CN109575060B - Synthesis of spiro bisboron catalyst and application of spiro bisboron catalyst in hydrogenation reaction - Google Patents
Synthesis of spiro bisboron catalyst and application of spiro bisboron catalyst in hydrogenation reaction Download PDFInfo
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- 239000003054 catalyst Substances 0.000 title claims abstract description 31
- 125000003003 spiro group Chemical group 0.000 title claims abstract description 20
- 238000003786 synthesis reaction Methods 0.000 title description 9
- 230000015572 biosynthetic process Effects 0.000 title description 8
- 238000005984 hydrogenation reaction Methods 0.000 title description 2
- -1 spiro diene compound Chemical class 0.000 claims abstract description 44
- 238000006243 chemical reaction Methods 0.000 claims abstract description 30
- 150000001875 compounds Chemical class 0.000 claims abstract description 15
- ZOCHARZZJNPSEU-UHFFFAOYSA-N diboron Chemical compound B#B ZOCHARZZJNPSEU-UHFFFAOYSA-N 0.000 claims abstract description 15
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 claims abstract description 11
- 238000000034 method Methods 0.000 claims abstract description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 9
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 claims description 8
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 238000010992 reflux Methods 0.000 claims description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- PIOGLWMIXIMTAW-UHFFFAOYSA-N spiro[4.4]nonane-4,9-dione Chemical compound O=C1CCCC11C(=O)CCC1 PIOGLWMIXIMTAW-UHFFFAOYSA-N 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 5
- SWRGUMCEJHQWEE-UHFFFAOYSA-N ethanedihydrazide Chemical compound NNC(=O)C(=O)NN SWRGUMCEJHQWEE-UHFFFAOYSA-N 0.000 claims description 5
- 239000000543 intermediate Substances 0.000 claims description 5
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 4
- 239000004327 boric acid Substances 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 239000011630 iodine Substances 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 3
- 239000012046 mixed solvent Substances 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 claims description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 2
- DKNPRRRKHAEUMW-UHFFFAOYSA-N Iodine aqueous Chemical compound [K+].I[I-]I DKNPRRRKHAEUMW-UHFFFAOYSA-N 0.000 claims description 2
- 238000006069 Suzuki reaction reaction Methods 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- 238000004440 column chromatography Methods 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims description 2
- 239000012445 acidic reagent Substances 0.000 claims 2
- 238000000926 separation method Methods 0.000 claims 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims 1
- 125000000304 alkynyl group Chemical group 0.000 claims 1
- 238000001816 cooling Methods 0.000 claims 1
- 238000007599 discharging Methods 0.000 claims 1
- 239000012299 nitrogen atmosphere Substances 0.000 claims 1
- 230000003287 optical effect Effects 0.000 claims 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 1
- 238000007789 sealing Methods 0.000 claims 1
- 125000005504 styryl group Chemical group 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 3
- 125000000524 functional group Chemical group 0.000 abstract description 3
- 239000000758 substrate Substances 0.000 abstract description 3
- 150000003248 quinolines Chemical class 0.000 abstract description 2
- 229910010277 boron hydride Inorganic materials 0.000 abstract 1
- 238000012824 chemical production Methods 0.000 abstract 1
- 229910000510 noble metal Inorganic materials 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 238000002390 rotary evaporation Methods 0.000 description 6
- 239000012043 crude product Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 229910052786 argon Inorganic materials 0.000 description 4
- 229910052796 boron Inorganic materials 0.000 description 4
- YMWUJEATGCHHMB-DICFDUPASA-N dichloromethane-d2 Chemical compound [2H]C([2H])(Cl)Cl YMWUJEATGCHHMB-DICFDUPASA-N 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- JZICUKPOZUKZLL-MRVPVSSYSA-N (2r)-2-methyl-1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2N[C@H](C)CCC2=C1 JZICUKPOZUKZLL-MRVPVSSYSA-N 0.000 description 3
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 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 2
- 101001110286 Homo sapiens Ras-related C3 botulinum toxin substrate 1 Proteins 0.000 description 2
- 102100022122 Ras-related C3 botulinum toxin substrate 1 Human genes 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 2
- 239000002274 desiccant Substances 0.000 description 2
- 150000001993 dienes Chemical class 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 238000006197 hydroboration reaction Methods 0.000 description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- SMUQFGGVLNAIOZ-UHFFFAOYSA-N quinaldine Chemical compound C1=CC=CC2=NC(C)=CC=C21 SMUQFGGVLNAIOZ-UHFFFAOYSA-N 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- BWHDROKFUHTORW-UHFFFAOYSA-N tritert-butylphosphane Chemical compound CC(C)(C)P(C(C)(C)C)C(C)(C)C BWHDROKFUHTORW-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- DXLQEJHUQKKSRB-UHFFFAOYSA-N 1,1,1-trifluoro-n-pyridin-2-yl-n-(trifluoromethylsulfonyl)methanesulfonamide Chemical compound FC(F)(F)S(=O)(=O)N(S(=O)(=O)C(F)(F)F)C1=CC=CC=N1 DXLQEJHUQKKSRB-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- LFZAGIJXANFPFN-UHFFFAOYSA-N N-[3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-thiophen-2-ylpropyl]acetamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CCC(C=1SC=CC=1)NC(C)=O)C LFZAGIJXANFPFN-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- NJSUFZNXBBXAAC-UHFFFAOYSA-N ethanol;toluene Chemical compound CCO.CC1=CC=CC=C1 NJSUFZNXBBXAAC-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 239000012263 liquid product Substances 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- PHICBFWUYUCFKS-UHFFFAOYSA-N spiro[4.4]nonane Chemical group C1CCCC21CCCC2 PHICBFWUYUCFKS-UHFFFAOYSA-N 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
Classifications
-
- 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
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/027—Organoboranes and organoborohydrides
-
- 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
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/12—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing organo-metallic compounds or metal hydrides
- B01J31/14—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing organo-metallic compounds or metal hydrides of aluminium or boron
- B01J31/146—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing organo-metallic compounds or metal hydrides of aluminium or boron of boron
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
- C07D215/06—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms having only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to the ring nitrogen atom
-
- 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
- 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
- B01J2231/646—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes of aromatic or heteroaromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention relates to a compound having C2Synthesizing a symmetrical chiral spiro diene compound, and preparing a series of chiral spiro bisboron catalysts by reacting the chiral spiro diene compound with a boron hydride compound. The spiro diboron catalysts show high activity and enantioselectivity in asymmetric hydrogenation of quinoline compounds, and belong to the technical field of application. The method mainly solves the problems that the prior quinoline asymmetric hydrogenation reaction method needs to use a noble metal catalyst, has poor functional group tolerance and the like, realizes the nonmetal-catalyzed quinoline asymmetric hydrogenation reaction, and has wide reaction substrate range and strong functional group tolerance. The invention can be applied to pharmaceutical research and chemical production.
Description
Technical Field
The invention relates to a novel compound having C2The synthesis of the symmetrical spiro diene compound and the in-situ preparation of the spiro diboron catalyst by hydroboration reaction show high activity and enantioselectivity in the asymmetric hydrogenation of quinoline, and belong to the technical field of organic chemical synthesis methodology research and application.
Background
In 2006, professor d.w.stephan of university of toronto found B (C)6F5)3And the highly hindered bases (tri-tert-butylphosphine) do not form the classical lewis acid-base adducts but exist as acid-base pairs that can activate hydrogen at room temperature and reduce some unsaturated compounds. Based on this, some chiral boron catalysts were synthesized and used in asymmetric hydrogenation of various substrates (as shown in the following figure). However, the field is still in the beginning, the chiral boron catalyst reported at present is very limited, and the asymmetric hydrogenation reaction of a plurality of heterocyclic compounds is not solved, so that the development of a novel and efficient chiral catalyst is an important content of research in the field.
Disclosure of Invention
The content of the invention comprises: 1. preparing a novel chiral spirocyclic diene compound; 2. preparing a spiro diboron catalyst through a hydroboration reaction of a spiro diene compound and identifying the structure of the spiro diboron catalyst; 3. the application of the spiro bisboron catalyst in asymmetric hydrogenation of quinoline.
1. The chiral spirodiene compound of the present invention has the following structural formula (the absolute configuration of the spirocyclic skeleton is (R) or (S)):
the chiral spiro diene is characterized in that the molecule has a spiro [4.4] -nonane skeleton, and R groups in the structural formula are aryl or alkyl. The synthesis method comprises the following steps:
the first step is as follows: racemic spiro [4.4] -1, 6-nonanedione (rac-1) (the preparation reference: Synth. Commun.1999,29,3829.) and (R) -phenethylamino oxalyl hydrazine are reacted under the catalysis of iodine under reflux overnight to obtain a pair of diastereoisomer dihydrazone compound intermediates, and the (R) -dihydrazone compound with single configuration can be separated by twice recrystallization in ethanol, and the intermediate dihydrazone compound is hydrolyzed in an iodine-potassium iodide system to obtain an optically pure product (R) -spiro [4.4] -1, 6-nonanedione ((R) -1). Wherein the molar ratio of racemic spiro [4.4] -1, 6-nonanedione (rac-1) to (R) -phenethylamino oxalyl hydrazine is 1:1, and the iodine simple substance is catalytic amount.
The second step is that: reacting (R) -spiro [4.4] -1, 6-nonanedione ((R) -1) and 2- [ N-N-bis (trifluoromethanesulfonyl) amino ] pyridine in tetrahydrofuran at-78 ℃ with potassium bis (trimethylsilyl) amide as a base for 40 minutes to give an enol trifluoromethanesulfonate compound 2. Wherein the molar ratio of (R) -spiro [4.4] -1, 6-nonanedione ((R) -1), 2- [ N-bis (trifluoromethanesulfonyl) amino ] pyridine and bis (trimethylsilyl) amino potassium is 1:3: 3.
The third step: toluene and ethanol are mixed according to the volume ratio of 3:1 to serve as a mixed solvent, under the condition of heating reflux, the triflate enol ester compound (2) and an aryl or alkyl boric acid reagent undergo Suzuki coupling reaction in the presence of tetrakis (triphenylphosphine) palladium and alkali, and the chiral spirocyclic diene compound (3) is obtained after 5 hours of reaction. Wherein the molar ratio of the triflate enol ester compound (2) to the boric acid reagent is 1:4, and the dosage of the tetrakis (triphenylphosphine) palladium is 10 mol%. The boric acid reagent has a molecular formula of RB (OH)2And R is aryl or alkyl.
2. Preparation and structure identification of the chiral spiro-diboron catalyst:
in a glove box, a chiral spirocyclic diene compound and HB (C)6F5)2And adding a solvent toluene into a reaction bottle, stirring for 15 minutes at a specified temperature, and then recovering to room temperature to prepare the chiral spiro diboron catalyst. And adding isoquinoline or pyridine (L) to react with the prepared chiral spiro diboron catalyst, stirring for 30 minutes at room temperature, removing the solvent, and recrystallizing, separating and purifying to obtain an adduct of the chiral spiro diboron catalyst and the L. Chiral spirocyclic diene compound, HB (C)6F5)2And L (isoquinoline or pyridine) in a molar ratio of 1:2: 4. The structure of the adduct is confirmed by X-ray single crystal diffraction, and the structure of the prepared chiral spiro-diboron catalyst is further determined. Wherein, HB (C)6F5)2Other fluorine-containing aryl boron hydrides may be substituted.
3. The chiral spiro diboron catalyst is used for catalyzing asymmetric hydrogenation of quinoline:
the chiral spiro diboron catalyst can be applied to asymmetric hydrogenation of quinoline compounds to obtain 2-substituted tetrahydroquinoline compounds with high conversion number and extremely high enantioselectivity.
The invention has the advantages that:
1. the boron catalyst replaces a transition metal catalyst, so that the cost is saved, and the problem of heavy metal residue in the drug synthesis is solved.
2. The spirocyclic diboron catalyst is low in dosage, can be amplified to gram level experiments, and is mild in reaction conditions.
3. The developed asymmetric hydrogenation reaction can obtain 2-substituted tetrahydroquinoline with high reaction activity and extremely high enantioselectivity, and has wide substrate range and strong functional group compatibility.
Detailed description of the invention
The following examples will better illustrate the invention, but it should be emphasized that the invention is in no way limited to what is shown in these examples. The following examples show different aspects of the invention. The data presented include specific operating and reaction conditions and products. The purity of the product was identified by nuclear magnetism.
Example 1: synthesis of chiral spirocyclic diene Compound 3a
The first step is as follows: resolution of spiro [4.4] -1, 6-nonanedione
(R) -phenethylamino oxalyl hydrazide (4.15g,2eq) was added to a 250mL dry round bottom flask followed by 1.52g racemic spiro [4.4] -1, 6-nonanedione and a small amount of iodine, 120mL anhydrous dichloromethane were added under argon, an aqueous trap and reflux condenser were installed and heated to reflux overnight. After the reaction, the system is cooled to room temperature, diatomite is filtered to remove insoluble solid, dichloromethane is removed by reduced pressure rotary evaporation to obtain a yellow solid crude product, and anhydrous ethanol is recrystallized and purified to obtain 3.5g of white powdery solid dihydrazone compound intermediate with the yield of 66%.
2.0g of the dihydrazone compound intermediate was added to a 500mL eggplant-shaped bottleAnd recrystallizing twice by using absolute ethyl alcohol to obtain 600mg of the single-configuration dihydrazone compound with the yield of 60 percent.1H NMR(400MHz,CDCl3)9.71(s,2H),8.25(d,J＝8.3Hz,2H),7.39-7.22(m,8H),7.22-7.12(m,2H),5.17-4.98(m,2H),2.57-2.39(m,4H),2.36-2.26(m,2H),2.24-2.12(m,2H),1.91-1.71(m,4H),1.59(d,J＝6.8Hz,6H)；13C NMR(101MHz,CDCl3)172.8,158.7,155.1,142.1,128.7,127.6,126.2,57.8,49.6,37.4,28.0,21.6,21.5.
2.0g of the dihydrazone compound of a single configuration was charged into a 250mL round-bottomed flask, potassium iodide (800mg) and elemental iodine (200mg) were sequentially added, acetone (80mL) and water (20mL) were added as a mixed solvent, and the reaction solution was heated under reflux for 40 minutes and monitored by TLC. After the reaction is completed, dropwise adding saturated sodium thiosulfate solution while stirring to quench iodine, changing the reaction solution from brown yellow to colorless, carrying out reduced pressure rotary evaporation to remove acetone, extracting the residue with dichloromethane for three times, washing the combined organic phase with saturated sodium chloride solution, drying with anhydrous sodium sulfate, removing the solvent by rotary evaporation, and carrying out silica gel column chromatography on the crude product to obtain a white solid product (R) -spiro [ 4.4.4%]-1, 6-nonanedione ((R) -1) (385mg), 67% yield.1H NMR(400MHz,CDCl3)2.42-2.13(m,8H),1.93-1.77(m,4H)；13C NMR(101MHz,CDCl3)217.0,64.5,38.6,34.4,19.9.
The second step is that: synthesis of Compound 2
Under the protection of argon, the (R) -spiro [4.4] is reacted]-1, 6-nonanedione ((R) -1) (400mg) and 2- [ N, N-bis (trifluoromethanesulfonyl) amino]Pyridine (2.4eq,2.3g) was added to a dry 100mL Schlenk reaction flask, purged 3 times, and added to 30mL of anhydrous tetrahydrofuran. The system is cooled to-78 ℃, bis (trimethylsilyl) amino potassium (3eq) is dropwise added into the reaction system under the protection of argon, the reaction is kept for 40 minutes after the dropwise addition, and the reaction is monitored by TLC. Quenching the reaction by using a saturated sodium bicarbonate solution after the reaction is finished, extracting the reaction solution for three times (3X 20mL) by using ethyl acetate, washing the combined organic phase by using a 5% sodium hydroxide solution and a saturated sodium chloride solution in turn, drying anhydrous potassium carbonate, filtering to remove a drying agent, carrying out reduced pressure rotary evaporation to remove the solvent, carrying out chromatographic separation on the crude product by using a silica gel column to obtain a yellow liquid product, namely, a triflate enol ester compound (2) (915mg),the yield was 83%.1H NMR(400MHz,CDCl3)5.80(t,J＝2.5Hz,2H),2.52-2.38(m,4H),2.37-2.29(m,2H),2.04-1.97(m,2H)；13C NMR(101MHz,CDCl3)148.5,123.4,120.2,117.4,117.0,113.8,58.3,33.3,26.2.
The third step: synthesis of chiral spirocyclic dienes
Under the protection of argon, the alkene ester trifluoromethanesulfonate compound (2) (500mg), phenylboronic acid (4eq, 585mg) and tetrakis (triphenylphosphine) palladium (10 mol%) were added into a 100mL three-necked flask, the gas was purged 3 times, the degassed toluene ethanol mixture (3:1,30mL) and sodium carbonate solution (15mL) were added, the system was frozen and degassed three times with liquid nitrogen, and the mixture was returned to room temperature and heated at 80 ℃ for reflux for 5 hours. TLC monitors the reaction progress, after complete conversion, the system is cooled to room temperature, saturated ammonium chloride solution is added, an organic phase is separated, an aqueous phase is extracted with ethyl acetate for three times, the organic phase is washed with saturated salt water twice, dried by anhydrous sodium sulfate, filtered to remove a drying agent, solvent is removed by rotary evaporation, and a crude product is subjected to normal hexane column chromatography to obtain 327mg of white powdery solid 3a with the yield of 55%.1H NMR(400MHz,CDCl3)7.51-7.49(m,4H),7.23-7.14(m,6H),6.20(t,J＝2.6Hz,2H),2.51-2.42(m,4H),2.28-2.20(m,2H),2.08-2.02(m,2H)；13C NMR(101MHz,CDCl3)148.1,136.6,128.4,128.1,126.7,64.4,37.5,30.2.
Example 2: synthesis and identification of spiro-bis-boron catalyst 4a
In a glove box, 3a (13.6mg,0.05mmol) and HB (C) were added to the reaction flask in this order6F5)2(34.6mg,0.1mmol) and toluene (1.0mL) were reacted at 25 ℃ for 15 minutes. Further, isoquinoline (25.8mg,0.2mmol) and toluene (0.5mL) were added, and the reaction was continued at 25 ℃ for 30 minutes. After the reaction is finished, toluene is removed by reduced pressure distillation to obtain white powdery solid, and internal standard CH is added2Br2By passing1The nuclear magnetic yield was 95% by H NMR. The crude product was recrystallized from dichloromethane and n-hexane to give 4 a.2L.1H NMR(400MHz,CD2Cl2)8.74(s,2H),8.04(d,J＝6.8Hz,2H),7.83(t,J＝7.5Hz,2H),7.74(d,J＝8.1Hz,2H),7.62(t,J＝7.4Hz,2H),7.59-7.30(m,8H),7.16(t,J＝7.1Hz,2H),6.87(br,2H),6.69(br,2H),2.92(t,J＝9.6Hz,2H),2.32-2.18(m,2H),2.14(d,J＝9.0Hz,2H),1.80-1.54(m,4H),0.86(dd,J＝19.2,11.5Hz,2H)；13C NMR(101MHz,CD2Cl2)149.6,137.0,136.0,134.6,131.8,129.9,129.8,129.0,127.8,127.2,127.0,126.0,125.8,122.7,61.4,53.1,34.5,33.5,27.4.
Example 3: synthesis of (R) -2-methyl-1, 2,3, 4-tetrahydroquinoline (P1)
In a glove box filled with nitrogen, chiral spirodiene compound 3a (3.4mg,0.0125mmol,5 mol%) and HB (C)6F5)2(8.65mg,0.025mmol,10 mol%) was added to a 10mL cuvette, dissolved in 2mL of trifluorotoluene, and reacted at 25 ℃ for 15 minutes. The system was cooled to room temperature and then 2-methylquinoline S1(35.8mg,0.25mmol) and 3mL of trifluorotoluene were added, whereupon the tube was transferred to an autoclave and after three replacements of hydrogen gas, hydrogen was finally charged to 50bar and reacted at-20 ℃ for 24 h. After the reaction, hydrogen was released, the solvent was removed by rotary evaporation, and the residue was separated and purified by silica gel column chromatography to give a hydrogenated product P1 as a colorless oily liquid with a yield of 97% and an enantioselectivity of 90% ee.1H NMR(400MHz,CDCl3)7.00-6.95(m,2H),6.68-6.59(m,1H),6.51(d,J＝6.9Hz,1H),3.72(br,1H),3.50-3.30(m,1H),2.87-2.81(m,1H),2.80-2.70(m,1H),2.01-1.87(m,1H),1.69-1.54(m,1H),1.24(d,J＝6.2Hz,3H)；13C NMR(101MHz,CDCl3)144.9,129.4,126.8,121.2,117.1,114.1,47.2,30.2,26.7,22.7.
Claims (8)
1. A preparation method of a chiral spiro diboron catalyst comprises the following steps:
in a glove box, a chiral spirocyclic diene compound and HBArF 2And adding solvent toluene into the reaction bottle, and stirring at a specified temperatureAfter 15 minutes, the temperature is restored to room temperature, and the chiral spiro diboron catalyst is prepared; adding L to react with the prepared chiral spiro diboron catalyst, stirring at room temperature for 30 minutes, removing the solvent, recrystallizing, separating and purifying to obtain an adduct of the chiral spiro diboron catalyst and L; chiral spirocyclic diene Compound, HBArF 2And L in a molar ratio of 1:2: 4; the chiral spirocyclic diene compound has the following structural formula:
wherein, the R group is aryl or alkyl;
the structural formula of the adduct of the chiral spiro diboron catalyst and L is as follows:
wherein R is aryl or alkyl, Ar isFIs fluorine-containing aryl, and L is isoquinoline or pyridine.
2. The process according to claim 1, wherein the chiral spirocyclic diene compound is prepared by:
the first step is as follows: racemic spiro [4.4] -1, 6-nonanedione and (R) -phenethylamino oxalyl hydrazine are refluxed overnight under the catalysis of iodine to obtain a pair of diastereoisomer dihydrazone compound intermediates, the (R) -dihydrazone compound with single configuration is obtained by recrystallization twice in ethanol and separation, the (R) -dihydrazone compound is hydrolyzed in an iodine-potassium iodide system to obtain an optical pure product (R) -spiro [4.4] -1, 6-nonanedione ((R) -1),
wherein the molar ratio of the racemic spiro [4.4] -1, 6-nonanedione to (R) -phenethylamino oxalyl hydrazine is 1: 1;
the second step is that: reacting the (R) -spiro [4.4] -1, 6-nonanedione ((R) -1) and 2- [ N-N-bis (trifluoromethanesulfonyl) amino ] pyridine in tetrahydrofuran at-78 ℃ for 40 minutes using potassium bis (trimethylsilyl) amide as a base to give an enol trifluoromethanesulfonate compound (2),
wherein the molar ratio of the optically pure product (R) -spiro [4.4] -1, 6-nonanedione ((R) -1), 2- [ N-N-bis (trifluoromethanesulfonyl) amino ] pyridine and bis (trimethylsilyl) amino potassium is 1:3: 3;
the third step: toluene and ethanol are mixed according to the volume ratio of 3:1 to be used as a mixed solvent, under the condition of heating reflux, the triflate enol ester compound (2) and an aryl or alkyl boric acid reagent generate Suzuki coupling reaction in the presence of tetrakis (triphenylphosphine) palladium and alkali, and the chiral spirocyclic diene compound (3) is obtained after 5 hours of reaction,
wherein the molar ratio of said alkenyl triflate compound (2) to said aryl or alkyl boronic acid reagent is 1:4, said tetrakis (triphenylphosphine) palladium is present in an amount of 10 mol%, and said aryl or alkyl boronic acid reagent has the formula RB (OH)2And R is aryl or alkyl.
3. The method of claim 2, wherein: the absolute configuration of the chiral spirodiene compound is (R) or (S).
4. The method of claim 2, wherein: the aryl is phenyl, 4-fluorophenyl, 3-phenyl or 4-phenyl.
5. Use of a chiral spirocyclic bisboron catalyst according to any one of claims 1 to 4 for catalyzing asymmetric hydrogenation of quinoline to give 2-substituted tetrahydroquinoline compounds, characterized in that: the structural formula of the quinoline is as follows:
wherein, R is1,R2Are all alkyl, aryl, styryl, alkynyl, conjugated dienyl or conjugated alkenylalkynyl.
6. The use according to claim 5, wherein the chiral spirocyclic diene compound of claim 1 and the HBAr of claim 1 are added sequentially to a reaction flask under nitrogen atmosphereF 2And trifluorotoluene, stirring for 15 minutes at the specified temperature, cooling to room temperature, adding 2-substituted quinoline, transferring to a high-pressure kettle, sealing, replacing with hydrogen for three times, filling to reaction pressure, reacting at-20 ℃, discharging residual hydrogen in the kettle carefully after reacting for 24 hours, heating the reaction system to room temperature, reducing pressure to remove the solvent, and performing column chromatography separation to obtain a 2-substituted tetrahydroquinoline product.
7. Use according to claim 6, characterized in that: the dosage of the trifluorotoluene is 1.0-2.0mL for each millimole of 2-substituted quinoline.
8. Use according to claim 6, characterized in that: the reaction pressure of hydrogen is 2-5 MPa.
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Non-Patent Citations (3)
| Title |
|---|
| C2-Symmetric Bicyclic Bisborane Catalysts: Kinetic or Thermodynamic Products of a Reversible Hydroboration of Dienes;Xian-Shuang Tu et al.;《Angew. Chem. Int. Ed.》;20190913;第15096-15100页 * |
| Chiral Dienes as "Ligands" for Borane-Catalyzed Metal-Free Asymmetric Hydrogenation of Imines;Yongbing Liu et al.;《Journal of the American Chemical Society》;20130422;第6810-6813页 * |
| 喹啉及其衍生物氢化还原技术进展;王璇等;《化工时刊》;20141130;第36-39页 * |
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