine is characterized in that the chiral pyridine derivative shown as the formula (9) and PhMe are mixed2Si-B(NiPr2)2Reacting in toluene at 125-135 ℃ to obtain chiral pyridine-derived N, B ligand shown in formula (1);
wherein R is methyl, ethyl, isopropyl, benzyl, 3, 5-dimethylbenzyl, 3, 5-diisopropylbenzyl, 3, 5-di-tert-butylbenzyl, 3, 5-diphenylbenzyl, phenyl, 3, 5-dimethylphenyl, 3, 5-dimethoxyphenyl, 3, 5-diisopropylphenyl, 3, 5-di-tert-butylphenyl or 3, 5-diphenylphenyl.
3. The method for preparing the chiral pyridine-derived N, B ligand according to claim 2, which comprises the following steps: under nitrogen atmosphere, 1mmol of chiral pyridine derivative shown as formula (9) and 1.1-1.3 mmol of PhMe2Si-B(NiPr2)2And mixing the chiral pyridine and anhydrous toluene, and then reacting for 24-36 h at 125-135 ℃ to obtain the chiral pyridine derived N, B ligand.
4. The method for preparing a chiral pyridine-derived N, B ligand according to claim 2, wherein the chiral pyridine derivative represented by formula (9) is prepared by the following process:
mixing chiral diol, ketal, p-toluenesulfonic acid, stannous chloride and dichloroethane shown in formula (7), and reacting at 80-100 ℃ to obtain chiral chloropyridine derivative shown in formula (8);
the ketal formula is as follows:
wherein R is methyl, ethyl, isopropyl, benzyl, 3, 5-dimethylbenzyl, 3, 5-diisopropylbenzyl, 3, 5-di-tert-butylbenzyl, 3, 5-diphenylbenzyl, phenyl, 3, 5-dimethylphenyl, 3, 5-dimethoxyphenyl, 3, 5-diisopropylphenyl, 3, 5-di-tert-butylphenyl or 3, 5-diphenylphenyl;
mixing a chiral chloropyridine derivative shown in a formula (8) and phenylenediamine in palladium acetate, 2 '-bis- (diphenylphosphino) -1,1' -binaphthyl and toluene, and then carrying out C-N bond coupling reaction to obtain a chiral pyridine derivative shown in a formula (9);
5. the process for the preparation of chiral pyridine derived N, B ligands according to claim 4,
mixing chiral diol, ketal, p-toluenesulfonic acid, stannous chloride, a 4A molecular sieve and anhydrous dichloroethane, and stirring at 80-100 ℃ for 4-8 h to obtain a chiral chloropyridine derivative shown in a formula (8); wherein the ratio of the amounts of the chiral diol, the ketal, the p-toluenesulfonic acid and the stannous chloride is 1: (1.5-2): (0.02-0.05): (0.02-0.05);
mixing the chiral chloropyridine derivative shown in the formula (8), o-phenylenediamine, palladium acetate, 2,2 '-bis- (diphenylphosphino) -1,1' -binaphthyl, cesium carbonate and anhydrous toluene under a nitrogen atmosphere, and stirring at 90-100 ℃ for 10-16 h to obtain the chiral pyridine derivative shown in the formula (9); wherein the ratio of the amounts of the chiral chloropyridine derivative, o-phenylenediamine, palladium acetate, 2 '-bis- (diphenylphosphino) -1,1' -binaphthyl and cesium carbonate is 1: (1.2-2): (0.02-0.05): (0.04-0.1): (1.5-2).
6. The method of claim 4, wherein the chiral diol is prepared by the following steps:
(1) performing cyclopropanation reaction on bromo-cyclopentenone and malonic diester to generate ketone shown in a formula (2);
wherein R is1Is methyl, ethyl, isopropyl, tert-butyl or benzyl;
(2) reacting ketone shown in a formula (2) with (R) -tert-butyl sulfinamide and tetraethyl titanate to obtain sulfinyl imine, and hydrolyzing to obtain chiral ketone shown in a formula (3) or a formula (3');
(3) placing chiral ketone shown in a formula (3) or a formula (3') and hydroxylamine into ethanol for reaction to obtain oxime shown in a formula (4);
(4) adding oxime shown in a formula (4) into toluene, adding iron powder, acetic anhydride and acetic acid, and reacting to obtain enamide shown in a formula (5);
(5) dissolving the enamine shown in the formula (5) in N, N-dimethylformamide, then dropwise adding phosphorus oxychloride, and reacting to obtain the chiral chloropyridine derivative shown in the formula (6);
(6) the chiral chloropyridine derivative shown in the formula (6) is dissolved in dichloromethane, and an ester group is reduced to a hydroxyl group by diisobutylaluminum hydride to obtain a chiral diol.
7. The process for the preparation of chiral pyridine derived N, B ligands according to claim 6,
the specific process of the step (1) is as follows: mixing bromo-cyclopentenone, diethyl malonate, tetrahexylammonium bromide, potassium carbonate and 1, 2-dichloroethane, and stirring at 80-90 ℃ for 8-12 hours to obtain racemic ketone shown in formula (2); wherein the mass ratio of the brominated cyclopentenone, diethyl malonate, tetrahexylammonium bromide and potassium carbonate is 1: (1.0-1.5): (0.1-0.2): (4-6);
the specific process of the step (2) is as follows: mixing racemic ketone (R) -tert-butyl sulfenamide shown in formula (2), tetraethoxytitanate and anhydrous 1, 2-dichloroethane, and stirring at 80-90 ℃ for 12-18 h to obtain a pair of enantiomeric ketone shown in formula (3) and formula (3'); wherein the ratio of the amounts of racemic ketone, (R) -tert-butylsulfinamide, tetraethyl titanate is 1: (1.0-1.5): (2-3);
the specific process of the step (3) is as follows: dissolving chiral ketone and hydroxylamine aqueous solution shown in formula (3) or formula (3') in ethanol, and stirring for 2-4 h at 60-80 ℃; obtaining oxime represented by a formula (4); wherein the ratio of the amount of substance of chiral ketone to hydroxylamine is 1: (3-5).
8. The process for the preparation of chiral pyridine derived N, B ligands according to claim 6,
the specific process of the step (4) is as follows: dissolving oxime shown in a formula (4) in toluene, then adding reduced iron powder, dropwise adding a mixture of acetic acid and acetic anhydride at 0 ℃, and stirring for 2-4 h to obtain enamide shown in a formula (5); wherein the mass ratio of the oxime, the reduced iron powder, the acetic acid and the acetic anhydride is 1: (8-10): (3-5): (3-5);
the specific process of the step (5) is as follows: dissolving enamine shown in a formula (5) in anhydrous N, N-dimethylformamide, dropwise adding phosphorus oxychloride at 0 ℃, heating to 60-80 ℃ after dropwise adding, and reacting for 6-10 h to obtain chiral chloropyridine derivatives shown in a formula (6); wherein the mass ratio of the enamine to the phosphorus oxychloride is 1: (7-10);
the specific process of the step (6) is as follows: dissolving the chiral chloropyridine derivative shown in the formula (6) in anhydrous dichloromethane, dropwise adding n-hexane solution of diisobutyl aluminum hydride at 0 ℃, and stirring at room temperature for 4-6 hours after dropwise adding to obtain chiral diol shown in the formula (7); wherein the dosage ratio of the chiral chloropyridine derivative to the diisobutylaluminum hydride is 1 mmol: 6-8 mL.
9. Use of a chiral pyridine-derived N, B ligand according to claim 1 in iridium-catalysed asymmetric boriding reactions.
10. The application of the compound as claimed in claim 9, wherein the chiral N, B ligand, methoxy (cyclooctadiene) iridium dimer and bis pinacol borate are pre-stirred in N-hexane for 5-30 min, diarylpyridine is added, stirring is carried out at 60-80 ℃ for 2-8 h, and purification is carried out to obtain the chiral arylboron compound; wherein the ratio of the chiral N, B ligand, methoxy (cyclooctadiene) iridium dimer, bis (pinacolato) borate to diarylpyridine is (0.04-0.1): (0.02-0.05): (1.2-2): 1.
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