CN114426560A - Chiral diphosphine ligand and rhodium complex thereof, and preparation method and application thereof - Google Patents
Chiral diphosphine ligand and rhodium complex thereof, and preparation method and application thereof Download PDFInfo
- Publication number
- CN114426560A CN114426560A CN202210080600.8A CN202210080600A CN114426560A CN 114426560 A CN114426560 A CN 114426560A CN 202210080600 A CN202210080600 A CN 202210080600A CN 114426560 A CN114426560 A CN 114426560A
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- China
- Prior art keywords
- chiral
- diphosphine ligand
- chiral diphosphine
- ion
- rhodium complex
- Prior art date
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- VURFVHCLMJOLKN-UHFFFAOYSA-N diphosphane Chemical compound PP VURFVHCLMJOLKN-UHFFFAOYSA-N 0.000 title claims abstract description 104
- 239000003446 ligand Substances 0.000 title claims abstract description 66
- 239000010948 rhodium Substances 0.000 title claims abstract description 40
- 229910052703 rhodium Inorganic materials 0.000 title claims abstract description 34
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 56
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 24
- 150000003283 rhodium Chemical class 0.000 claims abstract description 7
- 238000006138 lithiation reaction Methods 0.000 claims abstract description 6
- -1 3, 5-dimethylphenyl Chemical group 0.000 claims description 48
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 35
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 29
- 239000002904 solvent Substances 0.000 claims description 25
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 23
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 22
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- 125000000217 alkyl group Chemical group 0.000 claims description 15
- 125000004432 carbon atom Chemical group C* 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 11
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 8
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 7
- 125000003118 aryl group Chemical group 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- 239000004912 1,5-cyclooctadiene Substances 0.000 claims description 6
- XYFCBTPGUUZFHI-UHFFFAOYSA-N phosphine group Chemical group P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 6
- 150000001450 anions Chemical class 0.000 claims description 5
- 125000003107 substituted aryl group Chemical group 0.000 claims description 5
- RQEUFEKYXDPUSK-ZETCQYMHSA-N (1S)-1-phenylethanamine Chemical compound C[C@H](N)C1=CC=CC=C1 RQEUFEKYXDPUSK-ZETCQYMHSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 4
- 239000005051 trimethylchlorosilane Substances 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- VYXHVRARDIDEHS-UHFFFAOYSA-N 1,5-cyclooctadiene Chemical group C1CC=CCCC=C1 VYXHVRARDIDEHS-UHFFFAOYSA-N 0.000 claims description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 3
- AFJXJDKUWZPRQX-UHFFFAOYSA-N [3,5-bis(trifluoromethyl)phenyl]boron Chemical compound [B]C1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 AFJXJDKUWZPRQX-UHFFFAOYSA-N 0.000 claims description 3
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 3
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical class ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 3
- 125000000467 secondary amino group Chemical class [H]N([*:1])[*:2] 0.000 claims description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 3
- 239000012279 sodium borohydride Substances 0.000 claims description 3
- 239000008096 xylene Substances 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 2
- 125000000129 anionic group Chemical group 0.000 claims description 2
- XGRJZXREYAXTGV-UHFFFAOYSA-N chlorodiphenylphosphine Chemical compound C=1C=CC=CC=1P(Cl)C1=CC=CC=C1 XGRJZXREYAXTGV-UHFFFAOYSA-N 0.000 claims description 2
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims description 2
- 238000006268 reductive amination reaction Methods 0.000 claims description 2
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 claims description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims 1
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 abstract description 17
- 239000002253 acid Substances 0.000 abstract description 11
- 150000002148 esters Chemical class 0.000 abstract description 11
- 238000006467 substitution reaction Methods 0.000 abstract description 5
- 150000001576 beta-amino acids Chemical class 0.000 abstract description 4
- 150000001412 amines Chemical class 0.000 abstract description 3
- 230000003197 catalytic effect Effects 0.000 abstract description 3
- RQEUFEKYXDPUSK-UHFFFAOYSA-N 1-phenylethylamine Chemical compound CC(N)C1=CC=CC=C1 RQEUFEKYXDPUSK-UHFFFAOYSA-N 0.000 abstract description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 2
- 238000010189 synthetic method Methods 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 102
- 238000005481 NMR spectroscopy Methods 0.000 description 51
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 34
- 239000003054 catalyst Substances 0.000 description 31
- 238000005984 hydrogenation reaction Methods 0.000 description 21
- 239000001257 hydrogen Substances 0.000 description 16
- 229910052739 hydrogen Inorganic materials 0.000 description 16
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 16
- 238000003756 stirring Methods 0.000 description 16
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 238000004128 high performance liquid chromatography Methods 0.000 description 12
- 238000007789 sealing Methods 0.000 description 11
- 239000003480 eluent Substances 0.000 description 10
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- 239000012043 crude product Substances 0.000 description 9
- 230000008018 melting Effects 0.000 description 9
- 238000002844 melting Methods 0.000 description 9
- ZFDIRQKJPRINOQ-UHFFFAOYSA-N transbutenic acid ethyl ester Natural products CCOC(=O)C=CC ZFDIRQKJPRINOQ-UHFFFAOYSA-N 0.000 description 9
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical group [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- 101000652482 Homo sapiens TBC1 domain family member 8 Proteins 0.000 description 8
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 8
- 102100030302 TBC1 domain family member 8 Human genes 0.000 description 8
- 125000001072 heteroaryl group Chemical group 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 238000002390 rotary evaporation Methods 0.000 description 8
- 239000000741 silica gel Substances 0.000 description 8
- 229910002027 silica gel Inorganic materials 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 239000000758 substrate Substances 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- 238000000354 decomposition reaction Methods 0.000 description 6
- FJBFPHVGVWTDIP-UHFFFAOYSA-N dibromomethane Chemical compound BrCBr FJBFPHVGVWTDIP-UHFFFAOYSA-N 0.000 description 6
- 230000005311 nuclear magnetism Effects 0.000 description 6
- 238000011002 quantification Methods 0.000 description 6
- 238000004809 thin layer chromatography Methods 0.000 description 6
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 229910052786 argon Inorganic materials 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- 150000002500 ions Chemical class 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 150000002431 hydrogen Chemical class 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- GZNDMPGAAUXELR-UHFFFAOYSA-N [Cl-].CC=1C=C(C=C(C=1)C)[PH2+]C1=CC(=CC(=C1)C)C Chemical class [Cl-].CC=1C=C(C=C(C=1)C)[PH2+]C1=CC(=CC(=C1)C)C GZNDMPGAAUXELR-UHFFFAOYSA-N 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000012300 argon atmosphere Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 238000007872 degassing Methods 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 229910017744 AgPF6 Inorganic materials 0.000 description 1
- 241001026602 Quintana Species 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- GAERDAQCQVVXLC-UHFFFAOYSA-N [Cl-].C(C)(C)(C)C=1C=C(C=C(C1)C(C)(C)C)[PH2+]C1=CC(=CC(=C1)C(C)(C)C)C(C)(C)C Chemical compound [Cl-].C(C)(C)(C)C=1C=C(C=C(C1)C(C)(C)C)[PH2+]C1=CC(=CC(=C1)C(C)(C)C)C(C)(C)C GAERDAQCQVVXLC-UHFFFAOYSA-N 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 239000002259 anti human immunodeficiency virus agent Substances 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- MANCOSWQQLOKBP-UHFFFAOYSA-N bis(4-methoxyphenyl)phosphanium;chloride Chemical compound Cl.C1=CC(OC)=CC=C1PC1=CC=C(OC)C=C1 MANCOSWQQLOKBP-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- FCEBDAANWYNQMO-UHFFFAOYSA-N chloro-bis(3,5-dimethylphenyl)phosphane Chemical compound CC1=CC(C)=CC(P(Cl)C=2C=C(C)C=C(C)C=2)=C1 FCEBDAANWYNQMO-UHFFFAOYSA-N 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- 238000010668 complexation reaction Methods 0.000 description 1
- 150000004696 coordination complex Chemical class 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 description 1
- RHWKPHLQXYSBKR-BMIGLBTASA-N dolutegravir Chemical compound C([C@@H]1OCC[C@H](N1C(=O)C1=C(O)C2=O)C)N1C=C2C(=O)NCC1=CC=C(F)C=C1F RHWKPHLQXYSBKR-BMIGLBTASA-N 0.000 description 1
- 229960002542 dolutegravir Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- RNBWGWPKGHGLOY-WAYWQWQTSA-N ethyl (z)-3-acetamidobut-2-enoate Chemical compound CCOC(=O)\C=C(\C)NC(C)=O RNBWGWPKGHGLOY-WAYWQWQTSA-N 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000004896 high resolution mass spectrometry Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 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 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- QRUBYZBWAOOHSV-UHFFFAOYSA-M silver trifluoromethanesulfonate Chemical compound [Ag+].[O-]S(=O)(=O)C(F)(F)F QRUBYZBWAOOHSV-UHFFFAOYSA-M 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 238000005303 weighing Methods 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/50—Organo-phosphines
- C07F9/5022—Aromatic phosphines (P-C aromatic linkage)
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
- B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
- B01J31/2409—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring with more than one complexing phosphine-P atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- 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
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0073—Rhodium compounds
-
- 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
- B01J2231/645—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes of C=C or C-C triple bonds
-
- 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
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/80—Complexes comprising metals of Group VIII as the central metal
- B01J2531/82—Metals of the platinum group
- B01J2531/822—Rhodium
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a chiral diphosphine ligand, a rhodium complex thereof, a preparation method and application thereof. Specifically, starting from optically pure 1-phenylethylamine, carrying out lithiation, substitution and other reactions, and respectively introducing two aryl phosphine substituents at ortho positions of amino and phenyl to prepare a chiral diphosphine ligand; the chiral diphosphine ligand is complexed with rhodium salt to generate a corresponding rhodium complex. The rhodium complex of the chiral diphosphine ligand developed by the invention can catalyze the asymmetric hydrogenation reaction of beta-dehydroamino acid ester, shows excellent catalytic activity and high enantioselectivity, provides a synthetic method suitable for industrialization for optically active beta-amino acid and derivatives thereof, and has good application prospect.
Description
Technical Field
The invention relates to a chiral diphosphine ligand and a rhodium complex thereof, a preparation method of the chiral diphosphine ligand and the rhodium complex thereof and application of the rhodium complex as a catalyst in an asymmetric catalytic hydrogenation reaction of beta-dehydroamino acid ester.
Background
Chiral beta-amino acid and derivatives thereof are important molecules, and fragments thereof exist in a plurality of drug molecules (such as anti-HIV drugs, dolutegravir and hypoglycemic drugs, namely, imilaride) [ (1) Juaristi, E.; quintana, d.; escalante, j.aldrich Acta 1994,27,3.(2) Nicolaou, k.c.; dai, w.m.; guy, r.k.angelw.chem.int.ed.engl.1994, 33,15.(3) Hughes, d.l.org.processres.dev.2019,23,716 ]. Thus, efficient asymmetric synthesis of chiral β -amino acids and their derivatives has received widespread attention [ cardiolo, g.; tomasini, c.chem.soc.rev.1996,25,117 ].
The asymmetric catalytic hydrogenation of the beta-dehydro amino acid ester has the advantages of easily obtained raw materials, simple operation, high atom utilization rate, clean process and the like, and is an effective method for preparing the optically active beta-amino acid ester derivative. The development of a chiral catalyst with high efficiency and high selectivity is the key of the practical application of the reaction.
Over the last forty years, the research on asymmetric catalytic hydrogenation of beta-dehydroamino acid ester has made great progress, people developed various metal complex catalysts modified by monophosphine ligands or diphosphine ligands for the reaction, and some of the catalysts have made very high enantioselectivity, but the reported catalyst efficiency is usually not high (the catalyst dosage is usually 1 mol%), and the problems of complex ligand structure, difficult synthesis, poor stability, use of solvents unsuitable for industrial production and the like exist, so that the industrial application of the catalysts is limited to [ (1) Tang, w.; zhang, x.chem.rev.2003,103,3029.(2) Xie, j. -h.zhu, s. -f.; zhou, q. — l.chem.rev.2011,111,1713.ager, d.j.; de Vries.A.H.M.; de vries.j.g.chem.soc.rev.2012,41,3340 ].
Disclosure of Invention
The rhodium complex catalyst of the invention shows excellent catalytic activity and high enantioselectivity, provides a synthetic method suitable for industrialization for optically active beta-amino acid and derivatives thereof, and has good application prospect.
Specifically, the invention provides a chiral diphosphine ligand shown in the following general formula I, which is prepared by starting from optically pure 1-phenylethylamine, and respectively introducing two aryl phosphine substituent groups at ortho positions of amino and phenyl of the chiral diphosphine ligand through lithiation, substitution and other reactions; further, the chiral diphosphine ligand is complexed with rhodium salt to generate a corresponding rhodium complex. The rhodium complex can be used as a catalyst for asymmetric hydrogenation of beta-dehydroamino acid ester.
The novel chiral diphosphine ligand has the following structural formula I:
wherein: r1Is an alkyl group; r2Is aryl or substituted aryl.
The alkyl group as mentioned above means a straight chain or branched alkyl group having 1 to 24 carbon atoms. For example: methyl, ethyl, benzyl, cyclohexyl, n-butyl, n-tridecyl, adamantyl, and the like. The alkyl group is preferably a linear or branched alkyl group having 1 to 13 carbon atoms, particularly preferably a linear or branched alkyl group having 1 to 7 carbon atoms, and most preferably a methyl group, an ethyl group or a benzyl group.
The aryl or substituted aryl as mentioned above means an aryl or substituted aryl having 1 to 24 carbon atoms. For example: phenyl, naphthyl, 4-methoxyphenyl, 3, 5-dimethylphenyl, 4-methylphenyl, 3, 5-di-tert-butylphenyl, 2-methylphenyl, 4-tert-butylphenyl and the like. Phenyl or substituted phenyl having 1 to 24 carbon atoms is preferable, substituted phenyl having 8 to 24 carbon atoms is particularly preferable, and 4-methoxyphenyl, 3, 5-dimethylphenyl, 3, 5-di-tert-butylphenyl are most preferable.
Preferably, R1Is methyl, ethyl, benzyl, R2Is 4-methoxyphenyl, 3, 5-dimethylphenyl or 3, 5-di-tert-butylphenyl.
The preferred chiral bisphosphine ligands I of the present invention have the following structure.
The invention also provides a preparation method of the chiral diphosphine ligand I, which comprises the following steps:
(1) in a first solvent, at the temperature of minus 35 ℃, ortho-lithiation reaction is carried out on (S) -1-phenylethylamine, n-butyllithium and trimethylchlorosilane, and then the ortho-lithiation reaction is carried out on the ortho-lithiation reaction and disubstituted phosphorus chloride to prepare an ortho-phosphine substituted intermediate II, wherein the reaction formula is as follows:
wherein the first solvent in the step (1) is one or a mixture of more than two of diethyl ether, tetrahydrofuran, methyl tert-butyl ether and toluene.
The molar ratio of (S) -1-phenylethylamine, n-butyl lithium, trimethylchlorosilane to disubstituted phosphorus chloride is 1: 2-8: 1-3: 1 to 4.
(2) In a second solvent, at the temperature of 0-60 ℃, the ortho phosphine substituted intermediate II, aldehyde and sodium borohydride are subjected to reductive amination reaction to prepare a secondary amine intermediate III, wherein the reaction formula is as follows:
wherein the second solvent in the step (2) is one or a mixture of more than two of methanol, ethanol, toluene, tetrahydrofuran and dichloromethane.
R in the reaction formula of step (2)3Is a ratio R1An alkane having one less carbon atom.
(3) In a solvent, triethylamine is used as alkali at 0-120 ℃, and a secondary amine intermediate III is reacted with diphenyl phosphorus chloride to prepare a chiral diphosphine ligand I, wherein the reaction formula is as follows:
wherein R is1-R2As defined above.
Wherein the third solvent in the step (3) is one or a mixture of more than two of dichloromethane, toluene and tetrahydrofuran.
The invention also provides a chiral diphosphine ligand rhodium complex IV which has the following structural formula:
wherein R is1-R2As defined above.
X-Comprises the following steps: chloride ion, tetrafluoroborate ion, hexafluorophosphate ion, hexafluoroantimonate ion, trifluoromethanesulfonate ion, tetrakis (3, 5-bistrifluoromethylphenyl) boron anion.
The chiral diphosphine ligand rhodium complex IV can be prepared by the following two methods
Such as X-The complex is chloride ion, tetrafluoroborate ion, hexafluorophosphate ion, hexafluoroantimonate ion or trifluoromethanesulfonate ion, and is prepared by complexing chiral diphosphine ligand with rhodium salt and silver salt of corresponding anion for 2-4 hours in a solvent at 20-30 ℃ to obtain chiral diphosphine ligand rhodium complex containing different anions, wherein the reaction formula is as follows:
such as X-Is tetra (3, 5-ditrifluoromethylphenyl) boron anion, and is prepared by chiral diphosphine ligand, corresponding rhodium salt and NaBAr in solvent at 20-30 deg.CFComplexing for 2-4 hours to obtain the product containing BArF-an anionic chiral diphosphine ligand rhodium complex of the formula:
wherein:
R1-R2as defined above
Y is 1, 5-cyclooctadiene.
The solvents described in both processes are: one or more of dichloromethane, benzene, toluene, xylene, diethyl ether, tetrahydrofuran, 1, 4-dioxane, methanol, ethanol and isopropanol.
The invention also provides an application of the chiral diphosphine ligand rhodium complex IV as a catalyst for asymmetric catalytic hydrogenation of beta-dehydroamino acid ester. The reaction equation is as follows:
wherein:
Rxis alkyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl;
Ryis alkyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl;
Rzis alkyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl;
the double bond in the raw material is Z-configuration, E-configuration or the mixture of the two.
R is as described abovex,Ry,RzThe alkyl group has 1 to 24 carbon atoms, phenyl group, substituted phenyl group, heteroaryl group, and substituted heteroaryl group. For example: methyl, ethyl, cyclohexyl, n-butyl, phenyl, 4-methylphenyl, pyridyl, 4-methylpyridyl, and the like. Preferably an alkyl or aryl group having 1 to 13 carbon atoms, particularly preferably an alkyl group having 1 to 7 carbon atoms, most preferably, RxIs methyl, RyIs methyl or ethyl or isopropyl or phenyl, RzIs ethyl.
The application of the chiral diphosphine ligand rhodium complex IV comprises the steps of sequentially adding reactants, a catalyst and a degassing solvent into a hydrogenation inner tube under the argon atmosphere, and then stirring at room temperature under the hydrogen atmosphere until the reaction is finished.
The application of the chiral diphosphine ligand rhodium complex IV comprises the following reaction conditions of asymmetric catalytic hydrogenation: the solvent is one or more organic solvents selected from benzene, toluene, xylene, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 1, 4-dioxane, methanol, ethanol, isopropanol, and tert-butanol; the dosage of the catalyst is 0.01-10 mol%; the hydrogen pressure is 1atm-100 atm; the concentration of the substrate is 0.001-10.0M; the reaction temperature is 0-100 ℃; the reaction is carried out for 1 to 72 hours.
The preferred amount of catalyst is 0.1 to 1 mol%, more preferably 1 mol%.
The preferred hydrogen pressure is 10atm to 60atm, and the more preferred hydrogen pressure is 30 atm.
The preferred substrate concentration is 0.01-1.0M, and the more preferred substrate concentration is 0.1M.
The preferred reaction temperature is 20-100 deg.C, more preferably 25 deg.C.
The preferred reaction time is 12 to 48 hours, and more preferably 12 hours.
The invention has the advantages and beneficial effects that:
the chiral diphosphine ligand provided by the invention has the advantages of simple preparation process and cheap and easily-obtained raw materials; the chiral diphosphine ligand and rhodium salt are complexed to prepare a corresponding chiral diphosphine ligand rhodium complex which is used as a catalyst, and has a definite structure and high stability. The asymmetric hydrogenation of various beta-dehydroamino acid esters is realized, the conversion number can reach 1900 (the ratio of the amounts of the target product and the catalyst) and the enantioselectivity is 91% ee. The novel chiral diphosphine ligand rhodium complex catalyst provided by the invention is one of the most efficient rhodium catalysts for asymmetric hydrogenation of beta-dehydroamino acid ester, and has a good application prospect.
Detailed Description
The present invention will be further understood by the following examples, which should not be construed as limiting the scope of the above-described subject matter of the present invention to the following examples, and all the technologies achieved based on the above-described contents of the present invention are within the scope of the present invention.
General description:
abbreviations are used in the following examples and have the following meanings:
me is a methyl group, Et is an ethyl group,ipr is an isopropyl group, and the compound is,tbu isTert-butyl, Ph is phenyl, Bn is benzyl, COD is 1, 5-cyclooctadiene, OTf is trifluoromethanesulfonate, MeOH is methanol, EtOH is ethanol, THF is tetrahydrofuran, DCM is dichloromethane, PE is petroleum ether, EA is ethyl acetate, tolumene is toluene, MTBE is methyl tert-butyl ether, Ar is argon, rt refers to room temperature.
eq is equivalent, S/C is the ratio of the amount of substrate to the amount of catalyst material, TLC is thin layer chromatography, NMR is nuclear magnetic resonance, HRMS is high resolution mass spectrometry.
Purifying the used solvent by standard operation before use, degassing and drying; all reagents are commercially available or synthesized according to the existing literature method and purified before use.
Example 1: preparation of intermediate (S) -1- (2-diarylphosphine) phenylethylamine IIa-IIc
(S) -1- (2-bis (3, 5-dimethylphenyl) phosphine) phenylethylamine (IIa)
A250 mL three-necked flask was placed under argon, after which extra dry ether (50mL) and (S) -1-phenylethylamine (3.82mL,30mmol) were added, the system was stirred well and placed under-35 ℃ pre-cooling. N-butyllithium (12mL,30mmol,2.5M in THF) was added dropwise to the system with stirring. After the dropwise addition, the mixture was stirred at-35 ℃ for 30 min. Then trimethylchlorosilane (4.26mL,30mmol, after dropwise addition, was stirred at-35 ℃ for 1.5h, then n-butyllithium (36mL,90mmol,2.5M in THF) was added dropwise to the system at-35 ℃ under stirring, after dropwise addition was complete, the temperature was raised to room temperature within 2h, stirring was continued overnight, then an ether solution of bis (3, 5-dimethylphenyl) phosphorus chloride (12.45g,45mmol in 30mL Et at-35 ℃ C. under stirring was slowly added dropwise to the reaction system at-35 ℃ C2O), stirring for 4h at-35 ℃ after the dropwise addition. The system was then warmed to room temperature and reacted for 8 h. The reaction was monitored by TLC, and after completion of the reaction, 1M hydrochloric acid was added dropwise to the system at 0 ℃ with stirring until two phases were clarified, the mixture was separated by a separatory funnel, the aqueous phase was extracted with MTBE (100 mL. times.3), the organic phases were combined, and the organic phase was washed with a saturated saline solution, after whichDried over anhydrous magnesium sulfate. Filtration and concentration of the filtrate by rotary evaporation gave a crude product which was separated by column chromatography on silica gel (eluent dichloromethane/methanol 20:1, v/v). 3.35g of the compound IIa is finally obtained as a yellow solid, the total yield of the three-step reaction is 31 percent and alpha]D 26＝41.7(c 0.50,CHCl3) The melting point is 92-95 ℃.
1 H NMR(400MHz,CDCl3)δ7.63(ddd,J＝7.8,4.2,1.3Hz,1H),7.40(td,J＝7.5,1.4Hz,1H),7.18(td,J＝7.5,1.4Hz,1H),7.02–6.85(m,7H),4.60(p,J＝6.6Hz,1H),2.27(d,J＝2.2Hz,12H),2.21(s,2H),1.31(d,J＝6.5Hz,3H).
13 C NMR(101MHz,CDCl3)δ151.32,151.10,146.26,145.95,135.29,133.65,132.61,132.52,130.12,128.35,128.21,127.75,126.18,125.35,58.62,26.52,23.21.
31 P NMR(162MHz,CDCl3)δ-16.37.
HRMS(ESI)calcd for[M+H,C24H29NP]+:362.20376,found:362.20363.
The following compounds (IIb-IIc) were synthesized in the same manner as in example 1, except that: (IIb) is a substitution of bis (3, 5-dimethylphenyl) phosphonium chloride for bis (4-methoxyphenyl) phosphonium chloride, and (IIc) is a substitution of bis (3, 5-dimethylphenyl) phosphonium chloride for bis (3, 5-di-tert-butylphenyl) phosphonium chloride.
The structural formula of (S) -1- (2-bis (4-methoxyphenyl) phosphine) phenylethylamine (IIb) is as follows:
yellow powder, yield 30%, [ alpha ]]D 26＝65.2(c 0.50,CHCl3) Melting point 89-91 ℃.
1 H NMR(400MHz,CDCl3)δ7.56(ddd,J＝7.8,4.2,1.4Hz,1H),7.37–7.32(m,2H),7.23(dt,J＝7.3,1.6Hz,3H),7.15(td,J＝7.5,1.4Hz,1H),6.94–6.86(m,5H),4.50(p,J＝6.6Hz,1H),3.82(s,6H),2.16(s,2H),1.21(d,J＝6.5Hz,3H).
13 C NMR(101MHz,CDCl3)δ149.68,149.36,140.96,139.56,139.23,138.99,138.36,137.25,136.21,135.62,132.21,129.26,124.23,118.26,58.56,53.15,24.71.
31 P NMR(162MHz,CDCl3)δ-20.08.
HRMS(ESI)calcd for[M+H,C22H25NO2P]+:366.16229,found:366.16221.
The structural formula of (S) -1- (2-bis (3, 5-di-tert-butylphenyl) phosphine) phenylethylamine (IIc) is as follows:
yellow powder, yield 18%, [ alpha ]]D 26＝38.6(c 0.50,CHCl3) Melting point 111-.
1 H NMR(400MHz,CDCl3)δ7.54–7.43(m,1H),7.35(td,J＝7.0,1.6Hz,1H),7.24(td,J＝7.0,1.6Hz,1H),6.92–6.67(m,7H),4.42(p,J＝6.6Hz,1H),2.62(s,2H),2.08-1.92(m,36H),1.29(d,J＝6.5Hz,3H).
13 C NMR(101MHz,CDCl3)δ149.33,148.59,141.23,139.65,137.69,133.31,132.65,131.76,131.26,127.96,125.66,122.65,121.23,60.01,36.25,31.26,22.89.
31 P NMR(162MHz,CDCl3)δ-16.22.
HRMS(ESI)calcd for[M+H,C36H53NP]+:530.39156,found:530.39141.
Example 2: preparation of intermediate (S) -N-alkyl-1- (2-diarylphosphine) phenylethylamine IIIa-IIIe (S) -N-ethyl-1- (2-diphenylphosphino) phenylethylamine (IIIa)
(S) -1- (2-diphenylphosphino) phenylethylamine (3.05g,10mmol) and acetaldehyde (0.66g,15mmol) were added to a 50mL Schlenck flask and the system was placed under argon, after which extra dry methanol (20mL) was added and stirred at room temperature for 1 h. Then the system was placed in an ice-water bath for pre-cooling, and sodium borohydride (1.14g,30mmol) was added rapidly, the ice-water bath was removed and the reaction was carried out at room temperature for 3 h. The reaction was monitored by TLC, and after completion of the reaction, the system was quenched by adding water at 0 ℃ under stirring, dichloromethane was added to the system until two phases were clear, separated by a separatory funnel, the aqueous phase was extracted with dichloromethane (50mL × 3), the organic phases were combined, washed with saturated brine, and then dried over anhydrous magnesium sulfate. Filtration and concentration of the filtrate by rotary evaporation gave a crude product which was separated by column chromatography on silica gel (eluent petroleum ether/ethyl acetate 2:1, v/v). The final product was 3.17g of compound IIIa as a white viscous liquid in a 95% yield, [ alpha ]]D 26＝51.2(c 0.50,CHCl3)。
1 H NMR(400MHz,CDCl3)δ7.47(ddd,J＝7.9,4.3,1.4Hz,1H),7.27–7.12(m,11H),6.99(td,J＝7.5,1.4Hz,1H),6.76(ddd,J＝7.7,4.3,1.4Hz,1H),4.53(p,J＝6.6Hz,1H),2.37–2.14(m,2H),1.29–1.16(m,1H),1.11(d,J＝6.5Hz,3H),0.80(t,J＝7.1Hz,3H).
13 C NMR(101MHz,CDCl3)δ150.49,150.27,137.29,137.19,136.93,136.82,135.22,135.09,134.28,134.11,134.09,133.91,133.50,129.51,128.80,128.79,128.65,128.58,126.98,126.08,126.02,55.03,54.79,41.92,23.56,15.54.
31 PNMR(162MHz,CDCl3)δ-17.03.
HRMS(ESI)calcd for[M+H,C22H25NP]+:334.17246,found:334.17251.
The following compounds (IIIb to IIIe) were synthesized in the same manner as in example 2, except that: r is to be1Ethyl of (iii) is replaced by benzyl, (IIIc) differs in that: r is to be2The phenyl group of (c) is replaced by a 3, 5-dimethylphenyl group, (IIId) is distinguished by: r is to be2Substitution of phenyl group ofIs 4-methoxyphenyl, (IIIe) is distinguished in that: r is to be2The phenyl group of (a) is replaced by a 3, 5-di-tert-butylphenyl group.
(S) -N-benzyl-1- (2-diphenylphosphino) phenylethylamine (IIIb)
White viscous liquid, yield 96%, [ alpha ]]D 26＝52.9(c 0.50,CHCl3)。
1 H NMR(400MHz,CDCl3)δ7.66–7.59(m,1H),7.35–7.02(m,17H),6.80(ddd,J＝7.7,4.3,1.4Hz,1H),4.65(p,J＝6.6Hz,1H),3.44–3.28(m,2H),1.48(s,1H),1.16(d,J＝6.4Hz,3H).
13 C NMR(101MHz,CDCl3)δ150.18,140.69,137.20,137.09,136.85,136.75,135.28,135.15,134.25,134.05,133.87,133.55,129.55,128.75,128.54,128.52,128.31,128.14,127.02,126.79,126.12,126.06,55.07,54.82,51.81,23.78.
31 P NMR(162MHz,CDCl3)δ-17.38.
HRMS(ESI)calcd for[M+H,C27H27NP]+:396.18811,found:396.18765.
(S) -N-methyl-1- (2-bis (3, 5-dimethylphenyl) phosphinophenyl) ethylamine (IIIc)
White viscous liquid, yield 87%, [ alpha ]]D 26＝45.1(c 0.50,CHCl3)。
1 H NMR(400MHz,CDCl3)δ7.63(ddd,J＝7.8,4.2,1.3Hz,1H),7.40(td,J＝7.5,1.4Hz,1H),7.18(td,J＝7.5,1.4Hz,1H),7.02–6.85(m,7H),4.60(p,J＝6.6Hz,1H),2.27(d,J＝2.2Hz,12H),2.21(s,3H),1.31(d,J＝6.5Hz,3H).
13 C NMR(101MHz,CDCl3)δ150.36,143.13,142.36,140.22,138.66,138.33,137.98,136.23,134.25,133.32,132.12,130.23,126.56,124.62,122.65,120.32,60.01,36.25,34.56,22.89.
31 P NMR(162MHz,CDCl3)δ-16.24.
HRMS(ESI)calcd for[M+H,C25H31NP]+:376.21941,found:76.21933.
(S) -N-methyl-1- (2-bis (4-methoxyphenyl) phosphinophenyl) ethylamine (IIId)
White viscous liquid, yield 85%, [ alpha ]]D 26＝66.3(c 0.50,CHCl3)。
1 H NMR(400MHz,CDCl3)δ7.55(ddd,J＝7.9,4.2,1.3Hz,1H),7.34(td,J＝7.5,1.4Hz,1H),7.24–7.16(m,4H),7.15–7.10(m,1H),6.97(ddd,J＝8.8,6.0,2.3Hz,1H),6.92–6.86(m,4H),4.50(p,J＝6.6Hz,1H),3.80(s,6H),2.14(s,3H),1.20(d,J＝6.5Hz,3H).
13 C NMR(101MHz,CDCl3)δ149.55,141.28,139.22,138.98,138.47,137.25,137.14,136.32,135.87,134.36,134.06,131.59,130.15,129.01,123.31,117.22,59.63,55.63,35.22,25.29.
31 P NMR(162MHz,CDCl3)δ-20.07.
HRMS(ESI)calcd for[M+H,C23H26NO2P]+:379.17012,found:379.17019.
(S) -N-methyl-1- (2-bis (3, 5-di-tert-butylphenyl) phosphinophenyl) ethylamine (IIIe)
A white viscous liquid, a white solid,the yield thereof was found to be 71%, [ alpha ]]D 26＝40.3(c 0.50,CHCl3)。
1 H NMR(400MHz,CDCl3)δ7.43–7.32(m,1H),7.28–7.24(m,2H),7.01–6.77(m,7H),4.36(p,J＝6.6Hz,1H),2.16(s,3H),2.08-1.92(m,36H),1.29(d,J＝6.5Hz,3H).
13 C NMR(101MHz,CDCl3)δ151.69,151.23,143.61141.26,137.12,135.36,133.65,132.76,132.01,128.36,124.26,123.12,121.59,59.85,36.25,33.89,32.45,30.24,23.59.
31 P NMR(162MHz,CDCl3)δ-16.88.
HRMS(ESI)calcd for[M+H,C37H55NP]+:544.40721,found:544.40715.
Example 3: preparation of chiral diphosphine ligand Ia-Ie
Chiral diphosphine ligands Ia
A100 mL three-necked flask was charged with IIIa (1.56g,4.6mmol), freshly distilled toluene (30mL) and freshly distilled triethylamine (3.2mL,23mmol) in that order, the system was degassed by freezing, and then placed under argon. The system is placed in an ice-water bath for precooling, then diphenylphosphine (1.3mL,6.9mmol) is added dropwise, and after the dropwise addition is finished, the ice-water bath is removed, and the reaction is carried out for 24h at 120 ℃. After TLC determines that the reaction is complete, heating is stopped, after the system returns to room temperature, suction filtration is carried out through diatomite, the crude product obtained after vacuum desolventizing of the filtrate is separated by neutral alumina column chromatography (eluent is petroleum ether/ethyl acetate ═ 50:1, v/v), and finally 1.72g of chiral diphosphine ligand Ia is obtained as a white solid, and the yield is as follows: 79%, melting point: 156 ℃ 158 ℃ (decomposition), [ alpha ]]D 27＝49.5(c 0.50,CHCl3)。
1 H NMR(400MHz,CDCl3)δ7.73(s,1H),7.51–7.20(m,21H),7.12(t,J＝7.1Hz,1H),6.91(s,1H),5.31(q,J＝16.4,12.5Hz,1H),3.03(dd,J＝13.0,6.5Hz,1H),2.88(dd,J＝11.9,5.9Hz,1H),1.54(d,J＝6.5Hz,3H),0.47(t,J＝6.5Hz,3H).
13 C NMR(101MHz,CDCl3)δ151.61,151.38,141.30,141.14,139.98,139.86,137.36,137.25,137.02,136.92,134.53,134.41,134.02,133.97,133.83,133.77,133.52,132.74,132.53,132.06,131.86,129.35,128.74,128.62,128.60,128.56,128.55,128.50,128.36,128.16,128.10,127.96,127.91,127.72,127.42,127.37,127.32,126.92,55.31,55.05,54.78,44.81,44.71,24.86,24.60,14.08,14.04.
31 P NMR(162MHz,CDCl3)δ43.44(d,J＝4.6Hz),-17.55(d,J＝4.8Hz).
HRMS(ESI)calcd for[M+H,C34H34NP2]+:518.21610,found:518.21613.
The following chiral bisphosphine ligands (Ib-Ie) were synthesized as in example 3, with the difference that: r is to be1Ethyl of (a) is replaced by benzyl, (Ic) is distinguished by: r is to be2The phenyl group of (d) is replaced with a 3, 5-dimethylphenyl group, the difference being that: r is to be2The phenyl group of (a) is replaced by a 4-methoxyphenyl group, (Ie) is distinguished in that: r is to be2The phenyl group of (a) is replaced by a 3, 5-di-tert-butylphenyl group.
Chiral diphosphine ligand Ib
White solid, yield: 72%, melting point: 122- & ltalpha & gt, 124 deg.C (decomposition) & ltalpha & gt]D 27＝54.0(c 0.50,CHCl3)。
1 H NMR(400MHz,CDCl3)δ7.89(d,J＝4.5Hz,1H),7.56–7.47(m,2H),7.35–7.28(m,7H),7.23(dd,J＝6.6,3.6Hz,10H),7.14–6.96(m,6H),6.90(ddd,J＝7.7,4.0,1.4Hz,1H),6.63(d,J＝7.0Hz,2H),5.17–5.06(m,1H),4.33–4.16(m,2H),1.46(d,J＝7.0Hz,3H)。
13 C NMR(101MHz,CDCl3)δ150.82,150.57,141.14,140.99,140.27,140.14,139.49,137.55,137.43,135.26,135.12,134.22,134.07,134.02,133.87,133.79,133.75,133.56,131.94,131.75,129.51,129.13,128.95,128.88,128.79,128.71,128.68,128.61,128.58,128.51,128.43,128.10,128.05,127.94,127.86,127.81,127.78,127.73,127.20,126.37,56.10,55.86,55.83,55.60,54.34,54.25,54.23,24.50,24.28.
31 P NMR(162MHz,CDCl3)δ45.18(d,J＝4.8Hz),-17.57(d,J＝5.1Hz).
HRMS(ESI)calcd for[M+H,C39H36NP2]+:578.23230,found:580.23228.
Chiral diphosphine ligand Ic
White viscous liquid, yield: 42%, [ alpha ]]D 26＝67.3(c 0.50,CHCl3)。
1 H NMR(400MHz,CDCl3)δ7.56(dd,J＝7.9,4.4Hz,1H),7.38(td,J＝7.3,1.8Hz,2H),7.32–7.19(m,9H),7.12–7.04(m,1H),6.94–6.80(m,7H),5.16(h,J＝7.2Hz,1H),2.28(d,J＝2.6Hz,3H),2.17(d,J＝11.7Hz,12H),1.50(d,J＝6.8Hz,3H).
13 C NMR(101MHz,CDCl3)δ150.23,150.18,150.00,149.96,140.45,140.28,139.77,139.63,137.92,137.89,137.85,137.82,137.12,137.01,136.95,136.85,135.74,135.60,133.87,132.91,132.70,132.03,131.95,131.84,131.78,131.76,131.58,130.54,130.48,129.02,128.29,128.14,128.10,128.05,127.98,127.05,126.63,60.36,60.11,60.08,36.12,36.00,23.03,22.81,21.44.
31 P NMR(162MHz,CDCl3)δ49.11(d,J＝9.1Hz),-17.00(d,J＝9.6Hz).
HRMS(ESI)calcd for[M+H,C37H40NP2]+:560.26271,found:560.26263.
Chiral diphosphine ligand Id
White viscous liquid, yield: 44%, [ alpha ]]D 27＝45.9(c 0.50,CHCl3)。
1H NMR(400MHz,CDCl3)δ7.48(dd,J＝7.8,4.4Hz,1H),7.31(dt,J＝7.0,3.6Hz,2H),7.19(qd,J＝8.3,3.8Hz,9H),7.11–6.98(m,5H),6.74(dd,J＝11.8,8.3Hz,5H),5.09(h,J＝7.2Hz,1H),3.65(d,J＝6.5Hz,6H),2.19(d,J＝2.6Hz,3H),1.39(d,J＝6.9Hz,3H).
13 C NMR(101MHz,CDCl3)δ160.22,160.19,149.81,149.76,149.59,149.54,140.32,140.16,139.67,139.53,136.48,136.33,135.63,135.54,135.42,135.33,133.27,132.85,132.64,131.97,131.78,128.88,128.27,128.22,128.17,128.07,128.05,128.01,127.94,126.96,126.77,126.75,126.73,126.70,114.33,114.29,114.25,114.21,60.15,59.91,59.62,55.20,36.01,36.00,35.91,35.90,27.00,22.84,22.62.
31 P NMR(162MHz,CDCl3)δ49.23(d,J＝9.5Hz),-20.61(d,J＝9.6Hz).
HRMS(ESI)calcd for[M+H,C35H36NO2P2]+:564.22101,found:564.22089.
Chiral diphosphine ligand Ie
White viscous liquid, yield: 36%, [ alpha ]]D 27＝55.3(c 0.50,CHCl3)。
1H NMR(400MHz,CDCl3)δ7.57–7.50(m,5H),7.47–7.36(m,6H),7.36–7.25(m,9H),4.96(h,J＝6.6Hz,1H),2.38(s,3H),1.41(s,3H),1.28(s,36H).
13 C NMR(101MHz,CDCl3)δ144.74,144.21,143.65,140.14,138.74,137.32,137.12,134.71,132.98,130.21,129.97,129.39,129.04,128.27,127.44,126.31,124.08,123.65,61.41,60.56,59.81,59.72,54.25,42.65,42.34,40.56,40.12,39.72,36.56,36.01,36.00,35.91,35.90,34.99,31.41,18.76.
31 P NMR(162MHz,CDCl3)δ49.23(d,J＝9.5Hz),-20.61(d,J＝9.6Hz).
HRMS(ESI)calcd for[M+H,C49H64NP2]+:728.45140,found:728.45139.
Example 4: preparation of chiral diphosphine ligand rhodium complex IVa-IVd
Chiral diphosphine ligand rhodium complex IVa
In a glove box, ligand Ia (103mg,0.20mmol) and [ Rh (COD) Cl were weighed into a 10mL Schlenk tube]2(49mg,0.10mmol)、NaBArF·1.3H2O (200mg,0.24mmol), which was then sealed off and taken out of the glove box and the system was left under argon atmosphere, followed by addition of ultra dry dichloromethane (2mL) with a syringe, complexation with stirring at room temperature for 3h, TLC determined the reaction was complete and stopped. Vacuum desolventizing the reaction solution, and purifying the target product by silica gel column chromatography (eluent is petroleum ether/ethyl acetate (5: 1, v/v)) to obtain the product containing BArF -Anionic chiral diphosphine ligand rhodium complex IVa 221mg as a tan solid, yield: 71%, melting point: 85-89 deg.C (decomposition), [ alpha ]]D 25＝66(c 0.50,CHCl3)。
1 H NMR(400MHz,CDCl3)δ7.98–7.86(m,2H),7.77(s,8H),7.60–7.40(m,16H),7.24(ddt,J＝29.3,22.0,7.4Hz,7H),6.90(dt,J＝29.8,9.0Hz,3H),6.32(t,J＝9.1Hz,2H),5.83(dt,J＝23.7,6.8Hz,2H),4.40–4.26(m,1H),3.94(d,J＝7.6Hz,1H),3.78(t,J＝6.5Hz,1H),3.22(dp,J＝13.3,6.6Hz,1H),2.86(dq,J＝16.1,8.2Hz,2H),2.47(dd,J＝16.7,8.0Hz,1H),2.28–2.06(m,4H),1.35(d,J＝7.1Hz,3H),0.65(t,J＝6.9Hz,3H).
13 C NMR(101MHz,CDCl3)δ162.53,162.04,161.54,161.05,144.52,144.39,136.13,136.00,134.87,133.01,132.97,131.99,131.89,131.84,131.82,131.65,131.55,131.29,131.27,131.15,130.94,130.92,130.86,130.81,130.70,130.49,130.37,129.95,129.46,129.32,129.21,129.14,129.01,128.91,128.79,128.67,128.51,128.27,127.85,127.79,127.71,125.96,125.69,125.61,123.25,120.54,117.53,117.48,108.90,108.83,97.06,97.00,96.86,96.52,94.45,94.33,94.25,58.97,58.80,58.63,53.42,40.39,40.33,34.13,32.72,32.68,29.74,28.37,27.09,18.69,18.58,17.41.
31 P NMR(162MHz,CDCl3)δ88.82(dd,J＝152.9,32.6Hz),17.49(dd,J＝149.0,32.7Hz)；
HRMS(ESI)calcd for[positive ion,C42H45NP2Rh]+:728.20822,found 728.20691.
The chiral diphosphine ligand rhodium complex IVb is prepared by the same method as the chiral diphosphine ligand rhodium complex IVa except that Ia is replaced by Ib.
Tan solid, yield: 58%, melting point: 96-98 deg.C (decomposition), [ alpha ]]D 25＝96(c 0.50,CHCl3)。
1 H NMR(400MHz,CDCl3)δ7.97(ddd,J＝10.4,6.7,3.0Hz,2H),7.87–7.81(m,8H),7.67–6.80(m,31H),6.51(dd,J＝10.6,7.6Hz,2H),6.14(m,1H),6.01(d,J＝7.8Hz,1H),4.53–4.32(m,2H),4.22(dd,J＝16.7,8.2Hz,1H),4.05(dd,J＝17.7,9.8Hz,2H),2.92(dq,J＝16.4,9.0Hz,1H),2.54(dd,J＝16.7,7.8Hz,1H),2.37–2.08(m,4H),1.10(d,J＝7.1Hz,3H)。
13 C NMR(101MHz,CDCl3)δ166.18,161.23,160.53,153.20,152.83,152.58,152.58,147.92,146.06,144.10,143.15,143.00,142.27,142.15,141.50,139.56,139.44,137.27,137.13,136.23,136.07,136.03,135.88,135.80,135.76,135.57,133.95,133.76,132.77,131.52,131.14,130.96,130.89,130.79,130.72,130.68,130.62,130.59,130.52,130.43,130.11,130.06,129.95,129.87,129.81,129.79,129.74,129.21,128.38,128.28,125.75,124.66,121.76,121.42,116.98,115.55,113.60,111.15,109.41,106.86,98.30,94.97,92.29,71.08,64.82,62.65,58.11,58.11,57.87,57.84,57.60,56.35,56.26,56.24,50.52,42.03,32.89,26.51,26.51,26.29,15.71.
31 P NMR(162MHz,CDCl3)δ90.23(dd,J＝155.0,30.8Hz),17.00(dd,J＝148.2,30.8Hz).
HRMS(ESI)calcd for[positive ion,C47H47NP2Rh]+:790.22393,found 790.22245.
Chiral diphosphine ligand rhodium complex IVc is prepared by the same method as chiral diphosphine ligand rhodium complex IVa except that Ia is replaced by Ic.
Tan solid, yield: 75%, melting point: 67-70 deg.C (decomposition), [ alpha ]]D 25＝84(c 0.50,CHCl3)。
1 H NMR(400MHz,CDCl3)δ7.64(d,J＝4.7Hz,9H),7.44–7.25(m,15H),7.16(t,J＝7.8Hz,2H),7.01(d,J＝8.7Hz,2H),6.94–6.74(m,4H),5.87(d,J＝11.0Hz,2H),5.76(dt,J＝11.9,6.0Hz,1H),5.38(t,J＝7.3Hz,1H),4.27(t,J＝7.7Hz,1H),3.91(d,J＝8.2Hz,1H),3.72–3.61(m,1H),2.75(dq,J＝17.0,9.0Hz,1H),2.41–2.35(m,1H),2.30(d,J＝6.8Hz,3H),2.16(s,6H),2.16–1.89(m,4H),2.01(s,6H),1.23(d,J＝6.9Hz,3H)
13 C NMR(101MHz,CDCl3)δ162.56,162.06,161.57,161.07,143.84,143.72,138.99,138.88,138.76,134.89,133.75,133.63,133.52,133.16,132.67,131.48,131.10,130.94,130.84,130.35,130.23,129.51,129.41,129.21,129.11,128.80,128.70,127.74,127.57,127.50,125.98,125.00,124.92,123.27,120.57,117.51,109.90,97.87,97.68,95.57,92.49,60.38,58.09,57.92,57.74,34.46,34.42,33.20,30.76,30.71,27.96,26.82,21.15,21.08,15.42,15.33,14.07.
31 P NMR(162MHz,CDCl3)δ89.07(dd,J＝154.1,32.9Hz),16.91(dd,J＝147.5,33.1Hz).
HRMS(ESI)calcd for[positive ion,C45H51NP2Rh]+:770.25460,found 770.25416.
The chiral diphosphine ligand rhodium complex IVd is prepared by the same method as chiral diphosphine ligand rhodium complex IVa except that Ia is replaced by Id.
Tan solid, yield: 68%, melting point: 62-65 deg.C (decomposition), [ alpha ]]D 25＝54(c 0.50,CHCl3)。
1 H NMR(400MHz,CDCl3)δ7.73(s,8H),7.53(s,4H),7.44(d,J＝9.9Hz,10H),7.31–7.24(m,3H),7.13(t,J＝7.5Hz,1H),7.06–6.95(m,4H),6.81(dd,J＝27.9,8.6Hz,3H),6.32(t,J＝9.3Hz,2H),5.85(dt,J＝11.9,6.0Hz,1H),5.45(d,J＝7.4Hz,1H),4.35(q,J＝9.7Hz,1H),4.12(s,1H),3.79(d,J＝16.9Hz,7H),2.79(dq,J＝16.7,8.7Hz,1H),2.42(d,J＝6.8Hz,3H),2.14(m,5H),1.37(d,J＝6.9Hz,3H)
13 C NMR(101MHz,CDCl3)δ162.49,162.20,161.99,161.49,161.00,137.54,137.40,134.83,133.59,133.47,132.67,132.37,131.56,130.95,130.78,130.68,130.29,130.17,129.26,129.15,128.78,127.71,127.57,125.93,123.22,121.64,120.51,118.94,118.46,117.48,114.92,114.81,114.70,114.59,97.56,95.83,93.17,57.71,55.37,55.26,53.42,34.16,33.00,32.96,30.83,30.78,28.25,26.96,15.70,15.60.
31 P NMR(162MHz,CDCl3)δ88.52(dd,J＝154.3,33.1Hz),14.20(dd,J＝147.5,33.3Hz).
HRMS(ESI)calcd for[positive ion,C43H47NO2P2Rh]+:774.21323,found 774.21251.
Example 5: asymmetric hydrogenation reaction research of catalyst IVa-IVd on Z-3-acetamido ethyl crotonate
In a glove box, catalysts IVa (3.6mg, 2.3. mu. mol,1.0 mol%), IVb (3.8mg, 2.3. mu. mol,1.0 mol%), IVc (3.7mg, 2.3. mu. mol,1.0 mol%), IVd (3.7mg, 2.3. mu. mol,1.0 mol%) were added into four hydrogenation inner tubes, then Z-3-acetamidobutenoic acid ethyl ester (40mg,0.23mmol) was added into each hydrogenation inner tube, the glove box was taken out with a sealing film, and the glove box was placed into a hydrogenation kettle, ethanol (1mL) which had been evaporated and degassed was stirred uniformly, the hydrogenation kettle was screwed down, hydrogen gas was rapidly replaced 3 times, hydrogen gas (25atm) was charged, and the reaction was stirred at room temperature (rt) for 12 hours. After the reaction is finished, transferring the reaction solution to a round-bottom flask, removing the solvent by rotary evaporation, adding dibromomethane as an internal standard, and determining the conversion rate and the yield by nuclear magnetism. The remaining crude product was passed through a short silica gel column (eluent EA) and the ee value (AD-3, 92:8 n-hexane/isopropanol; 1.0mL/min,210 nm) was determined by HPLC. The results are shown in Table 1 and show that catalyst IVc has the best catalytic performance in the asymmetric hydrogenation of beta-dehydroamino acid esters.
Table 1: experimental results of different catalysts for asymmetric hydrogenation of Z-3-acetamido ethyl crotonate
a 1H NMR quantification (internal standard CH)2Br2)
bHPLC, chiral column AD-3, n-hexane/isopropanol 92:8,1.0mL/min,210nm.
Example 6: effect of anions on asymmetric hydrogenation of ethyl Z-3-Acetaminocrotonate
In a glove box, ligands Ic (2.8mg, 5. mu. mol,1.1 mol%), [ Rh (COD) Cl]2(1.0mg, 2.3. mu. mol,0.5 mol%), ethyl Z-3-acetylaminocrotonate (80mg,0.47mmol) were each added to five hydrogenation tubes, after which AgBF was again added4(1.0mg,5μmol,1.1mol％)、AgPF6(1.3mg,5μmol,1.1mol％)、AgSbF4Respectively adding (1.7mg,5 mu mol,1.1 mol%) and AgOTf (1.3mg,5 mu mol,1.1 mol%) into four hydrogenation inner tubes, sealing with a sealing film, taking out of a glove box, putting into a hydrogenation kettle, quickly adding ethanol (2mL) which is evaporated and degassed, screwing down the hydrogenation kettle after uniformly stirring, quickly replacing hydrogen for 3 times, filling hydrogen (25atm), and stirring at room temperature for reaction for 12 hours. After the reaction is finished, transferring the reaction solution to a round-bottom flask, removing the solvent by rotary evaporation, adding dibromomethane as an internal standard, and determining the conversion rate and the yield by nuclear magnetism. The remaining crude product was passed through a short silica gel column (eluent EA) and the ee value (AD-3, 92:8 n-hexane/isopropanol; 1.0mL/min,210 nm) was determined by HPLC. The reaction results are shown in Table 2.
Table 2: experimental results of different catalysts for asymmetric hydrogenation of Z-3-acetamido ethyl crotonate
a1H NMR quantification (internal standard CH)2Br2)
bHPLC, chiral column AD-3, n-hexane/isopropanol 92:8,1.0mL/min,210nm.
cUnder the same experimental conditions, the substrate dosage is increased as follows: 400mg,2.3mmol.
dCatalyst IVc (3.6mg, 2.3. mu. mol,0.2 mol%), ethyl Z-3-acetylaminocrotonate (200mg,1.15mmol)
Example 7: effect of Hydrogen pressure on asymmetric hydrogenation of ethyl Z-3-Acetaminocrotonate
In a glove box, weighing Z-3-acetamido ethyl crotonate (40mg,0.23mmol) and a corresponding amount of catalyst IVc (3.7mg,2.3 mu mol,1.0 mol%) in sequence into a hydrogenation inner tube, sealing with a sealing film, taking out of the glove box, putting into a hydrogenation kettle, rapidly adding ethanol (2mL) which is evaporated and degassed, screwing down the hydrogenation kettle after uniformly stirring, rapidly replacing hydrogen for 3 times, filling hydrogen with different pressures, and stirring at room temperature for reaction for 12 hours. After the reaction is finished, transferring the reaction solution to a round-bottom flask, removing the solvent by rotary evaporation, adding dibromomethane as an internal standard, and determining the conversion rate and the yield by nuclear magnetism. The remaining crude product was passed through a short silica gel column (eluent EA) and the ee value was determined by HPLC.
Table 3: experimental results of hydrogen pressure on asymmetric hydrogenation of Z-3-acetamido ethyl crotonate
a 1H NMR quantification (internal standard CH)2Br2)
bHPLC, chiral column AD-3, n-hexane/isopropanol 92:8,1.0mL/min,210nm.
Example 8: influence of temperature on asymmetric hydrogenation of ethyl Z-3-acetamidobutenoate
In a glove box, Z-3-acetamido ethyl crotonate (40mg,0.23mmol) and catalyst IVc (3.7mg,2.3 mu mol,1.0 mol%) are weighed into a hydrogenation inner tube in sequence, a sealing film is used for sealing and taking out the glove box, the glove box is placed into a hydrogenation kettle, currently-evaporated and degassed ethanol (2mL) is rapidly added, the hydrogenation kettle is screwed after uniform stirring, hydrogen is rapidly replaced for 3 times, hydrogen (30atm) is filled, and the mixture is stirred and reacts for 12 hours under different temperature conditions. After the reaction is finished, transferring the reaction solution to a round-bottom flask, removing the solvent by rotary evaporation, adding dibromomethane as an internal standard, and determining the conversion rate and the yield by nuclear magnetism. The remaining crude product was passed through a short silica gel column (eluent EA) and the ee value was determined by HPLC.
Table 4: experimental results of asymmetric hydrogenation of Z-3-acetamido ethyl crotonate at different temperatures
a 1H NMR quantification (internal standard CH)2Br2)
bHPLC, chiral column AD-3, n-hexane/isopropanol 92:8,1.0mL/min,210nm.
Example 9: effect of catalyst dosage on asymmetric hydrogenation of ethyl Z-3-acetamidobutenoate
In a glove box, a catalyst IVc (3.7mg,2.3 mu mol,1.0 mol%) and a corresponding amount of Z-3-acetamido ethyl crotonate are sequentially weighed into a hydrogenation inner tube, a sealing film is used for sealing and taking out of the glove box, the glove box is placed into a hydrogenation kettle, ethanol (2-5mL) which is evaporated and degassed at present is rapidly added, the hydrogenation kettle is screwed after uniform stirring, hydrogen is rapidly replaced for 3 times, hydrogen (30atm) is filled, and the mixture is stirred and reacts for 12 hours at room temperature. After the reaction is finished, transferring the reaction solution to a round-bottom flask, removing the solvent by rotary evaporation, adding dibromomethane as an internal standard, and determining the conversion rate and the yield by nuclear magnetism. The remaining crude product was passed through a short silica gel column (eluent EA) and the ee value was determined by HPLC. The experimental results show that the conversion number can reach 4400 at the maximum, and the ee value is 70 percent.
Table 5: experimental result of using catalyst amount for asymmetric hydrogenation of Z-3-acetamido ethyl crotonate
a 1H NMR quantification (internal standard CH)2Br2)
bHPLC, chiral column AD-3, n-hexane/isopropanol 92:8,1.0mL/min,210nm.
cReaction time: 48h
Example 10: study on substrate application range of asymmetric hydrogenation of beta-dehydroamino acid ester
In a glove box, catalyst IVc (3.7mg,2.3 mu mol,1.0 mol%) and a corresponding amount of beta-dehydroamino acid ester substrate are sequentially weighed into a hydrogenation inner tube, a sealing film is used for sealing and taking out of the glove box, the catalyst is placed into a hydrogenation kettle, currently evaporated and degassed ethanol (2mL) is rapidly added, the hydrogenation kettle is screwed after uniform stirring, hydrogen is rapidly replaced for 3 times, hydrogen (30atm) is filled, and the reaction is stirred at room temperature for 12 hours. After the reaction is finished, transferring the reaction solution to a round-bottom flask, removing the solvent by rotary evaporation, adding dibromomethane as an internal standard, and determining the conversion rate and the yield by nuclear magnetism. The remaining crude product was passed through a short silica gel column (eluent EA) and the ee value was determined by HPLC.
Table 6: experimental results of research on substrate application range of asymmetric hydrogenation of beta-dehydroamino acid ester
a 1H NMR quantification (internal standard CH)2Br2)
bHPLC, chiral column AD-3, n-hexane/isopropanol 92:8,1.0mL/min,210nm.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various changes and modifications can be made without departing from the inventive concept, and these changes and modifications are all within the scope of the present invention.
Claims (10)
1. A chiral bisphosphine ligand having the formula I:
wherein: r1Is an alkyl group; r2Is aryl or substituted aryl.
2. Chiral bisphosphine ligand according to claim 1, characterized in that: said R1Is a linear or branched alkyl group having 1 to 24 carbon atoms.
3. Chiral bisphosphine ligand according to claim 2, characterized in that: said R1Is a linear or branched alkyl group having 1 to 7 carbon atoms.
4. A chiral bisphosphine ligand according to claim 3, characterized in that: said R1Is methyl, ethyl or benzyl.
5. Chiral bisphosphine ligand according to claim 1, characterized in that: said R2Is aryl or substituted aryl having 6 to 24 carbon atoms; said R2Is a phenyl group which is mono-or polysubstituted at 2 to 5 positions.
6. Chiral bisphosphine ligand according to claim 5, characterized in that: said R2Is 4-methoxyphenyl, 3, 5-dimethylphenyl or 3, 5-di-tert-butylphenyl.
7. Chiral bisphosphine ligand according to claim 1, characterized in that: said R1Is methyl, ethyl or benzyl, R2Is 4-methoxyphenyl, 3, 5-dimethylphenyl or 3, 5-di-tert-butylphenyl.
8. A process for the preparation of a chiral bisphosphine ligand according to any of claims 1 to 7, characterized in that: the method comprises the following steps:
(1) in a solvent, carrying out ortho lithiation on (S) -1-phenylethylamine under the conditions of n-butyllithium and trimethylchlorosilane at the temperature of-35 ℃, and then reacting with disubstituted phosphorus chloride to prepare an ortho phosphine substituted intermediate II, wherein the reaction formula is as follows:
(2) in a solvent, carrying out reductive amination on a compound II, aldehyde and sodium borohydride at 0-60 ℃ to prepare a secondary amine intermediate III, wherein the reaction formula is as follows:
(3) in a solvent, triethylamine is used as alkali at 0-120 ℃, and a compound III is reacted with diphenyl phosphorus chloride to prepare a chiral diphosphine ligand I, wherein the reaction formula is as follows:
9. a chiral diphosphine ligand rhodium complex comprising a chiral diphosphine ligand according to any one of claims 1 to 7, having the following formula IV:
X-comprises the following steps: chloride ion, tetrafluoroborate ion, hexafluorophosphate ion, hexafluoroantimonate ion, trifluoromethanesulfonate ion, tetrakis (3, 5-bistrifluoromethylphenyl) boronAn anion.
10. A process for the preparation of a chiral diphosphine ligand rhodium complex according to claim 9, characterized in that:
such as X-Is chloride ion, tetrafluoroborate ion, hexafluorophosphate ion, hexafluoroantimonate ion or trifluoromethanesulfonate ion, and the preparation method comprises the following steps: in a solvent, at the temperature of 20-30 ℃, the chiral diphosphine ligand is complexed with rhodium salt and silver salt of corresponding anions for 2-4 hours to prepare chiral diphosphine ligand rhodium complex containing different anions, and the reaction formula is as follows:
such as X-Is a tetra (3, 5-bistrifluoromethylphenyl) boron anion, and the preparation method comprises the following steps: chiral diphosphine ligand, corresponding rhodium salt and NaBAr in solvent at 20-30 deg.cFComplexing for 2-4 hours to obtain the product containing BArF-an anionic chiral diphosphine ligand rhodium complex of the formula:
wherein: y is 1, 5-cyclooctadiene;
the solvents are all as follows: one or more of dichloromethane, benzene, toluene, xylene, diethyl ether, tetrahydrofuran, 1, 4-dioxane, methanol, ethanol and isopropanol.
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| CN116178455A (en) * | 2023-04-26 | 2023-05-30 | 江苏欣诺科催化剂股份有限公司 | Preparation method of ferrocene chiral phosphine ligand |
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| WO2016045589A1 (en) * | 2014-09-26 | 2016-03-31 | 上海交通大学 | Method for preparing chiral γ-secondary amino alcohol |
| WO2021083018A1 (en) * | 2019-10-30 | 2021-05-06 | 浙江九洲药业股份有限公司 | Preparation method for and application of 3-substituted chiral spiro aminophosphine ligand on pyridine ring |
| CN113527367A (en) * | 2021-07-14 | 2021-10-22 | 南开沧州渤海新区绿色化工研究有限公司 | Chiral diphosphine ligand rhodium complex containing tetra (3, 5-bistrifluoromethylphenyl) boron anion and preparation method and application thereof |
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| WO2016045589A1 (en) * | 2014-09-26 | 2016-03-31 | 上海交通大学 | Method for preparing chiral γ-secondary amino alcohol |
| WO2021083018A1 (en) * | 2019-10-30 | 2021-05-06 | 浙江九洲药业股份有限公司 | Preparation method for and application of 3-substituted chiral spiro aminophosphine ligand on pyridine ring |
| CN113527367A (en) * | 2021-07-14 | 2021-10-22 | 南开沧州渤海新区绿色化工研究有限公司 | Chiral diphosphine ligand rhodium complex containing tetra (3, 5-bistrifluoromethylphenyl) boron anion and preparation method and application thereof |
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