CN117586310A - Binaphthyl amine derived chiral phosphine oxide ligand promoted nickel catalysis C (sp 3 ) Asymmetric cyclization of the-H bond - Google Patents
Binaphthyl amine derived chiral phosphine oxide ligand promoted nickel catalysis C (sp 3 ) Asymmetric cyclization of the-H bond Download PDFInfo
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- CN117586310A CN117586310A CN202210964711.5A CN202210964711A CN117586310A CN 117586310 A CN117586310 A CN 117586310A CN 202210964711 A CN202210964711 A CN 202210964711A CN 117586310 A CN117586310 A CN 117586310A
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- 239000003446 ligand Substances 0.000 title claims abstract description 61
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 title claims abstract description 49
- 229910052759 nickel Inorganic materials 0.000 title claims abstract description 8
- 238000006555 catalytic reaction Methods 0.000 title claims abstract description 7
- ZAPYLSLVQJQGEY-UHFFFAOYSA-N 1-naphthalen-1-ylnaphthalen-2-amine Chemical compound C1=CC=C2C(C3=C4C=CC=CC4=CC=C3N)=CC=CC2=C1 ZAPYLSLVQJQGEY-UHFFFAOYSA-N 0.000 title claims description 7
- AUONHKJOIZSQGR-UHFFFAOYSA-N oxophosphane Chemical compound P=O AUONHKJOIZSQGR-UHFFFAOYSA-N 0.000 title description 8
- 238000007363 ring formation reaction Methods 0.000 title description 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 43
- 238000000034 method Methods 0.000 claims abstract description 17
- 230000004913 activation Effects 0.000 claims abstract description 14
- 239000003054 catalyst Substances 0.000 claims abstract description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 99
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 96
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 81
- 239000012299 nitrogen atmosphere Substances 0.000 claims description 37
- 238000004440 column chromatography Methods 0.000 claims description 33
- 239000012074 organic phase Substances 0.000 claims description 33
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 claims description 32
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 32
- 238000005406 washing Methods 0.000 claims description 20
- 238000001035 drying Methods 0.000 claims description 19
- 239000007864 aqueous solution Substances 0.000 claims description 18
- 238000001816 cooling Methods 0.000 claims description 18
- 238000003756 stirring Methods 0.000 claims description 18
- 239000007788 liquid Substances 0.000 claims description 17
- 239000000243 solution Substances 0.000 claims description 17
- -1 dinitrogen phosphorus oxygen Chemical compound 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 9
- 229910052751 metal Inorganic materials 0.000 claims description 7
- 239000002184 metal Substances 0.000 claims description 7
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 6
- 239000002994 raw material Substances 0.000 claims description 5
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000002841 Lewis acid Substances 0.000 claims description 2
- 150000001263 acyl chlorides Chemical class 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 238000010790 dilution Methods 0.000 claims description 2
- 239000012895 dilution Substances 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 150000007517 lewis acids Chemical class 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 229910001392 phosphorus oxide Inorganic materials 0.000 claims description 2
- 239000002243 precursor Substances 0.000 claims description 2
- 239000007858 starting material Substances 0.000 claims description 2
- MDDUHVRJJAFRAU-YZNNVMRBSA-N tert-butyl-[(1r,3s,5z)-3-[tert-butyl(dimethyl)silyl]oxy-5-(2-diphenylphosphorylethylidene)-4-methylidenecyclohexyl]oxy-dimethylsilane Chemical group C1[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)C(=C)\C1=C/CP(=O)(C=1C=CC=CC=1)C1=CC=CC=C1 MDDUHVRJJAFRAU-YZNNVMRBSA-N 0.000 claims description 2
- VSAISIQCTGDGPU-UHFFFAOYSA-N tetraphosphorus hexaoxide Chemical compound O1P(O2)OP3OP1OP2O3 VSAISIQCTGDGPU-UHFFFAOYSA-N 0.000 claims description 2
- 229930192474 thiophene Natural products 0.000 claims description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 abstract description 6
- AFCIMSXHQSIHQW-UHFFFAOYSA-N [O].[P] Chemical compound [O].[P] AFCIMSXHQSIHQW-UHFFFAOYSA-N 0.000 abstract description 6
- 125000001931 aliphatic group Chemical group 0.000 abstract description 6
- 230000003197 catalytic effect Effects 0.000 abstract description 3
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 abstract description 2
- 230000003213 activating effect Effects 0.000 abstract description 2
- 238000001308 synthesis method Methods 0.000 abstract description 2
- DVWQNBIUTWDZMW-UHFFFAOYSA-N 1-naphthalen-1-ylnaphthalen-2-ol Chemical compound C1=CC=C2C(C3=C4C=CC=CC4=CC=C3O)=CC=CC2=C1 DVWQNBIUTWDZMW-UHFFFAOYSA-N 0.000 abstract 3
- 230000000694 effects Effects 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 abstract 1
- 230000009257 reactivity Effects 0.000 abstract 1
- 238000005481 NMR spectroscopy Methods 0.000 description 76
- 239000000047 product Substances 0.000 description 42
- 230000015572 biosynthetic process Effects 0.000 description 38
- 238000003786 synthesis reaction Methods 0.000 description 38
- 238000004128 high performance liquid chromatography Methods 0.000 description 32
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 31
- MCULRUJILOGHCJ-UHFFFAOYSA-N triisobutylaluminium Chemical compound CC(C)C[Al](CC(C)C)CC(C)C MCULRUJILOGHCJ-UHFFFAOYSA-N 0.000 description 31
- 239000003109 Disodium ethylene diamine tetraacetate Substances 0.000 description 28
- 235000019301 disodium ethylene diamine tetraacetate Nutrition 0.000 description 28
- 239000007787 solid Substances 0.000 description 18
- 238000007865 diluting Methods 0.000 description 16
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- 150000004985 diamines Chemical class 0.000 description 5
- 238000003818 flash chromatography Methods 0.000 description 5
- SEZSRPYCOMAEDL-UHFFFAOYSA-N 2-diphenylphosphoryl-1-(2-diphenylphosphorylnaphthalen-1-yl)naphthalene Chemical compound C=1C=CC=CC=1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(=O)(C=1C=CC=CC=1)C=1C=CC=CC=1)(=O)C1=CC=CC=C1 SEZSRPYCOMAEDL-UHFFFAOYSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 238000004293 19F NMR spectroscopy Methods 0.000 description 2
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000003912 environmental pollution Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 230000005311 nuclear magnetism Effects 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 229910052723 transition metal Inorganic materials 0.000 description 2
- 150000003624 transition metals Chemical class 0.000 description 2
- MENHXVNCWVKFRA-UHFFFAOYSA-N 1,4-oxazin-2-one Chemical compound O=C1C=NC=CO1 MENHXVNCWVKFRA-UHFFFAOYSA-N 0.000 description 1
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 1
- JBIJLHTVPXGSAM-UHFFFAOYSA-N 2-naphthylamine Chemical compound C1=CC=CC2=CC(N)=CC=C21 JBIJLHTVPXGSAM-UHFFFAOYSA-N 0.000 description 1
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 1
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 241000790917 Dioxys <bee> Species 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 229910003310 Ni-Al Inorganic materials 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 150000003862 amino acid derivatives Chemical class 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 150000003857 carboxamides Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 229910052741 iridium Inorganic materials 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- XIPFMBOWZXULIA-UHFFFAOYSA-N pivalamide Chemical compound CC(C)(C)C(N)=O XIPFMBOWZXULIA-UHFFFAOYSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 150000003556 thioamides Chemical class 0.000 description 1
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6581—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms
- C07F9/6584—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms having one phosphorus atom as ring hetero atom
- C07F9/65848—Cyclic amide derivatives of acids of phosphorus, in which two nitrogen atoms belong to the ring
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- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- 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
- B01J31/1845—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 phosphorus
- B01J31/185—Phosphites ((RO)3P), their isomeric phosphonates (R(RO)2P=O) and RO-substitution derivatives thereof
- B01J31/186—Mono- or diamide derivatives thereof
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/86—Oxygen atoms
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- 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
- C07D215/16—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
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- 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
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
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- C07D455/02—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing not further condensed quinolizine ring systems
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- B01J2231/30—Addition reactions at carbon centres, i.e. to either C-C or C-X multiple bonds
- B01J2231/32—Addition reactions to C=C or C-C triple bonds
- B01J2231/324—Cyclisations via conversion of C-C multiple to single or less multiple bonds, e.g. cycloadditions
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Abstract
The invention provides a simple and efficient synthesis method, synthesizes a novel binaphthol-derived skeleton phosphorus-oxygen ligand, utilizes the newly developed phosphorus-oxygen ligand, realizes that the binaphthol-derived phosphorus-oxygen ligand is used for connecting a nickel-aluminum bimetallic catalyst to realize the enantioselective nickel catalytic aliphatic C (sp) 3 ) A method for activating H, which belongs to the technical field of asymmetric catalysis application. The key of the invention for solving the problems is that: 1. find a novel binaphthol-derived phosphorus-oxygen ligand which is efficient and specific to reactivity, site selectivity and corresponding selectivity, and realize nickel catalysis of aliphatic C (sp) of formamide 3 ) -a method of asymmetric H activation; 2. by utilizing the ligand characteristic, the bimetallic catalytic system is designed, so that the reaction activity is greatly improved, and the preparation is easier and more efficient.
Description
Technical Field
The present invention relates to a method for preparing a phosphorus oxide ligand (H) derived by using binaphthyl amine 8 Implementation of enantioselective nickel-catalyzed aliphatic C (sp) of formamide with BINAPO bridged nickel-aluminum bimetallic catalyst 3 ) The method for activating H provides a series of chiral nitrogen-containing heterocycles, and belongs to the technical field of asymmetric catalysis application.
Background
Chiral compounds are widely found in pharmaceuticals, agrochemicals and biologically active natural products. The method of achieving C-H enantioselective activation by transition metals is one of the most convenient and economical ways to obtain chiral molecules present in large amounts of natural products and bioactive compounds such as pharmaceuticals and pesticides. Currently, widely explored C-H bonds are C (sp 2 ) -H or C (sp) -H bonds. In contrast, due to C (sp 3 ) Sterically hindered and inactive around H bond, non-activated C (sp 3 ) The achievement of enantioselective activation of the H bond presents a great challenge.
Noble metals such as Pd, rh and Ir have been able to catalyze widely enantioselective C (sp 3 ) H bond activation reaction, providing good yields and high ee. However, the same strategy is generally ineffective for most 3d transition metals that are very sensitive to substrate and ligand structures. To date, only Matsunaga, yoshino and its colleagues have reported a successful example. They use achiral Cp-Co (III) and amino acid derivatives as chiral anions to promote primary C (sp) of thioamides 3 ) Enantioselective amidation of the H bond. In view of the high earth abundance, low cost and low biotoxicity advantages of 3d metals, 3d metal catalyzed enantioselective C (sp 3 ) An H bond activation reaction is very necessary.
In summary, although nickel-catalyzed C-H bond activation even enantioselective nickel-catalyzed carbon (sp 2 ) The activation of the H bond has progressed considerably, but enantioselective Ni-catalyzed aliphatic C (sp 3 ) H-bond activation remains a difficult challenge to achieve.
The invention comprises the following steps:
enantioselective nickel catalyzed aliphatic C (sp 3 ) The H activation reaction did not give good results by trying both the dioxy backbone phosphorus-oxygen ligand and other dinitrogen phosphorus-oxygen ligands, and good results could be achieved with binaphthyl-amine derived phosphorus-oxygen ligands.
One of the key points of the invention for solving the problems is that the binaphthyl amine and acyl chloride are subjected to nucleophilic substitution reaction to prepare a novel dinitrogen phosphorus oxide precursor. The method is characterized by comprising the following specific steps:
1: a three-necked Schlenk flask was charged with the corresponding substituted diamine 5 (1.0 mmol,1.0 equiv.) in dry THF (10 mL) under N 2 N-butyllithium was added to hexane (2.5M, 0.8mL,2 mmol) at-78deg.C in 10 minutes under an atmosphere. The mixture was stirred at the same temperature for 0.5 hours and then heated to room temperature for 0.5 hours. The mixture was then cooled to room temperature and freshly distilled PCl was added dropwise again at-78 ℃ 3 (95. Mu.L, 1.0mmol,1.0 equiv.). The solution was warmed to room temperature and stirred for 1 hour. H was added to the resulting solution 2 O (18. Mu.L, 1.0mmol,1.0 equiv.) and stirred for 0.5 hours. The solvent was removed under reduced pressure and the residue was purified by flash chromatography to give pure phosphine oxide L.
2. R in the invention can be Ph, tBu and the like, but is not limited to the groups;
the invention has the advantages that:
1. the method is simple and convenient to operate, and the target product can be obtained through one-step reaction.
2. The product of the invention has stable structure and can exist in air stably.
3. The ligand structure related by the invention is easy to modify.
The invention also aims to provide a simple and practical method, which uses a novel H for the first time 8 -bis (2-naphthylamine) derived chiral phosphine oxide (H) 8 BINAPO to achieve enantioselective Nickel catalyzed C (sp) of formamide 3 ) Activation of H provides a series of nitrogen-containing heterocycles in 40-95% yields with ee of 70-95%. H 8 The BINAPO linked Ni-Al bimetallic catalyst may be activated with formyl C (sp 2 ) H bond activation and subsequent acceleration of aliphatic C (sp 3 ) -H activation plays a key role.
The second point of the invention to solve the problem is that the novel diazo-phospho-oxide ligand participates in nickel catalysis C (sp 3 ) -a method for asymmetric activation of H-bonds and use thereof. The method is characterized by comprising the following specific steps:
1. sequentially adding a ligand, a metal catalyst, raw materials and a solvent into a reaction bottle in a nitrogen atmosphere, then adding Lewis acid, stirring for 2-8 hours at a specified temperature, cooling to room temperature, adding ethyl acetate for dilution, adding 2mL of 5% ethylene diamine tetraacetic acid disodium salt aqueous solution for washing, separating liquid, drying an organic phase with anhydrous sodium sulfate, and separating by column chromatography to obtain a target product 3;
2. the metal catalyst of the invention is Ni (cod) 2 The catalyst is generally used in an amount of 5mol%.
3. The ligand involved in the invention is chiral bi-N framework secondary phosphine oxide, and the dosage of the ligand is generally 5mol percent.
4. Al according to the present invention i Bu 3 The amount of the n-hexane solution having a concentration of 1mol/L is generally 40mol%.
5. The solvent used in the present invention was toluene solution in an amount of 2.5mL per millimole of 1 starting material.
6. R in the raw material 1 used in the present invention 2 Methyl, cyclohexyl, cycloheptyl; r is R 2 Is hydrogen, cyclohexyl, cycloheptyl; r is R 3 Substituents such as isopropyl, cyclohexyl and alkoxy, but not limited to these groups; r is a substituent group such as ethyl, phenyl, thiophene, etc., but is not limited to these groups.
The invention has the advantages that:
1. most of the reagents used in the invention are commercially available, the chiral ligand to be synthesized has wide sources of raw materials and low cost, can exist stably at normal temperature and normal pressure, and is convenient to operate and process without special treatment.
2. The ligand synthesis method is simple in ligand synthesis and convenient to operate, the defect of long ligand synthesis steps used in the traditional method is avoided, and the requirement on equipment is simple. Greatly reduces the production cost for synthesizing the compounds.
3. The invention can obtain the optically pure product in one step, and the post-treatment is simple and convenient, thereby avoiding the method that the chiral product can be obtained only by relay reaction before, and greatly reducing the reaction cost of the product.
4. The catalyst used in the invention is cheap, the dosage of metal, ligand and the like is low, and the requirements of good catalytic effect, cost reduction, convenient post-treatment process, environmental pollution reduction and the like are maintained.
5. The reaction of the invention is completely atom economical, meets the requirement of green chemistry, does not have other byproducts in mass production, and meets the requirements of simplifying the process, reducing the cost, reducing the environmental pollution and the like.
Detailed description of the preferred embodiments
The following examples of ligand synthesis will better illustrate the invention, but it will be emphasized that the invention is in no way limited to the examples presented. The following examples show different sides of the invention. The data presented include specific operations and reaction conditions and products. The purity of the product was identified by nuclear magnetism.
Example 1: synthesis of Phosphonoxy ligand L1
A three-necked Schlenk flask was charged with the corresponding substituted diamine (1.0 mmol,1.0 equiv.) in dry THF (10 mL) and N-butyllithium was added to hexane (2.5M, 0.8mL,2 mmol) over 10 minutes at-78deg.C under an N2 atmosphere. The mixture was stirred at the same temperature for 0.5 hours and then heated to room temperature for 0.5 hours. The mixture was then cooled to room temperature and freshly distilled PCl was added dropwise again at-78 ℃ 3 (95. Mu.L, 1.0mmol,1.0 equiv.). The solution was warmed to room temperature and stirred for 1 hour. H was added to the resulting solution 2 O (18. Mu.L, 1.0mmol,1.0 equiv.) and stirred for 0.5 hours. The solvent was removed under reduced pressure and the residue was purified by flash chromatography to give pure phosphine oxide L1 as a white solid in 50% yield. 1 H NMR(400MHz,CDCl 3 )δ7.97(d,J=8.7Hz,1H),7.87(dd,J=12.8,8.6Hz,2H),7.77(d,J=8.2Hz,1H),7.71(d,J=8.8Hz,1H),7.65(d,J=8.6Hz,1H),7.50(d,JP-H=612.0Hz,1H),7.38(t,J=7.4Hz,1H),7.30(t,J=7.4Hz,1H),7.02(t,J=7.6Hz,1H),6.93(t,J=7.6Hz,1H),6.73(dd,J=16.6,7.8Hz,2H),6.63-6.46(m,8H),6.45-6.38(m,2H),4.96(dd,J=14.4,7.6Hz,1H),4.78-4.58(m,2H),4.44(dd,J=14.4,6.8Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ138.0,136.9,136.1,136.1,135.6,132.8,132.6,132.3,131.9,131.4,130.8,129.8,129.5,128.1,127.9,127.9,127.8,127.7,127.6,127.5,127.0,126.6,126.1,125.9,125.7,125.2,124.2,123.6,51.9,51.9,49.7,49.6. 31 P NMR(162MHz,CDCl 3 )δ22.9.HRMS(ESI)m/z:[M+H] + calcd.for C 34 H 38 N 2 OP 511.1934,found 511.1926.
Example 2: synthesis of phosphine oxide ligand L2
Into a three-necked Schlenk flask was charged the corresponding substituted diamine (1.0 mmol,1.0 eq)v.) dry THF (10 mL) and N-butyllithium was added to hexane (2.5 m,0.8mL,2 mmol) over 10 minutes at-78 ℃ under an N2 atmosphere. The mixture was stirred at the same temperature for 0.5 hours and then heated to room temperature for 0.5 hours. The mixture was then cooled to room temperature and freshly distilled PCl was added dropwise again at-78 ℃ 3 (95. Mu.L, 1.0mmol,1.0 equiv.). The solution was warmed to room temperature and stirred for 1 hour. H was added to the resulting solution 2 O (18. Mu.L, 1.0mmol,1.0 equiv.) and stirred for 0.5 hours. The solvent was removed under reduced pressure and the residue was purified by flash chromatography to give pure phosphine oxide L20 as a white solid in 60% yield. 1 H NMR(400MHz,CDCl 3 )δ7.88-7.80(m,2H),7.79-7.71(m,2H),7.63(d,J=8.8Hz,1H),7.52(d,J=8.8Hz,1H),7.30-7.21(m,2H),7.18-6.99(m,4H),7.02(d,J P-H =599.6Hz,1H),3.54-3.42(m,2H),3.24(dd,J=14.0,7.6Hz,1H),3.12(t,J=15.8Hz,1H),0.16(s,18H). 13 C NMR(100MHz,CDCl 3 )δ141.7,139.5,139.5,132.5,132.3,131.7,131.4,130.8,129.9,129.8,128.3,128.3,127.8,127.7,126.3,126.2,125.5,125.3,123.5,123.1,59.2,59.2,57.4,57.3,33.9,33.9,33.5,33.5,27.5,27.3. 31 P NMR(162MHz,CDCl 3 )δ27.0.HRMS(ESI)m/z:[M+H] + calcd.for C 30 H 36 N 2 OP 471.2560,found 471.2553.
Example 3: synthesis of Phosphonoxy ligand L3
A three-necked Schlenk flask was charged with the corresponding substituted diamine (1.0 mmol,1.0 equiv.) in dry THF (10 mL) and N-butyllithium was added to hexane (2.5M, 0.8mL,2 mmol) over 10 minutes at-78deg.C under an N2 atmosphere. The mixture was stirred at the same temperature for 0.5 hours and then heated to room temperature for 0.5 hours. The mixture was then cooled to room temperature and freshly distilled PCl was added dropwise again at-78 ℃ 3 (95. Mu.L, 1.0mmol,1.0 equiv.). The solution was warmed to room temperature and stirredAnd 1 hour. H was added to the resulting solution 2 O (18. Mu.L, 1.0mmol,1.0 equiv.) and stirred for 0.5 hours. The solvent was removed under reduced pressure and the residue was purified by flash chromatography to give pure phosphine oxide L21 as a white solid in 38% yield. 1 H NMR(400MHz,CDCl 3 )δ7.30(d,J P-H =597.6Hz,1H),7.27(d,J=9.2Hz,1H),7.21(d,J=8.4Hz,1H),7.12-6.94(m,8H),6.78(d,J=7.6Hz,2H),6.70(d,J=7.4Hz,2H),4.85(dd,J=14.4,8.0Hz,1H),4.59-4.46(m,2H),4.31(dd,J=14.4,6.8Hz,1H),2.76(t,J=6.0Hz,2H),2.69(t,J=6.0Hz,2H),2.23-2.03(m,2H),1.72-1.63(m,2H),1.62-1.54(m,2H),1.53-1.21(m,6H). 13 C NMR(100MHz,CDCl 3 )δ138.5,138.4,137.7,137.5,137.4,137.2,136.8,136.1,136.0,136.0,135.2,135.2,134.7,134.7,134.6,129.1,128.7,128.2,127.9,127.9,127.3,127.0,123.1,123.1,122.6,122.5,51.9,51.8,49.8,49.7,29.8,29.7,27.4,27.2,22.8,22.7,22.6. 31 P NMR(162MHz,CDCl 3 )δ22.9.HRMS(ESI)m/z:[M+H] + calcd.for C 34 H 36 N 2 OP 519.2560,found 519.2555.
Example 4: synthesis of Phosphonoxy ligand L4
A three-necked Schlenk flask was charged with the corresponding substituted diamine (1.0 mmol,1.0 equiv.) in dry THF (10 mL) and N-butyllithium was added to hexane (2.5M, 0.8mL,2 mmol) over 10 minutes at-78deg.C under an N2 atmosphere. The mixture was stirred at the same temperature for 0.5 hours and then heated to room temperature for 0.5 hours. The mixture was then cooled to room temperature and freshly distilled PCl was added dropwise again at-78 ℃ 3 (95. Mu.L, 1.0mmol,1.0 equiv.). The solution was warmed to room temperature and stirred for 1 hour. H was added to the resulting solution 2 O (18. Mu.L, 1.0mmol,1.0 equiv.) and stirred for 0.5 hours. The solvent was removed under reduced pressure and the residue was purified by flash chromatography to give pure secondaryPhosphine oxide L22, white solid, yield 35%. 1 H NMR(400MHz,CDCl 3 )δ7.26(d,J=8.0Hz,1H),7.16(d,J=8.0Hz,1H),7.10(d,J=8.0Hz,2H),6.87(d,J P-H =594.0Hz,1H),3.53-3.33(m,2H),3.24-3.13(m,1H),3.13-3.03(m,1H),2.93-2.73(m,4H),2.69-2.54(m,2H),2.34-2.20(m,2H),1.90-1.66(m,6H),1.55-1.36(m,2H),0.46(d,J=4.8Hz,18H). 13 C NMR(100MHz,CDCl 3 )δ141.1,138.4,138.4,138.0,137.1,135.6,135.5,135.0,134.9,134.7,133.8,133.8,129.0,129.0,128.8,128.7,122.3,122.3,122.0,121.9,59.0,58.9,57.4,57.3,33.8,33.7,33.4,33.3,29.2,28.2,27.7,27.5,22.7,22.6,22.5,22.4. 31 P NMR(162MHz,CDCl 3 )δ27.1.HRMS(ESI)m/z:[M+H] + calcd.for C 30 H 44 N 2 OP 479.3186,found 479.3180.
The following carboxamide enantioselectivity C (sp 3 ) Examples of implementation of the H-activation reaction the invention will be better illustrated, but it will be emphasized that the invention is in no way limited to what is represented by these examples of implementation. The following examples show different sides of the invention. The data presented include specific operations and reaction conditions and products. The purity of the product was identified by nuclear magnetism. The chirality of the product is detected by chiral high performance liquid chromatography.
Example 1: synthesis of (R) -1-Isopropyl-6-methyl-3,4-dipropyl-5,6-dihydropyridin-2 (1H) -one
Ligand H is added into the reaction bottle in sequence in nitrogen atmosphere 8 -BINAPO(4.8mg,5mol%),Ni(cod) 2 (2.75 mg,5 mol%), 1a (25.8 mg,0.2 mmol), toluene (0.5 mL), then 2a (44.1 mg,0.4 mmol), triisobutylaluminum (1M, 80. Mu.L, 40 mol%), stirring at 80℃for 2 hours, cooling to room temperature, diluting with ethyl acetate, washing with 2mL of 5% aqueous disodium ethylenediamine tetraacetate, separating, and the organic phase was washed with anhydrous sulfurDrying sodium acid, concentrating, and separating by column chromatography to obtain the target product 3a, which is yellow oily liquid with a yield of 90%. 1 H NMR(400MHz,CDCl 3 )δ4.80-4.67(m,1H),3.64-3.54(m,1H),2.57-2.43(m,2H),2.23-2.05(m,3H),1.92(d,J=16.4,1H),1.49-1.32(m,4H),1.21-1.09(m,9H),0.96-0.87(m,6H). 13 C NMR(100MHz,CDCl 3 )δ164.3,142.0,130.3,44.8,44.4,35.9,35.8,28.6,23.2,21.3,20.7,20.6,20.2,14.4,14.3.HRMS(ESI)m/z:[M+H] + calcd.for C 15 H 28 NO 238.2165,found 238.2172.HPLC condition:Chiralpak IA column,n-hexane/i-PrOH=98∶2,1.0mL/min,254nm,t r-minor =8.1min,t r-major =9.9min,91%ee.111.1(c 1.0,CHCl 3 ).
Example 2: synthesis of (R) -3,4-Diethyl-1-isopropyl-6-methyl-5, 6-dihydroxyfridin-2 (1H) -one
Ligand H is added into the reaction bottle in sequence in nitrogen atmosphere 8 -BINAPO(4.8mg,5mol%),Ni(cod) 2 (2.75 mg,5 mol%), 1a (25.8 mg,0.2 mmol), toluene (0.5 mL), then 2b (32.8 mg,0.4 mmol), triisobutylaluminum (1M, 80. Mu.L, 40 mol%), stirring at 80℃for 2 hours, cooling to room temperature, diluting with ethyl acetate, adding 2mL of 5% aqueous solution of disodium ethylenediamine tetraacetate, washing, separating, drying the organic phase with anhydrous sodium sulfate, concentrating and separating by column chromatography to obtain the target product 3b as a colorless oily liquid, yield 83%. 1 H NMR(400MHz,CDCl 3 )δ4.82-4.66(m,1H),3.67-3.53(m,1H),2.59-2.39(m,2H),2.29-2.17(m,2H),2.13-2.02(m,1H),1.91(d,J=16.4Hz,1H),1.14(dd,J=12.0,6.4Hz,9H),1.05-0.93(m,6H). 13 C NMR(100MHz,CDCl 3 )δ164.3,142.9,131.0,44.6,44.3,35.3,26.5,21.3,20.6,20.1,19.6,14.6.11.9.HRMS(ESI)m/z:[M+H] + calcd.for C 13 H 24 NO 210.1852,found 210.1855.HPLC condition:Chiralpak IA column,n-hexane/i-PrOH=99∶1,1.0mL/min,254nm,t r-minor =14.0min,t r-major =15.4min,93%ee.110.0(c 1.0,CHCl 3 ).
Example 3: synthesis of (R) -3,4-Dihexyl-1-isopropyl-6-methyl-5, 6-dihydopyridin-2 (1H) -one
Ligand H is added into the reaction bottle in sequence in nitrogen atmosphere 8 -BINAPO(4.8mg,5mol%),Ni(cod) 2 (2.75 mg,5 mol%), 1a (25.8 mg,0.2 mmol), toluene (0.5 mL), then 2c (88.9 mg,0.4 mmol), triisobutylaluminum (1M, 80. Mu.L, 40 mol%), stirring at 80℃for 2 hours, cooling to room temperature, diluting with ethyl acetate, adding 2mL of 5% aqueous solution of disodium ethylenediamine tetraacetate, washing, separating, drying the organic phase with anhydrous sodium sulfate, concentrating and separating the target product 3c by column chromatography, colorless oily liquid, yield 86%. 1 H NMR(400MHz,CDCl 3 )δ4.81-4.65(m,1H),3.63-3.53(m,1H),2.56-2.42(m,2H),2.23-2.02(m,3H),1.91(d,J=16.4,1H),1.42-1.22(m,16H),1.19-1.10(m,9H),0.92-0.79(m,6H). 13 C NMR(100MHz,CDCl 3 )δ164.3,142.0,130.3,44.7,44.4,35.8,33.8,31.8,31.8,30.0,29.7,29.5,27.3,26.6,22.8,22.7,21.3,20.6,20.2,14.2,14.2.HRMS(ESI)m/z:[M+H] + calcd.for C 21 H 40 NO 322.3104,found 322.3111.HPLC condition:Chiralpak IA column,n-hexane/i-PrOH=99∶1,1.0mL/min,254nm,t r-minor =11.6min,t r-major =12.5min,93%ee.96.0(c 1.0,CHCl 3 ).
Example 4: synthesis of (R, E) -5- (((tert-butyl methyl) oxy) methyl) -2- (4-phenylbut-3-en-2-yl) pyridine
Ligand H is added into the reaction bottle in sequence in nitrogen atmosphere 8 -BINAPO(4.8mg,5mol%),Ni(cod) 2 (2.75 mg,5 mol%), 1a (25.8 mg,0.2 mmol), toluene (0.5 mL), then 2d (66.5 mg,0.4 mmol) of triisobutylaluminum (1M, 80. Mu.L, 40 mol%) was added thereto, stirred at 80℃for 2 hours, cooled to room temperature, diluted with ethyl acetate, washed with 2mL of 5% aqueous disodium ethylenediamine tetraacetate, separated, the organic phase was dried over anhydrous sodium sulfate, concentrated and then separated by column chromatography to obtain the objective product 3d as a colorless oily liquid in 93% yield. 1 H NMR(400MHz,CDCl 3 )δ4.86-4.67(m,1H),3.73-3.52(m,1H),2.52(dd,J=16.8,6.4Hz,1H),2.47-2.37(m,1H),2.25-2.12(m,2H),2.09-1.98(m,1H),1.90(d,J=16.4Hz,1H),1.65-1.45(m,2H),1-33-1.21(m,4H),1.15(q,J=6.6Hz,9H),0.91(d,J=6.8Hz,12H). 13 C NMR(100MHz,CDCl 3 )δ164.3,142.1,131.2,44.6,44.3,39.2,36.5,35.9,31.7,28.6,28.4,24.6,22.6,22.5,21.4,20.6,20.2.HRMS(ESI)m/z:[M+H] + calcd.for C 19 H 36 NO 294.2791,found 294.2787.HPLC condition:Chiralpak IA column,n-hexane/i-PrOH=99∶1,1.0mL/min,254nm,t r-minor =12.2min,tr -major =15.7min,93%ee.93.9(c 1.0,CHCl 3 ).
Example 5: synthesis of (R) -1-Isopropyl-3,4-bis (3-methoxypropyl) -6-methyl-5, 6-dihydroxymatridin-2 (1H) -one
Ligand H is added into the reaction bottle in sequence in nitrogen atmosphere 8 -BINAPO(4.8mg,5mol%),Ni(cod) 2 (2.75 mg,5 mol%), 1a (25.8 mg,0.2 mmol), toluene (0.5 mL), then 2e (68.1 mg,0.4 mmol), triisobutylaluminum (1M, 80. Mu.L, 40 mol%), stirring at 80℃for 2 hours, cooling to room temperature, diluting with ethyl acetate, adding 2mL of 5% aqueous disodium ethylenediamine tetraacetate, washing, separating, drying the organic phase with anhydrous sodium sulfate, concentrating and separating the target product 3e by column chromatography to obtain a colorless oily liquid with a yield of 48%. 1 H NMR(400MHz,CDCl 3 )δ4.82-4.67(m,1H),3.69-3.59(m,1H),3.42-3-35(m,4H),3.32(d,J=5.2Hz,6H),2.62-2.46(m,2H),2.36-2.16(m,3H),1.94(d,J=16.8Hz,1H),1.76-1.60(m,4H),1.23-1.09(m,9H). 13 C NMR(100MHz,CDCl 3 )δ164.1,141.9,130.1,72.7,72.3,58.8,58.5,44.9,44.5,35.9,30.3,29.7,27.4,23.1,21.3,20.6,20.2.HRMS(ESI)m/z:[M+H] + calcd.for C 17 H 32 NO 3 298.2377,found 298.2370.HPLC condition:Chiralpak OD-H column,n-hexane/i-PrOH=97∶3,1.0mL/min,254nm,t r-minor =10.3min,t r-major =11.2min,90%ee.36.7(c 0.5,CHCl 3 ).
Example 6: synthesis of (R) -1-Isopropyl-6-methyl-3,4-diphenyl-5, 6-dihydopyridin-2 (1H) -one
Ligand H is added into the reaction bottle in sequence in nitrogen atmosphere 8 -BINAPO(4.8mg,5mol%),Ni(cod) 2 (2.75 mg,5 mol%), 1a (25.8 mg,0.2 mmol), toluene (0.5 mL), then 2f (71.2 mg,0.4 mmol) was added, triisobutylaluminum (1M, 80. Mu.L, 40 mol%), stirred at 80℃for 2 hours, cooled to room temperature, diluted with ethyl acetate2mL of 5% ethylenediamine tetraacetic acid disodium salt aqueous solution is added for washing, the solution is separated, the organic phase is dried by anhydrous sodium sulfate, and the target product 3f is obtained by column chromatography separation after concentration, and the yield is 67%. 1 H NMR(400MHz,CDCl 3 )δ7.24-7.07(m,8H),7.06-6.94(m,2H),4.93-4.73(m,1H),3.94-3.80(m,1H),3.16(dd,J=16.8,5.8Hz,1H),2.51(d,J=16.8Hz,1H),1.48(d,J=6.4Hz,3H),1.28(d,J=6.4Hz,6H). 13 C NMR(100MHz,CDCl 3 )δ163.6,142.8,140.7,140.5,136.4,132.7,131.5,131.1,128.4,128.1,127.6,127.5,126.8,126.7,125.3,45.4,45.1,38.3,21.4,20.6,20.4.HRMS(ESI)m/z:[M+H] + calcd.for C 21 H 24 NO 306.1852,found 306.1853.HPLC condition:Chiralpak IA column,n-hexane/i-PrOH=96∶4,1.0mL/min,254nm,t r-minor =11.4min,t r-major =14.4min,92%ee.124.0(c 1.0,CHCl 3 ).
Example 7: synthesis of (R) -1-isopopyyl-6-methyl-3, 4-di-p-tolyl-5, 6-dihydopyridin-2 (1H) -one
Ligand H is added into the reaction bottle in sequence in nitrogen atmosphere 8 -BINAPO(4.8mg,5.mol%),Ni(cod) 2 (2.75 mg,5 mol%), 1a (25.8 mg,0.2 mmol), toluene (0.5 mL), then 2g (82.4 mg,0.4 mmol) of triisobutylaluminum (1M, 80. Mu.L, 40 mol%) was added thereto, stirred at 80℃for 2 hours, cooled to room temperature, diluted with ethyl acetate, washed with 2mL of 5% aqueous disodium ethylenediamine tetraacetate, separated, and the organic phase was dried over anhydrous sodium sulfate, concentrated and then separated by column chromatography to obtain 3g of the objective product as a white solid in a yield of 81%. 1 H NMR(400MHz,CDCl 3 )δ7.09-6.95(m,6H),6.94-6.87(m,2H),4.92-4.76(m,1H),3.93-3.76(m,1H),3.11(dd,J=16.4,6.4Hz,1H),2.47(d,J=16.4,1H),2.26(s,6H),1.44(d,J=6.4,3H),1.26(d,J=6.4,6H). 13 C NMR(100MHz,CDCl 3 )δ163.9,142.2,137.7,137.3,136.2,133.6,132.1,130.9,128.8,128.4,128.3,45.3,45.0,38.3,21.4,213,21.3,20.6,20.3.HRMS(ESI)m/z:[M+H] + calcd.for C 23 H 28 NO 334.2165,found 334.2160.HPLC condition:Chiralpak IA column,n-hexane/i-PrOH=95∶5,1.0mL/min,254nm,t r-minor =10.4min,t r-major =16.4min,94%ee.111.7(c 1.0,CHCl 3 ).
Example 8: synthesis of (R) -1-isopopyyl-6-methyl-3, 4-di-m-tolyl-5, 6-dihydopyridin-2 (1H) -one
Ligand H is added into the reaction bottle in sequence in nitrogen atmosphere 8 -BINAPO(4.8mg,5mol%),Ni(cod) 2 (2.75 mg,5 mol%), 1a (25.8 mg,0.2 mmol), toluene (0.5 mL), then added 2h (82.4 mg,0.4 mmol), triisobutylaluminum (1M, 80. Mu.L, 40 mol%), stirred at 80℃for 2h, cooled to room temperature, diluted with ethyl acetate, washed with 2mL of 5% aqueous disodium ethylenediamine tetraacetate, separated, the organic phase dried over anhydrous sodium sulfate, concentrated and separated by column chromatography to give the target product 3h as a white solid with a yield of 62%. 1 H NMR(400MHz,CDCl 3 )δ7.07-6.99(m,2H),6.98-6.88(m,3H),6.87-6.81(m,2H),6.78(d,J=7.6Hz,1H),4.92-4.78(m,1H),3.87-3.78(m,1H),3.13(dd,J=16.4,6.0Hz,1H),2.48(d,J=16.4,1H),2.23(s,3H),2.20(s,3H),1.46(d,J=6.4Hz,3H),1.46(d,J=6.8Hz,6H). 13 C NMR(100MHz,CDCl 3 )δ163.8,142.6,140.5,137.5,136.9,136.4,132.7,131.6,128.9,128.2,128.1,127.8,127.5,127.4,125.5,45.3,45.0,38.3,21.5,21.4,21.4,20.6,20.4.HRMS(ESI)m/z:[M+H] + calcd.for C 23 H 28 NO 334.2165,found 334.2160.HPLC condition:Chiralpak IA column,n-hexane/i-PrOH=96∶4,1.0mL/min,254nm,t r-minor =9.7min,t r-major =11.4min,91%ee.90.6(c 1.0,CHCl 3 ).
Example 9: synthesis of (R) -1-isopopyyl-6-methyl-3, 4-di-o-tolyl-5, 6-dihydopyridin-2 (1H) -one
Ligand H is added into the reaction bottle in sequence in nitrogen atmosphere 8 -BINAPO(4.8mg,5mol%),Ni(cod) 2 (2.75 mg,5 mol%), 1a (25.8 mg,0.2 mmol), toluene (0.5 mL), then 2i (82.4 mg,0.4 mmol) and triisobutylaluminum (1M, 80. Mu.L, 40 mol%) were added thereto, stirred at 80℃for 2 hours, cooled to room temperature, diluted with ethyl acetate, washed with 2mL of 5% aqueous disodium ethylenediamine tetraacetate, separated, the organic phase was dried over anhydrous sodium sulfate, and the desired product was isolated by column chromatography as a white solid in 69% yield. 1 H NMR(400MHz,CDCl 3 )δ7.24-6.79(m,7H),6.77-6.62(m,1H),4.96-4.62(m,1H),3.99-3.77(m,1H),3.33-3.10(m,1H),2.53-2.11(m,6H),1.92(s,1H),1.53(s,3H),1.36-1.23(m,6H). 13 C NMR(100MHz,CDCl 3 )δ163.4,144.5,140.8,136.5,134.3,131.8,130.4,130.3,129.6,127.3,127.1,125.8,125.4,125.2,124.8,45.9,45.6,38.2,29.8,21.5,21.2,20.9,20.3.HRMS(ESI)m/z:[M+H] + calcd.for C 23 H 28 NO 334.2165,found 334.2159.HPLC condition:Chiralpak IA column,n-hexane/i-PrOH=95∶5,1.0mL/min,254nm,t r-minor =8.6min,t r-major =10.0min,90%ee.-165.6(c 1.0,CHCl 3 ).
Example 10: synthesis of (R, E) -N-Methyl-N- (6- (4-phenyl-3-en-2-yl) pyridin-3-yl) benzamide
Ligand H is added into the reaction bottle in sequence in nitrogen atmosphere 8 -BINAPO(4.8mg,5mol%),Ni(cod) 2 (2.75 mg,5 mol%), 1a (25.8 mg,0.2 mmol), toluene (0.5 mL), then 2j (116.1 mg,0.4 mmol) was added, triisobutylaluminum (1M, 80. Mu.L, 40 mol%), stirred at 80℃for 2 hours, cooled to room temperature, diluted with ethyl acetate, washed with 2mL of 5% aqueous disodium ethylenediamine tetraacetate, separated, the organic phase dried over anhydrous sodium sulfate, concentrated and separated by column chromatography to obtain the target product 3j as a white solid in 93% yield. 1 H NMR(400MHz,CDCl 3 )δ7.16(t,J=8.0Hz,4H),7.05(d,J=8.4Hz,2H),6.95(d,J=8.4Hz,2H),4.91-4.74(m,1H),3.91-3.78(m,1H),3.11(dd,J=16.8,6.0Hz,1H),2.52(d,J=16.4Hz,1H),1.45(d,J=6.4Hz,3H),1.30-1.18(m,24H). 13 C NMR(100MHz,CDCl 3 )δ164.0,150.5,149.3,142.1,137.6,133.6,132.2,130.7,128.3,124.8,124.5,45.3,45.1,38.2,34.6,34.5,31.4,31.3,21.4,20.6,20.4.HRMS(ESI)m/z:[M+H] + calcd.for C 29 H 40 NO 418.3104,found 418.3099.HPLC condition:Chiralpak IA column,n-hexane/i-PrOH=96∶4,1.0mL/min,254nm,t r-minor =8.3min,t r-major =11.4min,90%ee.99.2(c 1.0,CHCl 3 ).
Example 11: synthesis of (R, E) -N-methyl-N- (6- (4-phenyl-3-en-2-yl) pyridin-3-yl) pivalamide
Ligand H is added into the reaction bottle in sequence in nitrogen atmosphere 8 -BINAPO(4.8mg,5mol%),Ni(cod) 2 (2.75 mg,5 mol%), 1a (25.8 mg,0.2 mmol), toluene (0.5 mL), then 2k (95.2 mg,0.4 mmol) of triisobutylaluminum (1M, 80. Mu.L, 40 mol%) was added thereto, stirred at 80℃for 2 hours, cooled to room temperature, diluted with ethyl acetate, washed with 2mL of 5% aqueous disodium ethylenediamine tetraacetate, separated, and the organic phase was dried over anhydrous sodium sulfate, concentrated and then separated by column chromatography to obtain the objective product 3k as a white solid in 78% yield. 1 H NMR(400MHz,CDCl 3 )δ7.06(d,J=8.4Hz,2H),6.97(d,J=8.4Hz,2H),7.16(t,J=8.0Hz,4H),4.91-4.75(m,1H),3.91-3.79(m,1H),3.78-3.67(m,6H),3.09(dd,J=16.8,6.0Hz,1H),2.49(d,J=16.4Hz,1H),1.44(d,J=6.4Hz,3H),1.27(d,J=6.4Hz,6H). 13 C NMR(100MHz,CDCl 3 )δ164.1,158.8,158.4,141.7,132.9,132.3,131.3,129.9,129.1,113.5,113.2,55.3,45.3,45.0,38.3,21.4,20.6,20.3.HPLC condition:Chiralpak IA column,n-hexane/i-PrOH=80∶20,1.0mL/min,254nm,t r-minor =7.7min,t r-major =10.5min,92%ee.116.4(c 1.0,CHCl 3 ).
Example 12: synthesis of (R) -1-Isopropyl-6-methyl-3,4-bis (4- (trifluoromethyl) phenyl) -5, 6-dihydopyridin-2 (1H) -one
Ligand H is added into the reaction bottle in sequence in nitrogen atmosphere 8 -BINAPO(4.8mg,5mol%),Ni(cod) 2 (2.75 mg,5 mol%), 1a (25.8 mg,0.2 mmol), toluene (0.5 mL), then 2k (138.4 mg,0.4 mmol) of triisobutylaluminum (1M, 80. Mu.L, 40 mol%) was added thereto, stirred at 80℃for 2 hours, cooled to room temperature, diluted with ethyl acetate, added 2mL of 5% ethylenediamine tetraethyleneWashing the acid disodium salt aqueous solution, separating the solution, drying the organic phase by using anhydrous sodium sulfate, concentrating, and separating by column chromatography to obtain the target product 3l, white solid with the yield of 54%. 1 H NMR(400MHz,CDCl 3 )δ7.13(d,J=8.4Hz,2H),7.03(d,J=7.2Hz,6H),4.87-4.71(m,1H),3.97-3.82(m,1H),3.14(dd,J=16.8,6.0Hz,1H),2.49(d,J=16.8Hz,1H),1.46(d,J=6.4Hz,3H),1.28(d,J=6.8Hz,6H). 13 C NMR(100MHz,CDCl 3 )δ163.0,148.6(q,J=13.8Hz),148.3(q,J=12.0Hz),142.3,138.6,134.7,132.6,132.2,129.9,121.7(q,J=256.0Hz),120.7,120.2,119.2(q,J=256.0Hz),45.7,45.2,38.3,21.4,20.6,20.4.19F NMR(376MHz,CDCl 3 )δ-57.8,-57.9.HRMS(ESI)m/z:[M+H] + calcd.for C 23 H 22 F 6 NO 3 474.1498,found 474.1492.HPLC condition:Chiralpak IA column,n-hexane/i-PrOH=95∶5,1.0mL/min,254nm,t r-minor =8.6min,t r-major =13.2min,92%ee.91.1(c 1.0,CHCl 3 ).
Example 13: synthesis of (R) -3,4-Bis (4-Fluorophenyl) -1-isopropyl-6-methyl-5, 6-dihydroxymatridin-2 (1H) -one
Ligand H is added into the reaction bottle in sequence in nitrogen atmosphere 8 -BINAPO(4.8mg,5mol%),Ni(cod) 2 (2.75 mg,5 mol%), 1a (25.8 mg,0.2 mmol), toluene (0.5 mL), then 2m (85.6 mg,0.4 mmol) of triisobutylaluminum (1M, 80. Mu.L, 40 mol%) was added thereto, stirred at 80℃for 2 hours, cooled to room temperature, diluted with ethyl acetate, washed with 2mL of 5% aqueous disodium ethylenediamine tetraacetate, separated, and the organic phase was dried over anhydrous sodium sulfate, and concentrated, followed by column chromatography to obtain the objective product of 3m as a white solid in 63% yield. 1 H NMR(400MHz,CDCl 3 )δ7.08(d,J=8.4Hz,2H),6.97(d,J=7.2Hz,2H),6.87(t,J=7.8Hz,4H),4.90-4.73(m,1H),3.92-3.81(m,1H),3.12(dd,J=16.8,6.0Hz,1H),2.47(d,J=16.8Hz,1H),1.45(d,J=6.4Hz,3H),1.27(d,J=6.8Hz,6H). 13 C NMR(100MHz,CDCl 3 )δ163.4,163.2(d,J=9.6Hz),160.8(d,J=7.2Hz),142.2,136.2(d,J=3.2Hz),132.8(d,J=8.0Hz),132.1(d,J=3.2Hz),131.9,130.2(d,J=8.0Hz),115.3(d,J=21.4Hz),114.7(d,J=21.2Hz),45.6,45.1,38.4,21.4,20.6,20.4.19F NMR(376MHz,CDCl 3 )δ-113.4,-115.5.HRMS(ESI)m/z:[M+H] + calcd.for C 21 H 22 F 2 NO 342.1664,found 342.1660.HPLC condition:Chiralpak IA column,n-hexane/i-PrOH=95∶5,1.0mL/min,254nm,t r-minor =11.8min,t r-major =18.0min,95%ee.147.4(c 0.5,CHCl 3 ).
Example 14: synthesis of (R) -3,4-Bis (3-Fluorophenyl) -1-isopropyl-6-methyl-5, 6-dihydroxymatridin-2 (1H) -one
Ligand H is added into the reaction bottle in sequence in nitrogen atmosphere 8 -BINAPO(4.8mg,5mol%),Ni(cod) 2 (2.75 mg,5 mol%), 1a (25.8 mg,0.2 mmol), toluene (0.5 mL), then 2n (85.6 mg,0.4 mmol) of triisobutylaluminum (1M, 80. Mu.L, 40 mol%) was added thereto, stirred at 80℃for 2 hours, cooled to room temperature, diluted with ethyl acetate, washed with 2mL of 5% aqueous disodium ethylenediamine tetraacetate, separated, and the organic phase was dried over anhydrous sodium sulfate, concentrated and then separated by column chromatography to obtain the objective product 3n as a white solid in 53% yield. 1 H NMR(400MHz,CDCl 3 )δ7.18-7.08(m,2H),6.95-6.80(m,4H),6.77(d,J=7.8Hz,1H),6.77(d,J=8.4Hz,1H),4.88-4.71(m,1H),3.94-3.80(m,1H),3.13(dd,J=16.8,6.0Hz,1H),2.46(d,J=16.8Hz,1H),1.46(d,J=6.8Hz,3H),1.27(d,J=6.8Hz,6H). 13 C NMR(100MHz,CDCl 3 )δ163.6(d,J=19.4Hz),162.9,161.2(d,J=17.6Hz),142.3(d,J=1.6Hz),142.2(d,J=7.6Hz),138.1(d,J=8.2Hz),132.3(d,J=1.6Hz),129.8(d,J=8.2Hz),129.1(d,J=8.2Hz),126.8(d,J=2.8Hz),124.0(d,J=2.8Hz),118.0(d,J=21.6Hz),115.1(d,J=21.8Hz),114.8(d,J=21.0Hz),114.1(d,J=21.0Hz),45.6,45.1,38.2,21.3,20.5,20.4.HRMS(ESI)m/z:[M+H] + calcd.for C 21 H 22 F 2 NO 342.1664,found 342.1661. 19 F NMR(376MHz,CDCl 3 )δ-112.7,-114.3.HPLC condition:Chiralpak IA-3 column,n-hexane/i-PrOH=95∶5,1.0mL/min,254nm,t r-minor =10.9min,t r-major =12.7min,90%ee.94.6(c 1.0,CHCl 3 ).
Example 15: synthesis of (R) -3,4-Bis (2-Fluorophenyl) -1-isopropyl-6-methyl-5, 6-dihydroxymatridin-2 (1H) -one
Ligand H is added into the reaction bottle in sequence in nitrogen atmosphere 8 -BINAPO(4.8mg,5mol%),Ni(cod) 2 (2.75 mg,5 mol%), 1a (25.8 mg,0.2 nmol), toluene (0.5 mL), then 2o (85.6 mg,0.4 mmol), triisobutylaluminum (1M, 80. Mu.L, 40 mol%), stirring for 2 hours at 80 ℃, cooling to room temperature, diluting with ethyl acetate, adding 2mL of 5% aqueous solution of disodium ethylenediamine tetraacetate, washing, separating, drying the organic phase with anhydrous sodium sulfate, concentrating and separating the target product by column chromatography to obtain 3o as a white solid with a yield of 84%. 1 H NMR(400MHz,CDCl 3 )δ7.19-7.09(m,2H),7.08-7.02(m,1H),7.01-6.85(m,5H),4.88-4.75(m,1H),3.92-3.81(m,1H),3.18(dd,J=16.8,6.0Hz,1H),2.43(d,J=16.8Hz,1H),1.50(d,J=6.6Hz,3H),1.28(d,J=6.8Hz,6H). 13 C NMR(100MHz,CDCl 3 )δ162.3,161.6,160.7,159.1,158.2,141.0,132.8,129.7(d,J=7.9Hz),129.1(d,J=8.1Hz),127.7(d,J=15.2Hz),124.0(d,J=16.2Hz),123.8(d,J=3.2Hz),123.3(d,J=2.7Hz),115.7(d,J=21.5Hz),115.0(d,Jr=22.2Hz),45.6,45.5,37.7,21.3,20.6,20.0.HRMS(ESI)m/z:[M+H] + calcd.for C 21 H 22 F 2 NO 342.1664,found 342.1661. 19 F NMR(376MHz,CDCl 3 )δ-113.6,-114.1.HPLC condition:Chiralpak IA-3 column,n-hexane/i-PrOH=95∶5,1.0mL/min,254nm,t r-minor =12.0min,t r-major =14.1min,91%ee.25.2(c 1.0,CHCl 3 ).
Example 16: synthesis of (R, E) -N, N-Diisopropyl-6- (4-phenylbut-3-eh-2-yl) nicotonamide
Ligand H is added into the reaction bottle in sequence in nitrogen atmosphere 8 -BINAPO(4.8mg,5mol%),Ni(cod) 2 (2.75 mg,5 mol%), 1a (25.8 mg,0.2 mmol), toluene (0.5 mL), then 2p (113.7 mg,0.4 mmol), triisobutylaluminum (1M, 80. Mu.L, 40 mol%), stirring at 80℃for 2 hours, cooling to room temperature, diluting with ethyl acetate, adding 2mL of 5% aqueous solution of disodium ethylenediamine tetraacetate, washing, separating, drying the organic phase with anhydrous sodium sulfate, concentrating and separating the target product by column chromatography to obtain 3p as a white solid with a yield of 48%. 1 H NMR(400MHz,CDCl 3 )δ7.46(d,J=9.6Hz,2H),7.07(d,J=8.4Hz,1H),7.04-6.75(m,5H),6.34(d,J=16.8Hz,2H),4.96-4.76(m,1H),3.93-3.81(m,1H),3.66(d,J=11.6,6H),3.23(dd,J=16.8,6.0Hz,1H),2.62(d,J=16.4Hz,1H),1.51(d,J=6.4Hz,3H),1.28(d,J=6.4Hz,6H). 13 C NMR(100MHz,CDCl 3 )δ164.7,142.7,135.8,135.7,132.4,132.1,129.1,128.2,128.1,128.0,127.9,125.3,123.5,123.1,120.6,110.0,108.6,108.2,101.2,45.0,44.9,39.1,32.8,32.8,21.4,20.6,20.3.HRMS(ESI)m/z:[M+H] + calcd.for C 27 H 30 N 3 O 412.2383,found 412.2380.HPLC condition:Chiralpak IA column,n-hexane/i-PrOH=80∶20,1.0mL/min,254nm,t r-minor =16.1min,t r-major =18.2min,93%ee.52.8(c 1.0,CHCl 3 ).
Example 17: synthesis of (R) -1-Isopropyl-6-methyl-3,4-di (thiophen-3-yl) -5, 6-dihydopyridin-2 (1H) -one
Ligand H is added into the reaction bottle in sequence in nitrogen atmosphere 8 -BINAPO(4.8mg,5mol%),Ni(cod) 2 (2.75 mg,5 mol%), 1a (25.8 mg,0.2 mmol), toluene (0.5 mL), then 2q (76.0 mg,0.4 mmol) of triisobutylaluminum (1M, 80. Mu.L, 40 mol%) was added thereto, stirred at 80℃for 2 hours, cooled to room temperature, diluted with ethyl acetate, washed with 2mL of 5% aqueous disodium ethylenediamine tetraacetate, separated, and the organic phase was dried over anhydrous sodium sulfate, and concentrated, followed by column chromatography to obtain the objective product 3q as a yellow liquid in 40% yield. 1 H NMR(400MHz,CDCl 3 )δ7.27(dd,J=3.2,1.2Hz,1H),7.18(dd,J=4.8,3.2Hz,1H),7.12-7.06(m,2H),6.89(dd,J=5.2,1.2Hz,1H),6.59(dd,J=5.2,1.2Hz,1H),4.91-4.77(m,1H),3.89-3.80(m,1H),3.00(dd,J=17.2,6.0Hz,1H),2.61(d,J=17.2,1H),1.42(d,J=6.4Hz,3H),1.25(d,J=7.0Hz,6H). 13 C NMR(100MHz,CDCl 3 )δ163.5,140.8,137.2,136.3,130.1,128.0,126.7,125.2,125.0,124.1,123.5,45.3,44.9,37.9,21.3,20.6,20.4.HRMS(ESI)m/z:[M+H] + calcd.for C 17 H 20 NOS 2 318.0981,found 318.0978.HPLC condition:Chiralpak IA-3 column,n-hexane/i-PrOH=90∶10,1.0mL/min,254nm,t r-minor =10.0min,t r-major =14.9min,90%ee.194.6(c 1.0,CHCl 3 ).
Example 18: synthesis of (R) -4-Butyl-1-isopropyl-6-methyl-3-phenyl-5, 6-dihydroxyfridin-2 (1H) -one
Ligand H is added into the reaction bottle in sequence in nitrogen atmosphere 8 -BINAPO(4.8mg,5mol%),Ni(cod) 2 (2.75 mg,5 mol%), 1a (25.8 mg,0.2 mmol), toluene (0.5 mL), then 2r (63.2 mg,0.4 mmol) of triisobutylaluminum (1M, 80. Mu.L, 40 mol%) was added thereto, stirred at 80℃for 2 hours, cooled to room temperature, diluted with ethyl acetate, washed with 2mL of 5% aqueous disodium ethylenediamine tetraacetate, separated, and the organic phase was dried over anhydrous sodium sulfate, and concentrated, followed by column chromatography to obtain the objective product 3r as a white solid in 20% yield. 1 H NMR(400MHz,CDCl 3 )δ7.42-7.34(m,2H),7.33-7.26(m,1H),7.22-7.14(m,2H),4.91-4.76(m,1H),3.78-3.64(m,1H),2.92(dd,J=16.8Hz,6.0Hz 1H),2.58-2.46(m,1H),2.24(d,J=16.8Hz,1H),2.18-2.09(m,1H),1.45-1.29(m,5H),1.28-1.14(m,8H),0.78(t,J=7.2,3H). 13 C NMR(100MHz,CDCl 3 )δ164.2,141.2,140.8,132.4,128.5,127.5,127.4,44.9,44.6,38.7,31.8,27.3,22.9,21.4,20.6,20.3,14.0.HRMS(ESI)m/z:[M+H] + calcd.for C19H28NO 286.2165,found 286.2171.HPLC condition:Chiralpak IA column,n-hexane/i-PrOH=96∶4,1.0mL/min,254nm,t r-minor =7.6min,t r-major =10.3min,87%ee.113.2(c 0.5,CHCl 3 ).
Example 19: synthesis of (R) -3-Butyl-1-isopropyyl-6-methyl-4-phenyl-5, 6-dihydroxyfridin-2 (1H) -one
Ligand H is added into the reaction bottle in sequence in nitrogen atmosphere 8 -BINAPO(4.8mg,5mol%),Ni(cod) 2 (2.75 mg,5 mol%), 1a (25.8 mg,0.2 mmol), toluene (0.5 mL), then 2r (63.2 mg,0.4 mmol) of triisobutylaluminum (1M, 80. Mu.L, 40 mol%) was added thereto, stirred at 80℃for 2 hours, cooled to room temperature, diluted with ethyl acetate, washed with 2mL of 5% aqueous disodium ethylenediamine tetraacetate, separated, and the organic phase was dried over anhydrous sodium sulfate, concentrated and then separated by column chromatography to obtain the objective product 3r', as a white solid, yield 39%. 1 H NMR(400MHz,CDCl 3 )δ7.38-7.30(m,2H),7.29-7.24(m,1H),7.22-7.14(m,2H),4.84-4.69(m,1H),3.83-3.69(m,1H),2.72(dd,J=16.8Hz,6.0Hz 1H),2.13(d,J=16.8Hz,1H),2.03(t,J=7.8Hz,2H),1.45-1.30(m,5H),1.28-1.12(m,8H),0.78(t,J=7.2,3H). 13 C NMR(100MHz,CDCl 3 )δ163.5,145.1,136.6,131.9,130.1,127.7,126.8,45.0,44.7,35.6,34.2,29.4,22.6,21.3,20.6,20.3,13.9.HRMS(ESI)m/z:[M+H] + calcd.for C 19 H 28 NO 286.2165,found 286.2171.HPLC condition:Chiralpak IA column,n-hexane/i-PrOH=97∶3,1.0mL/min,254nm,t r-minor =12.9min,t r-major =13.8min,93%ee.82.7(c 1.0,CHCl 3 ).
Example 20: synthesis of (R) -3- (Tert-butyl) -1-isopropyl-4,6-dimethyl-5, 6-dihydromatridin-2 (1H) -one
Ligand H is added into the reaction bottle in sequence in nitrogen atmosphere 8 -BINAPO(4.8mg,5mol%),Ni(cod) 2 (2.75 mg,5 mol%), 1a (25.8 mg,0.2 mmol), toluene (0.5 mL), then 2s (63.2 mg,0.4 mmol) of triisobutylaluminum (1M, 80. Mu.L, 40 mol%) was added thereto, stirred at 80℃for 2 hours, cooled to room temperature, diluted with ethyl acetate, washed with 2mL of 5% aqueous disodium ethylenediamine tetraacetate, separated, and the organic phase was dried over anhydrous sodium sulfate, concentrated and then separated by column chromatography to obtain the objective product 3s as a colorless oil, yield 54%. 1 H NMR(400MHz,CDCl 3 )δ4.81-4.64(m,1H),3.64-3.50(m,1H),2.48-2.36(m,1H),2.16(d,J=17.0,1H),2.00(d,J=2.0,3H),1.17(s,9H),1.16-1.08(m,9H). 13 C NMR(100MHz,CDCl 3 )δ166.2,147.6,125.5,44.6,43.9,36.4,34.4,29.3,21.3,20.4,19.7,15.5.HRMS(ESI)m/z:[M+H] + calcd.for C 14 H 26 NO 224.2009,found 224.2011.HPLC condition:Chiralpak IA-3 column,n-hexane/i-PrOH=95∶5,1.0mL/min,254nm,t r-minor =7.3min,t r-major =8.1min,89%ee.132.4(c 0.25,CHCl 3 )./>
Example 21: synthesis of (R) -1- (tert-Butyl) -6-methyl-3,4-dipropyl-5, 6-dihydropyridine-2 (1H) -one
Ligand H is added into the reaction bottle in sequence in nitrogen atmosphere 8 -BINAPO(4.8mg,5mol%),Ni(cod) 2 (2.75 mg,5 mol%), 1a' (28.6 mg,0.2 mmol), toluene (0.5 mL), then 2a (44.1 mg,0.4 mmol), triisobutylaluminum (1M, 80. Mu.L, 40 mol%), stirring at 80℃for 2 hours, cooling to room temperature, diluting with ethyl acetate, washing with 2mL of 5% aqueous disodium ethylenediamine tetraacetate,separating the solution, drying the organic phase with anhydrous sodium sulfate, concentrating, and separating by column chromatography to obtain the target product 4a as colorless oily substance, wherein the yield is 46%. 1 H NMR(400MHz,CDCl 3 )δ3.96-3.84(m,1H),2.58(dd,J=16.8,6.0Hz,1H),2.50-2.41(m,1H),2.26-1.99(m,3H),1.89(d,J=16.8,1H),1.46(s,9H),1.45-1.35(m,4H),1.13(d,J=6.4Hz,3H),0.93(q,J=7.8Hz,6H). 13 C NMR(100MHz,CDCl 3 )δ165.7,141.4,131.4,56.7,46.9,36.2,35.8,29.4,28.6,23.3,20.7,19.9,14.5,14.4.HRMS(ESI)m/z:[M+H] + calcd.for C 16 H 30 NO 252.2322,found 252.2319.HPLC condition:Chiralpak AD-H column,n-hexane/i-PrOH=98∶2,1.0mL/min,254nm,,t r-minor =5.5min,t r-major =6.7min.90%ee.59.4(c 1.0,CHCl 3 ).
Example 22: synthesis of (6R) -1- ((1S, 2R, 5R) -Adamantan-2-yl) -6-methyl-3,4-dipropyl-5,6-djhydropyridin-2 (1H) -one
Ligand H is added into the reaction bottle in sequence in nitrogen atmosphere 8 -BINAPO(4.8mg,5mol%),Ni(cod) 2 (2.75 mg,5 mol%), 1b (44.2 mg,0.2 mmol), toluene (0.5 mL), then 2a (44.1 mg,0.4 mmol), triisobutylaluminum (1M, 80. Mu.L, 40 mol%), stirring at 80℃for 2 hours, cooling to room temperature, diluting with ethyl acetate, adding 2mL of 5% aqueous solution of disodium ethylenediamine tetraacetate, washing, separating, drying the organic phase with anhydrous sodium sulfate, concentrating and separating by column chromatography to obtain the target product 4b as a white solid with a yield of 65%. 1 H NMR(400MHz,CDCl 3 )δ3.65(s,1H),3.33(s,1H),2.45-2.23(m,2H),2.18-2.05(m,2H),2.04-1.93(m,3H),1.92-1.84(m,2H),1.82-1.64(m,5H),1.63-1.31(m,10H),1.26(d,J=6.4Hz,3H),0.95(t,J=7.8Hz,3H),0.90(d,J=7.8Hz,3H). 13 C NMR(100MHz,CDCl 3 )δ167.9,153.4,131.3,63.1,45.2,38.9,37.9,36.8,36.5,35.6,30.9,30.5,29.8,29.6,27.6,27.0,23.6,23.5,22.4,22.3,15.0,14.6.HRMS(ESI)m/z:[M+H] + calcd.for C 22 H 36 NO 330.2791,found 330.2787.HPLC condition:Chiralpak IA column,n-hexane/i-PrOH=98∶2,1.0mL/min,254nm,t r-major =5.8min,t r-minor =6.9min,82%ee.53.6(c 0.5,CHCl 3 ).
Example 23: synthesis of (R) -1- (4, 4-dimethylchlorohexyl) -6-methyl-3,4-dipropyl-5, 6-dihydroxyridin-2 (1H) -one
Ligand H is added into the reaction bottle in sequence in nitrogen atmosphere 8 -BINAPO(4.8mg,5mol%),Ni(cod) 2 (2.75 mg,5 mol%), 1c (39.4 mg,0.2 mmol), toluene (0.5 mL), then 2a (44.1 mg,0.4 mmol), triisobutylaluminum (1M, 80. Mu.L, 40 mol%), stirring at 80℃for 2 hours, cooling to room temperature, diluting with ethyl acetate, adding 2mL of 5% aqueous solution of disodium ethylenediamine tetraacetate, washing, separating, drying the organic phase with anhydrous sodium sulfate, concentrating and separating by column chromatography to obtain the target product 4c as a colorless liquid with a yield of 56%. 1 H NMR(400MHz,CDCl 3 )δ4.38-4.14(m,1H),3.73-3,50(m,1H),2.58-2.42(m,2H),2.22-2.04(m,3H),1.92(d,J=16.4Hz,1H),1.70-1.54(m,3H),1.51-1.27(m,9H),1.15(d,J=6.8Hz,3H),0.99-0.84(m,12H). 13 C NMR(100MHz,CDCl 3 )δ164.3,141.9,130.4,53.7,45.4,38.9,38.7,35.9,38.7,35.9,35.8,32.9,29.7,28.6,27.1,26.3,24.2,23.1,20.7,20.3.HRMS(ESI)m/z:[M+H] + calcd.for C 20 H 36 NO 306.2791,found 306.2788.HPLC condition:Chiralpak IA column,n-hexane/i-PrOH=98∶2,1.0mL/min,254nm,t r-minor =11.1min,t r-major =18.6min,92%ee.93.5(c 1.0,CHCl 3 ).
Example 24: synthesis of R) -1- (2, 2-Dimethyl-1, 3-dioxan-5-yl) -6-methyl-3,4-dipropyl-5, 6-dihydopyridin-2 (1H) -one
Ligand H is added into the reaction bottle in sequence in nitrogen atmosphere 8 -BINAPO(4.8mg,5mol%),Ni(cod) 2 (2.75 mg,5 mol%), 1d (40.2 mg,0.2 mmol), toluene (0.5 mL), then 2a (44.1 mg,0.4 mmol), triisobutylaluminum (1M, 80. Mu.L, 40 mol%), stirring at 80℃for 2 hours, cooling to room temperature, diluting with ethyl acetate, adding 2mL of 5% aqueous solution of disodium ethylenediamine tetraacetate, washing, separating, drying the organic phase with anhydrous sodium sulfate, concentrating and separating by column chromatography to obtain the target product 4d, colorless liquid, yield 75%. 1 H NMR(400MHz,CDCl 3 )δ4.31-4.16(m,2H),4.11-3.94(m,4H),2.69(dd,J=16.8,6.2Hz,1H),2.50-2.37(m,1H),2.26-2.07(m,3H),1.98(d,J=16.8Hz,1H),1.52-1.31(m,10H),1.25(d,J=6.4Hz,3H),0.94(dt,J=14.6,7.2Hz,6H). 13 C NMR(100MHz,CDCl 3 )δ165.2,143.6,129.7,98.1,62.6,61.7,49.8,49.3,36.0,35.6,28.5,24.8,23.2,23.2,20.7,19.4,19.4,14.3.HRMS(ESI)m/z:[M+Na] + calcd.for C 18 H 31 NNaO 3 332.2196,found 332.2189.HPLC condition:Chiralpak IA-3 column,n-hexane/i-PrOH=96∶4,1.0mL/min,254nm,t r-minor =8.9min,t r-major =12.6min,92%ee.75.7(c 1.0,CHCl 3 ).
Example 25: synthesis of (R) -6-Methyl-3,4-dipropyl-1- (2, 4, 6-trimethylrenzyl) -5, 6-dihydopyridin-2 (1H) -one
Ligand H is added into the reaction bottle in sequence in nitrogen atmosphere 8 -BINAPO(4.8mg,5mol%),Ni(cod) 2 (2.75 mg,5 mol%), 1e (43.9 mg,0.2 mmol), toluene (0.5 mL), then 2a (44.1 mg,0.4 mmol), triisobutylaluminum (1M, 80. Mu.L, 40 mol%), stirring at 80℃for 2 hours, cooling to room temperature, diluting with ethyl acetate, adding 2mL of 5% aqueous solution of disodium ethylenediamine tetraacetate, washing, separating, drying the organic phase with anhydrous sodium sulfate, concentrating and separating the target product by column chromatography to obtain 4e, colorless liquid, yield 46%. 1 H NMR(400MHz,CDCl 3 )δ6.85(s,2H),5.29(d,J=14.8Hz,1H),4.16(d,J=14.8Hz,1H),3.27-3.10(m,1H),2.56-2.39(m,2H),2.29(s,6H),2.26(s,3H),2.18-2.02(m,2H),1.79(d,J=16.8Hz,2H),1.50-1.35(m,4H),1.09(d,J=6.4Hz,3H),1.00-0.84(m,6H). 13 C NMR(100MHz,CDCl 3 )δ164.5,142.9,138.3,137.0,131.0,129.3,110.1,46.6,40.8,36.0,34.6,28.6,23.3,21.0,20.8,20.2,17.3,14.4,14.3.HRMS(ESI)m/z:[M+H] + calcd.for C 22 H 34 NO 328.2635,found 328.2630.HPLC condition:Chiralpak IA column,n-hexane/i-PrOH=98∶2,1.0mL/min,254nm,t r-minor =11.5min,t r-major =12.3min,74%ee.66.6(c 0.5,CHCl 3 ).
Example 26: synthesis of (R) -1-Benz-6-methyl-3, 4-dipropyl-5, 6-dihydopyridin-2 (1H) -one
In a nitrogen atmosphere, toLigand H is added into the reaction bottle in sequence 8 -BINAPO(4.8mg,5mol%),Ni(cod) 2 (2.75 mg,5 mol%), 1f (50.6 mg,0.2 mmol), toluene (0.5 mL), then 2a (44.1 mg,0.4 mmol), triisobutylaluminum (1M, 80. Mu.L, 40 mol%), stirring at 80℃for 2 hours, cooling to room temperature, diluting with ethyl acetate, adding 2mL of 5% aqueous solution of disodium ethylenediamine tetraacetate, washing, separating, drying the organic phase with anhydrous sodium sulfate, concentrating and separating by column chromatography to obtain the target product 4f, colorless liquid, yield 45%. 1 H NMR(400MHz,CDCl 3 )δ7.34-7.28(m,6H),7.27-7.20(m,3H),7.14(s,1H),3.71-3.55(m,1H),2.88(dd,J=16.8,6.0Hz,1H),2.62-2.48(m,1H),2.30-2.19(m,2H),2.19-2.09(m,1H),1.93(d,J=16.8Hz,1H),1.55-1.37(m,4H),1.02-0.88(m,6H),0.56(d,J=6.4Hz,3H). 13 C NMR(100MHz,CDCl 3 )δ164.9,143.3,140.5,140.0,130.7,130.3,128.5,128.4,127.8,127.7,126.9,60.8,46.9,36.1,35.7,28.7,23.2,20.8,18.9,14.5,14.4.HRMS(ESI)m/z:[M+H] + calcd.for C 15 H 32 NO 362.2478,found 362.2472.HPLC condition:Chiralpak IA column,n-hexane/i-PrOH=96∶4,1.0mL/min,254nm,t r-minor =15.4min,t r-major =20.1min,93%ee.-100.0(c 0.5,CHCl 3 ).
Example 27: synthesis of (R) -1- (1, 3-Diphenyl-2-yl) -6-methyl-3,4-dipropyl-5, 6-dihydopyridin-2 (1H) -one
Ligand H is added into the reaction bottle in sequence in nitrogen atmosphere 8 -BINAPO(4.8mg,5mol%),Ni(cod) 2 (2.75 mg,5 mol%), 1g (56.2 mg,0.2 mmol), toluene (0.5 mL), then 2a (44.1 mg,0.4 mmol) and triisobutylaluminum (1M, 80. Mu.L, 40 mol%) were added thereto, stirred at 80℃for 2 hours, cooled to room temperature, added withDiluting with ethyl acetate, adding 2mL of 5% ethylenediamine tetraacetic acid disodium salt aqueous solution for washing, separating liquid, drying an organic phase by using anhydrous sodium sulfate, concentrating, and separating by column chromatography to obtain a target product of 4g, colorless liquid, and the yield is 55%. 1 H NMR(400MHz,CDCl 3 )δ7.42-6.86(m,10H),3.36(s,2H),3.01(d,J=8.2Hz,1H),2.88-2.83(m,1H),2.80-2.55(m,1H),2.52-2.43(m,1H),2.18-2.02(m,1H),2.01-1.84(m,2H),1.99-1.34(m,5H),1.27-1.14(m,2H),0.87(t,J=7.8Hz,3H),0.78(t,J=7.2Hz,3H),0.42(s,3H). 13 C NMR(100MHz,CDCl 3 )δ165.3,142.2,140.1,130.2,129.6,129.4,128.4,128.3,126.3,126.2,39.3,38.7,35.7,34.4,30.4,28.3,23.1,20.5,18.2,14.4,14.1.HRMS(ESI)m/z:[M+H] + calcd.for C 27 H 36 NO 390.2791,found 390.2787.HPLC condition:Chiralpak IA column,n-hexane/i-PrOH=98∶2,1.0mL/min,254nm,t r-minor =12.4min,t r-major =13.5min,90%ee.38.6(c 1.0,CHCl 3 ).
Example 28: synthesis of (S) -6, 9a-Trimethyl-2,3-dipropyl-1,6,7,8, 9a-hexahydro-4H-quinolizin-4-one
Ligand H is added into the reaction bottle in sequence in nitrogen atmosphere 8 -BINAPO(4.8mg,5mol%),Ni(cod) 2 (2.75 mg,5 mol%), 1h (33.8 mg,0.2 mmol), toluene (0.5 mL), then 2a (44.1 mg,0.4 mmol), triisobutylaluminum (1M, 80. Mu.L, 40 mol%), stirring at 80℃for 2h, cooling to room temperature, diluting with ethyl acetate, adding 2mL of 5% aqueous solution of disodium ethylenediamine tetraacetate, washing, separating, drying the organic phase with anhydrous sodium sulfate, concentrating and separating by column chromatography to obtain the target product 4h, colorless liquid, yield 40%. 1 H NMR(400MHz,CDCl 3 )δ2.44-2.32(m,2H),2.22-2.00(m,3H),1.89(d,J=16.8,1H),1.78-1.59(m,3H),1.58(s,3H),1.57-1.46(m,3H),1.21(s,6H),1.27-1.15(m,4H),0.99-0.85(m,6H). 13 C NMR(100MHz,CDCl 3 )δ167.8,142.7,131.2,55.5,55.1,46.3,42.4,40.0,35.5,32.4,28.7,24.5,24.1,23.3,20.6,16.2,14.4,14.2.HRMS(ESI)m/z:[M+H] + calcd.for C 18 H 32 NO 278.2478,found 278.2473.HPLC condition:Chiralpak AD-H column,n-hexane/i-PrOH=98∶2,1.0mL/min,254nm,t r-major =5.7min,t r-minor =6.2min,74%ee.-54.4(c 0.5,CHCl 3 ).
Example 29: synthesis of (R) -9a-Methyl-7,8-dipropyl-3,4,9 a-tetrahydrochyrido [2,1-c ] [1,4] oxazin-6 (1H) -one
Ligand H is added into the reaction bottle in sequence in nitrogen atmosphere 8 -BINAPO(4.8mg,5mol%),Ni(cod) 2 (2.75 mg,5 mol%), 1i (28.6 mg,0.2 mmol), toluene (0.5 mL), then 2a (44.1 mg,0.4 mmol), triisobutylaluminum (1M, 80. Mu.L, 40 mol%), stirring at 80℃for 2 hours, cooling to room temperature, diluting with ethyl acetate, adding 2mL of 5% aqueous solution of disodium ethylenediamine tetraacetate, washing, separating, drying the organic phase with anhydrous sodium sulfate, concentrating and separating the target product by column chromatography to obtain 4i as a white solid with a yield of 42%. 1 H NMR(400MHz,CDCl 3 )δ4.10-3.99(m,2H),3.63(d,J=11.2Hz,1H),3.56-3.45(m,1H),3.29(d,J=11.2Hz,1H),3.03-2.91(m,1H),2.45-2.35(m,1H),2.34-2.19(m,3H),2.18-2.09(m,1H),1.91(d,J=16.8Hz,1H),1.55-1.35(m,4H),1.25(s,3H),0.94(dt,J=14.8,7.2Hz,6H). 13 C NMR(100MHz,CDCl 3 )δ165.8,143.6,129.1,67.4,53.7,37.1,37.4,36.0,28.6,23.3,20.8,18.9,14.4,14.3.HRMS(ESI)m/z:[M+H] + calcd.for C 15 H 26 NO 2 252.1958,found 252.1954.HPLC condition:Chiralpak IA column,n-hexane/i-PrOH=95∶5,1.0mL/min,254nm,t r-minor =9.2min,t r-major =11.9min,70%ee.62.7(c 0.5,CHCl 3 ).
Example 30: synthesis of (4 aR,8 aR) -1-Cyclohexyl-3,4-dipropyl-4a,5,6,7, 8a-hexahydroquinolin-2 (1H) -one
Ligand H is added into the reaction bottle in sequence in nitrogen atmosphere 8 -BINAPO(4.8mg,5mol%),Ni(cod) 2 (2.75 mg,5 mol%), 1j (41.8 mg,0.2 mmol), toluene (0.5 mL), then 2a (44.1 mg,0.4 mmol), triisobutylaluminum (1M, 80. Mu.L, 40 mol%), stirring at 80℃for 2 hours, cooling to room temperature, diluting with ethyl acetate, adding 2mL of 5% aqueous solution of disodium ethylenediamine tetraacetate, washing, separating, drying the organic phase with anhydrous sodium sulfate, concentrating and separating by column chromatography to obtain the target product 4j as colorless liquid with a yield of 90%. 1 H NMR(400MHz,CDCl 3 )δ4.31-4.26(m,1H),3.29-3.15(m,1H),2.71-2.55(m,2H),2.45-2.34(m,1H),2.04-2.34(m,1H),2.07-1.93(m,2H),1.83-1.69(m,3H),1.68-1.59(m,4H),1.56-1.30(m,10H),1.29-1.14(m,2H),1.13-1.00(m,2H),0.94-0.84(m,6H). 13 C NMR(100MHz,CDCl 3 )δ164.1,145.2,132.1,53.2,52.7,37.7,31.8,31.4,31.2,28.8,28.5,27.7,26.2,26.1,25.7,25.1,23.3,22.2,22.1,14.3.HRMS(ESI)m/z:[M+H] + calcd.for C 21 H 36 NO 318.2791,found 318.2798.HPLC condition:Chiralpak IA column,n-hexane/i-PrOH=98∶2,1.0mL/min,254nm,t r-major =8.7min,t r-minor =9.9min,85%ee.-71.3(c 1.0,CHCl 3 ).
Example 31: synthesis of (4 aR,9 aR) -1-cyclopeptyl-3, 4-dipropyl-5,6,7,8,9 a-hexahydro-1H-cyclopepta [ b ] pyridin-2 (4 aH) -one
Ligand H is added into the reaction bottle in sequence in nitrogen atmosphere 8 -BINAPO(4.8mg,5mol%),Ni(cod) 2 (2.75 mg,5 mol%), 1k (47.44 mg,0.2 mmol), toluene (0.5 mL), then 2a (44.1 mg,0.4 mmol), triisobutylaluminum (1M, 80. Mu.L, 40 mol%), stirring at 80℃for 2 hours, cooling to room temperature, diluting with ethyl acetate, adding 2mL of 5% aqueous solution of disodium ethylenediamine tetraacetate, washing, separating, drying the organic phase with anhydrous sodium sulfate, concentrating and separating by column chromatography to obtain the target product 4k, colorless liquid, yield 95%. 1 H NMR(400MHz,CDCl 3 )δ4.35-4.19(m,1H),3.46-3.26(m,1H),2.74(q,J=6.8Hz,1H),2.60-2.47(m,1H),2.36-2.23(m,1H),2.19-2.09(m,1H),2.08-1.98(m,1H),1.97-1.91(m,1H),1.90-1.80(m,2H),1.78-1.54(m,11H),1.53-1.18(m,12H),0.89(q,J=7.2Hz,6H). 13 C NMR(100MHz,CDCl 3 )δ164.0,146.6,130.9,57.0,56.8,40.5,34.6,32.9,31.7,30.1,29.5,28.7,28.4,27.7,27.3,26.2,25.6,25.5,23.6,23.3,22.6,14.4,14.3.HRMS(ESI)m/z:[M+H] + calcd.for C 23 H 40 NO 2 346.3104,found 346.3101.HPLC condition:Chiralpak IA column,n-hexane/i-PrOH=98∶2,1.0mL/min,254nm,t r-major =8.7min,t r-minor =9.9min,85%ee.-50.4(c 1.0,CHCl 3 )。/>
Claims (8)
1. A novel dinitrogen phosphorus oxygen precursor is prepared by nucleophilic substitution reaction of binaphthyl amine and acyl chloride. The method is characterized by comprising the following specific steps:
2. r in the present invention may be Ph, t bu and the like, but are not limited to these groups.
3. The invention also provides application of the binaphthyl amine phosphorus oxide ligand to realize nickel catalysis of C (sp 3 ) -an asymmetric activation method of H bonds, characterized in that it comprises the specific steps of:
in nitrogen atmosphere, adding a ligand, a metal catalyst, raw materials and a solvent into a reaction bottle in sequence, then adding Lewis acid, stirring for 2 hours at a specified temperature, cooling to room temperature, adding ethyl acetate for dilution, adding 2mL of 5% ethylenediamine tetraacetic acid disodium salt aqueous solution for washing, separating liquid, drying an organic phase with anhydrous sodium sulfate, and separating by column chromatography to obtain a target product.
4. The metal catalyst of the invention is Ni (cod) 2 The catalyst is generally used in an amount of 5mol%.
5. The ligand involved in the invention is chiral bi-N framework secondary phosphine oxide, and the dosage of the ligand is generally 5mol percent.
6. Al according to the present invention t Bu 3 The amount of the n-hexane solution having a concentration of 1mol/L is generally 40mol%.
7. The solvent used in the present invention was toluene solution in an amount of 2.5mL per millimole of 1 starting material.
8. R in the raw material 1 used in the present invention 2 Methyl, cyclohexyl, cycloheptyl; r is R 2 Is hydrogen, cyclohexyl, cycloheptyl; r is R 3 Substituents such as isopropyl, cyclohexyl and alkoxy, but not limited to these groups; r is a substituent group such as ethyl, phenyl, thiophene, etc., but is not limited to these groups.
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