CN113861238A - Method for simultaneously synthesizing secondary/tertiary phosphine oxide compound with phosphine chiral center under catalysis of palladium/chiral ligand - Google Patents
Method for simultaneously synthesizing secondary/tertiary phosphine oxide compound with phosphine chiral center under catalysis of palladium/chiral ligand Download PDFInfo
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- CN113861238A CN113861238A CN202111222445.0A CN202111222445A CN113861238A CN 113861238 A CN113861238 A CN 113861238A CN 202111222445 A CN202111222445 A CN 202111222445A CN 113861238 A CN113861238 A CN 113861238A
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- aryl
- substituted
- alkyl
- palladium
- phosphine oxide
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- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 title claims abstract description 91
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 title claims abstract description 62
- 229910000073 phosphorus hydride Inorganic materials 0.000 title claims abstract description 45
- -1 phosphine oxide compound Chemical group 0.000 title claims abstract description 39
- 229910052763 palladium Inorganic materials 0.000 title claims abstract description 31
- 238000000034 method Methods 0.000 title claims abstract description 30
- 239000003446 ligand Substances 0.000 title claims abstract description 29
- 238000006555 catalytic reaction Methods 0.000 title claims abstract description 11
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 5
- AUONHKJOIZSQGR-UHFFFAOYSA-N oxophosphane Chemical group P=O AUONHKJOIZSQGR-UHFFFAOYSA-N 0.000 claims abstract description 40
- 238000006243 chemical reaction Methods 0.000 claims abstract description 24
- 239000003054 catalyst Substances 0.000 claims abstract description 18
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 13
- 239000000654 additive Substances 0.000 claims abstract description 12
- 230000000996 additive effect Effects 0.000 claims abstract description 12
- 230000002152 alkylating effect Effects 0.000 claims abstract description 12
- 239000003960 organic solvent Substances 0.000 claims abstract description 7
- 125000003118 aryl group Chemical group 0.000 claims description 49
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 48
- 125000001072 heteroaryl group Chemical group 0.000 claims description 35
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 25
- 125000003107 substituted aryl group Chemical group 0.000 claims description 23
- 125000000217 alkyl group Chemical group 0.000 claims description 20
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- 150000002367 halogens Chemical group 0.000 claims description 11
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 11
- 125000001424 substituent group Chemical group 0.000 claims description 11
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 125000003368 amide group Chemical group 0.000 claims description 9
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 9
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims description 9
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 8
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 8
- 125000001624 naphthyl group Chemical group 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims description 6
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 claims description 6
- 235000010290 biphenyl Nutrition 0.000 claims description 6
- 239000004305 biphenyl Substances 0.000 claims description 6
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 6
- 125000005561 phenanthryl group Chemical group 0.000 claims description 6
- SUSQOBVLVYHIEX-UHFFFAOYSA-N phenylacetonitrile Chemical compound N#CCC1=CC=CC=C1 SUSQOBVLVYHIEX-UHFFFAOYSA-N 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 claims description 5
- 125000006165 cyclic alkyl group Chemical group 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- WPFGFHJALYCVMO-UHFFFAOYSA-L rubidium carbonate Chemical compound [Rb+].[Rb+].[O-]C([O-])=O WPFGFHJALYCVMO-UHFFFAOYSA-L 0.000 claims description 5
- 229910000026 rubidium carbonate Inorganic materials 0.000 claims description 5
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 4
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 150000003222 pyridines Chemical class 0.000 claims description 4
- 229930192474 thiophene Natural products 0.000 claims description 4
- UKSZBOKPHAQOMP-SVLSSHOZSA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 UKSZBOKPHAQOMP-SVLSSHOZSA-N 0.000 claims description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 3
- LNAMMBFJMYMQTO-FNEBRGMMSA-N chloroform;(1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].ClC(Cl)Cl.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 LNAMMBFJMYMQTO-FNEBRGMMSA-N 0.000 claims description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 3
- 229910052808 lithium carbonate Inorganic materials 0.000 claims description 3
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims description 3
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 235000011181 potassium carbonates Nutrition 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- VYXHVRARDIDEHS-UHFFFAOYSA-N 1,5-cyclooctadiene Chemical compound C1CC=CCCC=C1 VYXHVRARDIDEHS-UHFFFAOYSA-N 0.000 claims description 2
- 239000004912 1,5-cyclooctadiene Substances 0.000 claims description 2
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 claims description 2
- CSIFGMFVGDBOQC-UHFFFAOYSA-N 3-iminobutanenitrile Chemical compound CC(=N)CC#N CSIFGMFVGDBOQC-UHFFFAOYSA-N 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- RFFFKMOABOFIDF-UHFFFAOYSA-N Pentanenitrile Chemical compound CCCCC#N RFFFKMOABOFIDF-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 125000004423 acyloxy group Chemical group 0.000 claims description 2
- TWKVUTXHANJYGH-UHFFFAOYSA-L allyl palladium chloride Chemical class Cl[Pd]CC=C.Cl[Pd]CC=C TWKVUTXHANJYGH-UHFFFAOYSA-L 0.000 claims description 2
- AYJRCSIUFZENHW-DEQYMQKBSA-L barium(2+);oxomethanediolate Chemical compound [Ba+2].[O-][14C]([O-])=O AYJRCSIUFZENHW-DEQYMQKBSA-L 0.000 claims description 2
- KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 claims description 2
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 claims description 2
- YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical compound Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 claims description 2
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 claims description 2
- 125000005245 nitryl group Chemical group [N+](=O)([O-])* 0.000 claims description 2
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical group [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- JABYJIQOLGWMQW-UHFFFAOYSA-N undec-4-ene Chemical compound CCCCCCC=CCCC JABYJIQOLGWMQW-UHFFFAOYSA-N 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 50
- 230000015572 biosynthetic process Effects 0.000 abstract description 13
- 238000003786 synthesis reaction Methods 0.000 abstract description 13
- 239000000758 substrate Substances 0.000 abstract description 4
- 230000003287 optical effect Effects 0.000 abstract description 3
- 238000002360 preparation method Methods 0.000 abstract description 3
- 238000001308 synthesis method Methods 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 60
- 238000004440 column chromatography Methods 0.000 description 22
- 239000012043 crude product Substances 0.000 description 22
- 239000000047 product Substances 0.000 description 21
- 239000007787 solid Substances 0.000 description 16
- 238000002474 experimental method Methods 0.000 description 12
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- 238000004679 31P NMR spectroscopy Methods 0.000 description 10
- 238000001228 spectrum Methods 0.000 description 10
- 239000011734 sodium Substances 0.000 description 7
- 239000002168 alkylating agent Substances 0.000 description 5
- 229940100198 alkylating agent Drugs 0.000 description 5
- 150000002894 organic compounds Chemical class 0.000 description 3
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 229910000144 sodium(I) superoxide Inorganic materials 0.000 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 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 238000005273 aeration Methods 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- BWJRMVLPCQPWGR-UHFFFAOYSA-N boron;phosphane Chemical group [B].P BWJRMVLPCQPWGR-UHFFFAOYSA-N 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 125000003003 spiro group Chemical group 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
- C07F9/53—Organo-phosphine oxides; Organo-phosphine thioxides
- C07F9/5325—Aromatic phosphine oxides or thioxides (P-C aromatic linkage)
-
- 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
- C07F9/53—Organo-phosphine oxides; Organo-phosphine thioxides
- C07F9/5333—Arylalkane phosphine oxides or thioxides
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
Abstract
The invention discloses a method for synthesizing a phosphine chiral center secondary/tertiary phosphine oxide compound under the catalysis of palladium/chiral ligand, wherein in the presence of an organic solvent and an additive, racemic secondary phosphine oxide shown in a formula I and an alkylating reagent shown in a formula II are subjected to a kinetic resolution reaction under the catalysis of a palladium catalyst/chiral ligand Xiao-Phos to obtain phosphine chiral center secondary phosphine oxide shown in a formula III and a phosphine chiral center tertiary phosphine oxide compound shown in a formula IV, and the reaction formula is shown in a formula (a). The method has the advantages of stable and easily obtained raw materials, simple method and wide substrate application range, provides a high-efficiency and atom-economic route for the kinetic resolution of racemic secondary phosphine oxide and the preparation of a phosphine chiral center compound, and has wide subsequent synthesis application of two obtained products with high optical activity, so the synthesis method provided by the invention has high practical application value.
Description
Technical Field
The invention belongs to the technical field of organic synthetic chemistry, and relates to a method for preparing a phosphine chiral center secondary phosphine oxide and a phosphine chiral center tertiary phosphine oxide by using a palladium/chiral ligand catalytic system to catalyze asymmetric alkylation of a secondary phosphine oxide with high enantioselectivity and realize efficient kinetic resolution of racemic secondary phosphine oxide.
Background
Organic compounds containing phosphine chiral centers have very important applications in the field of asymmetric catalysis (chem.Soc.Rev.2016,45, 5771-5794; chem.Rec.2016,16, 2655-2669). The construction of phosphine chiral tertiary phosphine compounds by asymmetric catalysis has been widely developed (Eur. J. org. chem.2020,2020, 3351-3366), however, the preparation of phosphine chiral center secondary phosphine compounds (secondary phosphine oxide, secondary phosphine borane) is still mainly obtained by chiral prosthetic group resolution (Synthesis 2021, doi:10.1055/a-1582-0169), and the asymmetric catalysis method is used to obtain such compounds little by little. The phosphine chiral center secondary phosphine compound as a key phosphine chiral center organic compound synthon can be quickly introduced into a specified molecular skeleton (J.Org.chem.2007,72, 816-822; J.Am.chem.Soc.2011,133, 10728-10731; Organometallics 2015,34, 1228-1237; Symmetry 2020,12,108-159), and has very important significance for efficiently constructing the phosphine chiral center organic compound.
The racemized secondary phosphine oxide with certain configuration stability is adopted as an initial phosphine reagent, a kinetic resolution strategy is introduced into an asymmetric catalytic system, the phosphine chiral center compound is efficiently constructed, meanwhile, a more practical phosphine chiral secondary phosphine oxide compound can be obtained with high enantioselectivity, the implementation and application values of the reaction can be obviously improved, and the atom economy is improved.
Disclosure of Invention
In order to solve the defects of the prior art, the invention aims to provide a method for simultaneously synthesizing a phosphine chiral center secondary/tertiary phosphine oxide compound under the catalysis of palladium/chiral ligand, under the condition of an organic solvent and an additive, racemic secondary phosphine oxide shown in a formula I and an alkylating reagent shown in a formula II are subjected to a kinetic resolution reaction under the catalysis of a palladium catalyst/chiral ligand Xiao-Phos to obtain phosphine chiral center secondary phosphine oxide shown in a formula III and a phosphine chiral center tertiary phosphine oxide compound shown in a formula IV, wherein the reaction formulas are as follows:
formula III and formula IV: represents chirality, being R or S;
R1、R2are each independently selected from C1～C12Alkyl, benzyl or substituted benzyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl of (a); r3Is selected from C1～C12Alkyl, benzyl or substituted benzyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, ferrocene; LG is selected from halogen, alkyl or aryl substituted acyloxy, alkyl or aryl substituted sulfonyloxy, alkyl or aryl substituted phosphonate, alkyl or aryl substituted phosphite; n is selected from 1,2 and 3;
wherein said alkyl group includes straight, branched and cyclic alkyl groups; the aryl is phenyl, naphthyl, biphenyl, phenanthryl or anthryl and other aromatic rings; the heteroaryl is thiophene, furan, pyridine, indole and the like; in the substituted benzyl, substituted aryl and substituted heteroaryl, the substituents are selected from halogen and C1～C12Alkyl of (C)1～C10Alkoxy group of (C)1～C10Siloxane group of (A), C1～C10Alkanoyl of (2), C1～C10Ester group of (1), C1～C10One or more of sulfonate, amido, hydroxyl, trifluoromethyl, nitro, cyano and aryl.
The specific synthesis method comprises the following steps: the method comprises the steps of using a palladium catalyst and a chiral ligand Xiao-Phos as a catalyst, adding a racemized secondary phosphine oxide compound, an alkylating reagent and an additive into an organic solvent, reacting at the temperature of 10-80 ℃ for 10-120 hours, and purifying after the reaction is finished to obtain a phosphine chiral center secondary phosphine oxide and a phosphine chiral center tertiary phosphine oxide.
In the present invention, the palladium catalyst is one selected from the group consisting of tris (dibenzylideneacetone) dipalladium, bis (dibenzylideneacetone) palladium, tris (dibenzylideneacetone) dipalladium chloroform adduct, allylpalladium chloride dimer, bis (triphenylphosphine) palladium dichloride, palladium chloride, [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride, tetraacetonitrile palladium tetrafluoroborate, (1, 5-cyclooctadiene) palladium dichloride, bis (tri-tert-butylphosphino) palladium, palladium acetate, bis (tri-tert-butylphosphino) palladium, diacetonitrile palladium chloride and tetratriphenylphosphine palladium.
In the invention, the chiral ligand is chiral tertiary butyl sulfinyl amide monophosphine ligand Xiao-Phos shown as a formula V or an enantiomer thereof,
in formula V: r4Is selected from C1～C12Alkyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl of (a); r5Selected from hydrogen, C1～C12Alkyl, benzyl or substituted benzyl, aryl or substituted aryl of (a); r6Is selected from C1～C12An alkyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl group of (a);
wherein said alkyl group includes straight, branched and cyclic alkyl groups; the aryl is phenyl, naphthyl, biphenyl, phenanthryl or anthryl and other aromatic rings; the heteroaryl is thiophene, furan, pyridine, indole and the like; in the substituted benzyl, substituted aryl and substituted heteroaryl, the substituents are selected from halogen and C1～C12Alkyl of (C)1～C10Alkoxy group of (C)1～C10Siloxane group of (A), C1～C10Alkanoyl of (2), C1～C10Ester group of (1), C1～C10One or more of sulfonate, amido, hydroxyl, trifluoromethyl, nitro, cyano, aryl and heteroaryl.
In the present invention, the additive is selected from lithium carbonate, sodium carbonate, potassium carbonate, rubidium carbonate, cesium carbonate, barium carbonate, potassium bicarbonate, sodium bicarbonate, pyridine or substituted pyridine,
1, 8-diazohetero-double spiro [ 2 ]5.4.0]One or more than two of undec-7-ene;
wherein, the substituents in the substituted pyridine are all selected from halogen and C1～C12Alkyl of (C)1～C10Alkoxy group of (C)1～C10Siloxane group of (A), C1～C10Alkanoyl of (2), C1～C10Ester group of (1), C1～C10One or more than two of sulfonate, amido, hydroxyl, trifluoromethyl, nitryl, cyano, aryl and heteroaryl; r7、R8、R9Are respectively and independently selected from hydrogen and C1～C12Alkyl, benzyl or substituted benzyl, aryl or substituted aryl.
Said R7、R8、R9In (1), the alkyl group includes straight chain, branched chain and cycloalkyl; aryl is phenyl, naphthyl, biphenyl, phenanthryl or anthryl and other aromatic rings; in the substituted benzyl and the substituted aryl, the substituents are selected from halogen and C1～C12Alkyl of (C)1～C10Alkoxy group of (C)1～C10Siloxane group of (A), C1～C10Alkanoyl of (2), C1～C10Ester group of (1), C1～C10One or more of sulfonate, amido, hydroxyl, trifluoromethyl, nitro, cyano, aryl and heteroaryl.
In the invention, the organic solvent can be one of dichloromethane, dichloroethane, acetonitrile, propionitrile, butyronitrile, valeronitrile, benzonitrile, phenylacetonitrile, diethyl ether, dibutyl ether, methyl tert-butyl ether, anisole, ethylene glycol dimethyl ether, ethyl acetate, 1, 4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, xylene, benzene, chlorobenzene, fluorobenzene, trifluorotoluene, chloroform and acetone, or any mixture thereof.
In the invention, the method comprises the following steps: the mole ratio of the racemized secondary phosphine oxide to the alkylating reagent to the palladium catalyst to the chiral ligand to the additive is (1-6) to 1, (0.03-0.1) to (0.09-0.20) to (2-4).
In the invention, the reaction temperature is 10-80 ℃.
As a preferred scheme, in the method for simultaneously preparing the secondary/tertiary phosphine oxide compound with the phosphine chiral center catalyzed by the palladium/chiral ligand, the method comprises the following steps:
R1、R2are respectively independently preferably selected from C1～C12Alkyl, aryl or substituted aryl of (a); r3Preferably selected from aryl or substituted aryl, heteroaryl or substituted heteroaryl; LG is preferably selected from alkyl or aryl substituted phosphonate groups, alkyl or aryl substituted phosphite groups; n is preferably selected from 1, 2;
wherein said alkyl group includes straight, branched and cyclic alkyl groups; the aryl is phenyl, naphthyl and other aromatic rings; the heteroaryl is pyridine and the like; in the substituted aryl and the substituted heteroaryl, the substituent is selected from halogen and C1～C12Alkyl of (C)1～C10Alkoxy group of (C)1～C10Siloxane group of (A), C1～C10Alkanoyl of (2), C1～C10Ester group of (1), C1～C10One or more of sulfonate, amido, hydroxyl, trifluoromethyl, nitro, cyano and aryl.
In the present invention, the palladium catalyst is preferably one selected from the group consisting of tris (dibenzylideneacetone) dipalladium, bis (dibenzylideneacetone) palladium, tris (dibenzylideneacetone) dipalladium chloroform adduct, palladium acetate and tetratriphenylphosphine palladium.
In the invention, the chiral tertiary butyl sulfinyl amide monophosphine ligand Xiao-Phos has the following structure:
In the present invention, the additive is preferably selected from lithium carbonate, potassium carbonate, rubidium carbonate, cesium carbonate, and mixtures thereof,
One or more than two of the above;
wherein R is7、R8、R9Are respectively and independently selected from hydrogen and C1～C12Alkyl, benzyl or substituted benzyl, aryl or substituted aryl.
Said R7、R8、R9In (1), the alkyl group includes straight chain, branched chain and cycloalkyl; aryl is phenyl, naphthyl and other aromatic rings; in the substituted benzyl and the substituted aryl, the substituents are selected from C1～C12Alkyl of (C)1～C10One or more of alkoxy, trifluoromethyl, aryl and heteroaryl.
In the present invention, the reaction solvent is preferably one or any mixture of dichloromethane, dichloroethane, acetonitrile, benzonitrile, phenylacetonitrile, anisole, ethylene glycol dimethyl ether, 1, 4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, toluene and acetone.
In the present invention, the feed ratio of the method is preferably: the mole ratio of the racemized secondary phosphine oxide to the alkylating reagent to the palladium catalyst to the chiral ligand to the additive is (2-4) to 1, (0.03-0.06), (0.09-0.18) to (2-4).
In the invention, the reaction temperature is preferably 40-55 ℃.
As a further preferred embodiment, the method for simultaneously preparing the phosphine chiral center secondary/tertiary phosphine oxide compound catalyzed by palladium/chiral ligand comprises the following steps:
in the present invention, the palladium catalyst is most preferably selected from tris (dibenzylideneacetone) dipalladium.
In the present invention, the chiral tertiary butyl sulfinamide monophosphine ligand Xiao-Phos is optimally selected from
Or an enantiomer thereof.
In the present invention, the additive is most preferably selected from rubidium carbonate.
In the present invention, the reaction solvent is most preferably selected from acetonitrile.
The beneficial effects of the invention include: the invention uses palladium catalyst and chiral ligand Xiao-Phos as catalyst, provides a high-efficiency and atom-economical route for kinetic resolution of racemic secondary phosphine oxide and preparation of phosphine chiral center compound, and the obtained phosphine chiral center secondary phosphine oxide and phosphine chiral center tertiary phosphine oxide compound with high optical activity have wide subsequent synthesis application, so the synthesis method provided by the invention has high practical application value.
Detailed Description
The present invention will be described in further detail with reference to the following specific examples. The procedures, conditions, experimental methods and the like for carrying out the present invention are general knowledge and common general knowledge in the art except for the contents specifically mentioned below, and the present invention is not particularly limited.
Example 1: synthesis of products III-1 and IV-1
The experimental steps are as follows: into a sealed tube having a volume of 15mL, tris (dibenzylideneacetone) dipalladium (0.01mmol,5 mol%), (S, R)S) X6(0.03mmol,15 mol%). The double calandria was connected, the gas was purged three times under argon, and racemic secondary phosphine I-1(0.4mmol), alkylating agent II-2(0.2mmol), rubidium carbonate (0.44mmol) and acetonitrile (2.0mL) were added while maintaining the aeration. The reaction system was closed and the reaction solution was reacted at 55 ℃. After the reaction is finished, filtering and concentrating the reaction system through a small amount of silica gel, and separating and purifying the obtained concentrate to respectively obtain a target compound III-1 and a target compound IV-1.
The resulting concentrated crude product was separated and purified by column chromatography to give the target compound III-1 as a white solid, 28.2mg, in a yield of 39% and an ee value of 91%. [ alpha ] to]D 20-37.9 (c ═ 0.33, chloroform). The spectrum of the product obtained is in accordance with the report in the literature (J.Am.chem.Soc.2016,138, 13183-13186).
Separating and purifying the obtained concentrated crude product by column chromatography to obtain a white solid target compound IV-148.6mg of a derivative thereof was obtained in a yield of 45% and an ee value of 93%. [ alpha ] to]D 20-96.6 (c ═ 0.33, chloroform).1H NMR(500MHz,CDCl3)δ(ppm):7.74-7.70(m,2H),7.47-7.39(m,3H),7.28-7.26(m,2H),7.19-7.16(m,2H),7.13-7.10(m,1H),3.53-3.38(m,2H),1.14(d,J＝14.5Hz,9H)；13C NMR(125MHz,CDCl3)δ(ppm):132.0(d,JC-P＝7.8Hz),131.9(d,JC-P＝6.6Hz),131.3(d,JC-P＝2.6Hz),130.1(d,JC-P＝5.0Hz),129.8(d,JC-P＝87.0Hz),128.3(d,JC-P＝2.1Hz),128.0(d,JC-P＝10.6Hz),126.5(d,JC-P＝2.4Hz),33.3(d,JC-P＝67.5Hz),31.3(d,JC-P＝58.4Hz),24.7；31P NMR(202MHz,CDCl3)δ(ppm):46.2；HRMS-ESI+(m/z):found[M+Na]+295.1215,calc’d[C17H21NaOP]+requires 295.1222.
Example 2: synthesis of products III-2 and IV-2
Experimental method of example 2 referring to example 1, racemic secondary phosphine oxide shown as formula I-2 was used, and the remaining procedures were the same as in example 1, to finally obtain the corresponding target compounds III-2 and IV-2.
The obtained concentrated crude product was separated and purified by column chromatography to obtain the objective compound III-2 as a white solid, 32.1mg, yield 41%, ee value 98%. [ alpha ] to]D 20-24.8 (c ═ 0.33, chloroform). The spectrum of the product obtained is in accordance with the report in the literature (Angew. chem. int. Ed.2020,59, 20645-20650).
The obtained concentrated crude product was separated and purified by column chromatography to give the target compound IV-2 as a white solid, 47.8mg, in a yield of 42% and an ee value of 96%. [ alpha ] to]D 20-68.6 (c ═ 0.33, chloroform).1H NMR(500MHz,CDCl3)δ(ppm):7.43(dd,J＝10.5Hz,J＝8.0Hz,1H),7.36(d,J＝8.0Hz,2H),7.30(t,J＝7.5Hz,1H),7.20-7.10(m,5H),3.54-3.45(m,2H),2.68(s,3H),1.14(d,J＝14.0Hz,9H)；13C NMR(125MHz,CDCl3)δ(ppm):145.2(d,JC-P＝3.1Hz),132.5(d,JC-P＝10.1Hz),132.5(d,JC-P＝7.4Hz),132.3(d,JC-P＝11.3Hz),131.0(d,JC-P＝2.8Hz),130.2(d,JC-P＝5.0Hz),128.1(d,JC-P＝1.9Hz),126.9(d,JC-P＝84.8Hz),126.3(d,JC-P＝2.3Hz),124.3(d,JC-P＝11.5Hz),34.8(d,JC-P＝66.3Hz),32.4(d,JC-P＝59.0Hz),24.8,21.8(d,JC-P＝2.0Hz)；31P NMR(202MHz,CDCl3)δ(ppm):51.5；HRMS-ESI+(m/z):found[M+Na]+309.1372,calc’d[C18H23NaOP]+requires 309.1379.
Example 3: synthesis of products III-3 and IV-3
Experimental method for example 3 referring to example 1, racemic secondary phosphine oxide shown in formula I-3 was used, and the remaining operation steps were the same as in example 1, to finally obtain the corresponding target compounds III-3 and IV-3.
The resulting concentrated crude product was separated and purified by column chromatography to give the target compound III-3 as a white solid, 33.2mg, in a yield of 42% and an ee value of 93%. [ alpha ] to]D 20-35.1 (c ═ 0.33, chloroform). The spectrum of the product obtained is in accordance with the report in the literature (Angew. chem. int. Ed.2020,59, 20645-20650).
The obtained concentrated crude product was separated and purified by column chromatography to give the target compound IV-3 as a white solid, 48.1mg, in a yield of 42% and an ee value of 93%. [ alpha ] to]D 20-89.9 (c ═ 0.33, chloroform).1H NMR(500MHz,CDCl3)δ(ppm):7.55(d,J＝10.5Hz,1H),7.46(t,J＝8.0Hz,1H),7.31-7.24(m,4H),7.17(t,J＝7.5Hz,2H),7.12-7.09(m,1H),3.49(dd,J＝15.0Hz,J＝15.0Hz,1H),3.39(dd,J＝15.0Hz,J＝9.5Hz,1H),2.34(s,3H),1.13(d,J＝15.0Hz,9H)；13C NMR(125MHz,CDCl3)δ(ppm):137.8(d,JC-P＝10.5Hz),132.8(d,JC-P＝7.3Hz),132.1(d,JC-P＝2.6Hz),132.0(d,JC-P＝7.8Hz),130.1(d,JC-P＝5.0Hz),129.4(d,JC-P＝87.0Hz),128.7(d,JC-P＝8.3Hz),128.3(d,JC-P＝2.0Hz),127.7(d,JC-P＝11.4Hz),126.4(d,JC-P＝2.4Hz),33.3(d,JC-P＝67.3Hz),31.3(d,JC-P＝58.3Hz),24.7,21.3；31P NMR(202MHz,CDCl3)δ(ppm):46.6；HRMS-ESI+(m/z):found[M+Na]+309.1378,calc’d[C18H23NaOP]+requires 309.1379.
Example 4: synthesis of products III-4 and IV-4
Experimental method for example 4 referring to example 1, racemic secondary phosphine oxide shown in formula I-4 was used, and the remaining procedures were the same as in example 1, to finally obtain the corresponding target compounds III-4 and IV-4.
The obtained concentrated crude product was separated and purified by column chromatography to give the target compound III-4 as a white solid, 30.8mg, in a yield of 39% and an ee value of 94%. [ alpha ] to]D 20-29.2 (c ═ 0.33, chloroform). The spectrum of the product obtained is in accordance with the report in the literature (Angew. chem. int. Ed.2020,59, 20645-20650).
The resulting concentrated crude product was separated and purified by column chromatography to give the target compound IV-4 as a white solid, 49.3mg, yield 43%, ee value 91%. [ alpha ] to]D 20-111.5 (c ═ 0.33, chloroform).1H NMR(600MHz,CDCl3)δ(ppm):7.58(dd,J＝9.6Hz,J＝8.4Hz,2H),7.27-7.26(m,2H),7.20(dd,J＝7.8Hz,J＝1.8Hz,2H),7.16(t,J＝7.2Hz,2H),7.10(dt,J＝7.8Hz,J＝1.2Hz,1H),3.47(dd,J＝15.0Hz,J＝15.0Hz,1H),3.37(dd,J＝15.0Hz,J＝9.0Hz,1H),2.34(s,3H),1.12(d,J＝14.4Hz,9H)；13C NMR(150MHz,CDCl3)δ(ppm):141.6(d,JC-P＝2.3Hz),132.0(d,JC-P＝7.8Hz),131.9(d,JC-P＝7.8Hz),130.1(d,JC-P＝4.8Hz),128.7(d,JC-P＝11.3Hz),128.2(d,JC-P＝1.4Hz),126.4(d,JC-P＝2.0Hz),126.2(d,JC-P＝89.7Hz),33.3(d,JC-P＝67.5Hz),31.3(d,JC-P＝58.4Hz),24.6,21.4；31P NMR(242MHz,CDCl3)δ(ppm):46.5；HRMS-ESI+(m/z):found[M+Na]+309.1376,calc’d[C18H23NaOP]+requires 309.1379.
Example 5: synthesis of products III-5 and IV-5
Experimental method for example 5 referring to example 1, racemic secondary phosphine oxide shown in formula I-5 was used, and the remaining procedures were the same as in example 1, to finally obtain the corresponding target compounds III-5 and IV-5.
The obtained concentrated crude product was separated and purified by column chromatography to give the target compound III-5 as a white solid (35.6 mg), with a yield of 38% and an ee value of 97%. [ alpha ] to]D 20-35.9 (c ═ 0.33, chloroform). The spectrum of the product obtained is in accordance with the report in the literature (Angew. chem. int. Ed.2020,59, 20645-20650).
The obtained concentrated crude product was separated and purified by column chromatography to give the target compound IV-5 as a white solid, 54.6mg, yield 43%, ee value 92%. [ alpha ] to]D 20-151.2 (c ═ 0.33, chloroform).1H NMR(500MHz,CDCl3)δ(ppm):8.35(d,J＝12.0Hz,1H),7.89-7.82(m,3H),7.68(dt,J＝8.5Hz,J＝1.5Hz,1H),7.55-7.48(m,2H),7.30(d,J＝7.5Hz,2H),7.14(t,J＝7.5Hz,2H),7.07(t,J＝7.0Hz,1H),3.61-3.49(m,2H),1.19(d,J＝14.5Hz,9H)；13C NMR(125MHz,CDCl3)δ(ppm):134.4(d,JC-P＝6.5Hz),134.3(d,JC-P＝2.3Hz),132.2(d,JC-P＝11.6Hz),131.8(d,JC-P＝7.9Hz),130.0(d,JC-P＝5.0Hz),128.7,128.2(d,JC-P＝2.0Hz),127.8,127.6,127.3(d,JC-P＝10.6Hz),126.9(d,JC-P＝84.6Hz),126.6(d,JC-P＝9.0Hz),126.6,126.4(d,JC-P＝2.4Hz),33.5(d,JC-P＝67.6Hz),31.2(d,JC-P＝58.4Hz),24.7；31P NMR(202MHz,CDCl3)δ(ppm):46.5；[α]D 20＝-151.2(c＝0.33,CHCl3)；HRMS-ESI+(m/z):found[M+Na]+345.1373,calc’d[C21H23NaOP]+requires 345.1379.
Example 6: synthesis of products III-6 and IV-6
Experimental method of example 6 referring to example 1, racemic secondary phosphine oxide shown in formula I-6 and an alkylating reagent shown in formula II-2 are adopted, and the rest of the operation steps are the same as example 1, so that corresponding target compounds III-6 and IV-6 are finally obtained.
The resulting concentrated crude product was separated and purified by column chromatography to give the objective compound III-6 as a colorless oily compound, 23.2mg, yield 32%, ee value 38%. [ alpha ] to]D 20-5.9 (c ═ 0.33, chloroform). The spectrum of the product obtained is in accordance with the literature (J.Am.chem.Soc.2019,141, 20556-20564).
The obtained concentrated crude product was separated and purified by column chromatography to give the target compound IV-6 as a white solid, 28.1mg, yield 26%, ee value 91%. [ alpha ] to]D 2021.6(c 0.33, chloroform).1H NMR(500MHz,CDCl3)δ(ppm):7.45(dd,J＝12.0Hz,J＝7.5Hz,1H),7.35(t,J＝7.5Hz,1H),7.21-7.15(m,5H),7.06-7.04(m,2H),3.33(qn,J＝13.5Hz,2H),2.54(s,3H),1.97-1.91(m,2H),1.68-1.48(m,2H),0.96(dt,J＝7.0Hz,J＝0.5Hz,3H)；13C NMR(125MHz,CDCl3)δ(ppm):141.7(d,JC-P＝7.9Hz),132.0(d,JC-P＝7.3Hz),131.8(d,JC-P＝3.3Hz),131.7(d,JC-P＝3.9Hz),131.5(d,JC-P＝2.6Hz),129.6(d,JC-P＝5.0Hz),129.6(d,JC-P＝89.6Hz),128.3(d,JC-P＝2.5Hz),126.6(d,JC-P＝3.0Hz),125.4(d,JC-P＝11.4Hz),38.7(d,JC-P＝61.0Hz),30.5(d,JC-P＝68.9Hz),21.4(d,JC-P＝2.9Hz),15.6(d,JC-P＝15.1Hz),15.1(d,JC-P＝4.0Hz)；31P NMR(202MHz,CDCl3)δ(ppm):40.4；HRMS-EI+(m/z):found[M]+272.1327,calc’d[C17H21OP]+requires 272.1325.
Example 7: synthesis of products III-7 and IV-7
Experimental method for example 7 referring to example 1, racemic secondary phosphine oxide shown in formula I-7 and an alkylating reagent shown in formula II-2 are adopted, and the rest of the operation steps are the same as example 1, so that corresponding target compounds III-7 and IV-7 are finally obtained.
The resulting concentrated crude product was separated and purified by column chromatography to give the objective compound III-7 as a colorless oily compound, 29.2mg, in a yield of 40% and an ee value of 95%. [ alpha ] to]D 20-17.7 (c ═ 0.33, chloroform). The spectrum of the product obtained is in accordance with the report in the literature (Angew. chem. int. Ed.2020,59, 20645-20650).
The resulting concentrated crude product was separated and purified by column chromatography to give the objective compound IV-7 as a colorless oily compound, 45.7mg, in a yield of 42% and an ee value of 95%. [ alpha ] to]D 202.1(c 0.33, chloroform).1H NMR(500MHz,CDCl3)δ(ppm):7.44-7.40(m,1H),7.30(tt,J＝7.5Hz,J＝1.5Hz,1H),7.16-7.09(m,5H),7.05-7.03(m,2H),3.45(t,J＝14.5Hz,1H),3.26(dd,J＝14.5Hz,J＝11.0Hz,1H),2.47(s,3H),2.27-2.20(m,1H),1.30(dd,J＝15.5Hz,J＝7.0Hz,3H),1.04(dd,J＝16.0Hz,J＝7.0Hz,3H)；13C NMR(125MHz,CDCl3)δ(ppm):142.3(d,JC-P＝7.4Hz),132.1(d,JC-P＝9.6Hz),132.0(d,JC-P＝7.3Hz),131.7(d,JC-P＝10.5Hz),131.2(d,JC-P＝2.6Hz),129.7(d,JC-P＝4.9Hz),128.3(d,JC-P＝87.4Hz),128.1(d,JC-P＝2.4Hz),126.4(d,JC-P＝2.6Hz),125.1(d,JC-P＝11.1Hz),36.2(d,JC-P＝59.4Hz),27.1(d,JC-P＝68.6Hz),21.4(d,JC-P＝2.3Hz),15.7(d,JC-P＝2.9Hz),15.3(d,JC-P＝3.1Hz)；31P NMR(202MHz,CDCl3)δ(ppm):46.6；[α]D 20＝-2.1(c＝0.33,CHCl3)；HRMS-EI+(m/z):found[M]+272.1325,calc’d[C17H21OP]+requires 272.1325.
Example 8: synthesis of products III-8 and IV-8
The experimental method of example 8 referring to example 1, racemic secondary phosphine oxide shown in formula I-8 and alkylating agent shown in formula II-2 are adopted, and the rest of the operation steps are the same as example 1, so that corresponding target compounds III-8 and IV-8 are finally obtained.
The resulting concentrated crude product was separated and purified by column chromatography to give the objective compound III-8 as a colorless oily compound (37.4 mg), yield 42%, ee value 68%. [ alpha ] to]D 20-11.1(c ═ 0.33, chloroform). The spectrum of the product obtained is in accordance with the report in the literature (Angew. chem. int. Ed.2020,59, 20645-20650).
The resulting concentrated crude product was separated and purified by column chromatography to give the target compound IV-8 as a white solid, 46.7mg, in a yield of 37% and an ee value of 96%. [ alpha ] to]D 20-11.1(c ═ 0.33, chloroform).1HNMR(500MHz,CDCl3)δ(ppm):7.43(ddd,J＝11.5Hz,J＝7.5Hz,J＝1.0Hz,1H),7.31(dt,J＝7.5Hz,J＝1.5Hz,1H),7.17-7.11(m,5H),7.06-7.04(m,2H),3.46(t,J＝14.5Hz,1H),3.26(dd,J＝14.5Hz,J＝11.0Hz,1H),2.47(s,3H),2.04-1.94(m,2H),1.89-1.86(m,1H),1.75-1.59(m,4H),1.43-1.34(m,1H),1.31-1.18(m,3H)；13C NMR(125MHz,CDCl3)δ(ppm):142.3(d,JC-P＝7.5Hz),132.2(d,JC-P＝9.4Hz),132.1(d,JC-P＝6.3Hz),131.7(d,JC-P＝10.4Hz),131.2(d,JC-P＝2.6Hz),129.7(d,JC-P＝5.0Hz),128.3(d,JC-P＝87.0Hz),128.2(d,JC-P＝2.4Hz),126.4(d,JC-P＝2.8Hz),125.1(d,JC-P＝11.1Hz),37.7(d,JC-P＝68.6Hz),35.8(d,JC-P＝59.6Hz),26.4(d,JC-P＝5.9Hz),26.2(d,JC-P＝5.4Hz),25.7(d,JC-P＝1.3Hz),25.2(d,JC-P＝3.0Hz),25.1(d,JC-P＝3.3Hz),21.5(d,JC-P＝2.4Hz)；31P NMR(202MHz,CDCl3)δ(ppm):44.0；HRMS-EI+(m/z):found[M]+312.1639,calc’d[C20H25OP]+requires 312.1638.
Examples 9 to 25
The present invention has wide substrate applicability, and many substrates can participate in the reaction according to the reaction conditions in example 1, and secondary phosphine oxide and tertiary phosphine oxide of phosphine chiral centers can be obtained with high yield and high stereoselectivity.
Examples 9-25 reference example 1 with the exception of "(1) replacing the compound of formula II-1 of example 1 with an equimolar amount of alkylating agent; (2) the chiral ligand is (S, R)S) -X6 or (S, R)S) -X10 "; (3) different reaction time length "; the other operation steps are the same as the example 1, and the corresponding secondary phosphine oxide compound and the tertiary phosphine oxide compound with the phosphine chiral center are finally obtained, wherein the reaction formula is as follows:
in the above reaction formula, the substituent R in the structural formula of formula IV3Are all the same as in the structural formula II.
Wherein, the molecular structural formulas of the alkylating reagents used in examples 9 to 25 are shown in II-3 to II-19 in Table 1, respectively.
The reaction results are shown in table 1.
In table 1 of the present application, racemic secondary phosphine oxide of formula I-1 is used in combination with different alkylating reagents as shown in formula II to prepare two corresponding target compounds, namely, phosphine chiral center secondary phosphine oxide of formula III-1 and phosphine chiral center tertiary phosphine oxide of formula IV. For example, the experimental procedure of example 9 of the present application was conducted in accordance with example 1 except that "the compound represented by the formula II-1 in example 1 was replaced with an equimolar amount of the compound represented by the formula II-3 and the reaction time was changed to 39 hours", and the other procedures were conducted in the same manner as in example 1 to finally obtain the corresponding compounds III-1 and IV-9, and the reaction results thereof are summarized in Table 1, in which the yield of the compound III-1 was 41%, the ee value was 90%, the yield of the compound IV-9 was 43%, and the ee value was 95%.
Table 1.
Example 26: synthesis of products III-1 and IV-26
EXAMPLE 26 Experimental procedure with reference to example 1, an alkylating agent of the formula II-20 and a chiral ligand (S, R) are employedS) -X10, and the remaining steps are the same as in example 1, to finally obtain the corresponding target compounds III-1 and IV-26.
The obtained concentrated crude product was separated and purified by column chromatography to obtain the objective compound III-1 as a white solid, 1.22g, in a yield of 42% and an ee value of 78%. The spectrum of the product obtained is in accordance with the report in the literature (J.Am.chem.Soc.2016,138, 13183-13186).
The obtained concentrated crude product is separated and purified by column chromatography to obtain the target compound IV-26 which is a white foamy solid with the yield of 27 percent and 0.99g,dr value of>20:1, ee value 99%. [ alpha ] to]D 20-1.8(c ═ 0.33, chloroform).1H NMR(500MHz,CDCl3)δ(ppm):7.77-7.67(m,4H),7.62-7.59(m,2H),7.45-7.39(m,2H),7.36-7.24(m,6H),3.50(dd,J＝14.5Hz,J＝14.5Hz,1H),3.37(dd,J＝15.0Hz,J＝8.5Hz,1H),1.09-1.05(m,18H)；13C NMR(125MHz,CDCl3)δ(ppm):133.2(dd,JC-P＝4.8Hz,JC-P＝2.6Hz),132.9(dd,JC-P＝8.9Hz,JC-P＝5.4Hz),132.2(dd,JC-P＝11.4Hz,JC-P＝7.8Hz),131.9(d,JC-P＝8.1Hz),131.7(d,JC-P＝7.8Hz),131.3(d,JC-P＝2.4Hz),131.1(d,JC-P＝2.4Hz),131.0(dd,JC-P＝89.3Hz,JC-P＝1.6Hz),130.9(dd,JC-P＝89.8Hz,JC-P＝3.6Hz),130.4(dd,JC-P＝7.3Hz,JC-P＝1.8Hz),129.2(dd,JC-P＝87.1Hz,JC-P＝4.1Hz),128.3(dd,JC-P＝11.3Hz,JC-P＝1.4Hz),127.9(d,JC-P＝10.9Hz),127.9(d,JC-P＝10.6Hz),33.6(d,JC-P＝70.3Hz),33.2(d,JC-P＝67.6Hz),31.0(d,JC-P＝57.8Hz),24.9,24.5；31P NMR(202MHz,CDCl3)δ(ppm):46.7,38.6；HRMS-ESI+(m/z):found[M+Na]+475.1923,calc’d[C27H34NaO2P2]+requires 475.1926.
Example 27: synthesis of products III-1 and IV-27
EXAMPLE 27 Experimental procedure referring to example 1, an alkylating agent of the formula II-21 and a chiral ligand (S, R) are employedS) -X10, and the remaining steps are the same as in example 1, to finally obtain the corresponding target compounds III-1 and IV-27.
The obtained concentrated crude product was separated and purified by column chromatography to obtain the objective compound III-1 as a white solid, 0.90g, with a yield of 41% and an ee value of 84%. The spectrum of the product obtained is in accordance with the report in the literature (J.Am.chem.Soc.2016,138, 13183-13186).
The obtained concentrated crude product was separated and purified by column chromatography to obtain the desired compound IV-27 as a white foamy solid, 1.05g, yield 36%, dr value>20:1, ee value 99%. [ alpha ] to]D 20-90.8(c ═ 0.33, chloroform).1HNMR(500MHz,CDCl3)δ(ppm):7.64-7.60(m,4H),7.41-7.37(m,2H),7.36-7.33(m,4H),7.30(s,1H),7.03(d,J＝7.5Hz,2H),6.94(t,J＝7.5Hz,1H),3.43(dd,J＝14.5Hz,J＝14.5Hz,2H),3.28(dd,J＝15.0Hz,J＝9.5Hz,2H),1.06(d,J＝14.5Hz,18H)；13C NMR(125MHz,CDCl3)δ(ppm):132.1(dd,JC-P＝5.3Hz,JC-P＝5.3Hz),131.9(dd,JC-P＝8.1Hz,JC-P＝1.5Hz),131.8(d,JC-P＝7.8Hz),131.1(d,JC-P＝2.4Hz),129.6(d,JC-P＝87.3Hz),128.2(dd,overlapping peaks),128.2(dd,overlapping peaks),127.9(d,JC-P＝10.8Hz),33.2(d,JC-P＝67.4Hz),31.1(d,JC-P＝58.5Hz),24.6；31P NMR(202MHz,CDCl3)δ(ppm):46.5；HRMS-ESI+(m/z):found[M+Na]+489.2084,calc’d[C28H36NaO2P2]+requires 489.2083.
Example 28
The invention can use palladium catalyst to match with chiral ligand Xiao-Phos as catalyst, to split the second level phosphine oxide, to obtain phosphine chiral center second level phosphine oxide and phosphine chiral center third level phosphine oxide compound with high optical activity and their enantiomers.
Experimental procedure for example 28 referring to example 1, except "chiral ligands (S, R) in example 1S) Replacement of X6 by its corresponding isomer (R, S)S) -X6 "; the rest operation steps are the same as the example 1, and corresponding secondary phosphine oxide Enantiomer-III-1 and tertiary phosphine oxide Enantiomer-IV-1 of the phosphine chiral center are finally obtained, and the reaction formulas are as follows:
the obtained concentrated crude product is separated and purified by column chromatography to obtain a target compound Enantiomer-III-1, the characterization data is consistent with that of the compound III-1, [ alpha ]]D 20+37.9(c ═ 0.33, chloroform).
The obtained concentrated crude product is separated and purified by column chromatography to obtain a target compound Enantiomer-IV-1, the characterization data is consistent with the compound IV-1, [ alpha ]]D 20+96.6(c ═ 0.33, chloroform).
The method can be used for constructing the phosphine chiral center secondary phosphine oxide and the phosphine chiral center tertiary phosphine oxide which are isomers with each other, has wide substrate applicability, can smoothly react by replacing the chiral ligands used in the examples 2 to 27 with corresponding isomers, and can obtain the phosphine chiral center secondary phosphine oxide and the phosphine chiral center tertiary phosphine oxide which are enantiomeric with the products in the examples 2 to 27 with high yield and high stereoselectivity.
The protection of the present invention is not limited to the above embodiments. Variations and advantages that may occur to those skilled in the art may be incorporated into the invention without departing from the spirit and scope of the inventive concept, which is set forth in the following claims.
Claims (9)
1. A method for synthesizing a phosphine chiral center secondary/tertiary phosphine oxide compound under the catalysis of palladium/chiral ligand is characterized in that in the presence of an organic solvent and an additive, racemic secondary phosphine oxide shown in a formula I and an alkylating reagent shown in a formula II are subjected to a kinetic resolution reaction under the catalysis of a palladium catalyst/chiral ligand Xiao-Phos to obtain phosphine chiral center secondary phosphine oxide shown in a formula III and a phosphine chiral center tertiary phosphine oxide compound shown in a formula IV, wherein the chemical reaction formulas are shown in the following formula (a):
formula III and formula IV: represents chirality, being R or S;
R1、R2are each independently selected from C1～C12Alkyl, benzyl or substituted benzyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl of (a); r3Is selected from C1～C12Alkyl, benzyl or substituted benzyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, ferrocene; LG is selected from halogen, alkyl or aryl substituted acyloxy, alkyl or aryl substituted sulfonyloxy, alkyl or aryl substituted phosphonate, alkyl or aryl substituted phosphite; n is selected from 1,2 and 3;
wherein said alkyl group includes straight, branched and cyclic alkyl groups; the aryl is phenyl, naphthyl, biphenyl, phenanthryl or anthryl; the heteroaryl is thiophene, furan, pyridine or indole; in the substituted benzyl, substituted aryl and substituted heteroaryl, the substituents are selected from halogen and C1～C12Alkyl of (C)1～C10Alkoxy group of (C)1～C10Siloxane group of (A), C1～C10Alkanoyl of (2), C1～C10Ester group of (1), C1～C10One or more of sulfonate, amido, hydroxyl, trifluoromethyl, nitro, cyano and aryl.
2. The method according to claim 1, wherein a palladium catalyst is used together with a chiral ligand Xiao-Phos as a catalyst, a racemic secondary phosphine oxide compound, an alkylating reagent and an additive are added into an organic solvent, the reaction temperature is 10-80 ℃, the reaction time is 10-120 hours, and after the reaction is finished, the secondary phosphine oxide at the chiral center of phosphine and the tertiary phosphine oxide at the chiral center of phosphine are obtained through purification.
3. The process according to claim 1 or 2, wherein the palladium catalyst is selected from one of tris (dibenzylideneacetone) dipalladium, bis (dibenzylideneacetone) palladium, tris (dibenzylideneacetone) dipalladium chloroform adduct, allylpalladium chloride dimer, bis (triphenylphosphine) palladium dichloride, palladium chloride, [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride, tetraacetonitrile palladium tetrafluoroborate, (1, 5-cyclooctadiene) palladium dichloride, bis (tri-tert-butylphosphino) palladium, palladium acetate, bis (tri-tert-butylphosphino) palladium, diacetonitrile palladium chloride, and tetratriphenylphosphine palladium.
4. The process according to claim 1 or 2, characterized in that the chiral ligand is a chiral tertiary butyl sulfinamide monophosphine ligand, Xiao-Phos, or an enantiomer thereof, as shown in formula V:
in formula V: r4Is selected from C1～C12Alkyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl of (a); r5Selected from hydrogen, C1～C12Alkyl, benzyl or substituted benzyl, aryl or substituted aryl of (a); r6Is selected from C1～C12An alkyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl group of (a);
wherein said alkyl group includes straight, branched and cyclic alkyl groups; the aryl is phenyl, naphthyl, biphenyl, phenanthryl or anthryl; the heteroaryl is thiophene, furan, pyridine or indole; in the substituted benzyl, substituted aryl and substituted heteroaryl, the substituents are selected from halogen and C1～C12Alkyl of (C)1～C10Alkoxy group of (C)1～C10Siloxane group of (A), C1～C10Alkanoyl of (2), C1～C10Ester group of (1), C1～C10One or more of sulfonate, amido, hydroxyl, trifluoromethyl, nitro, cyano, aryl and heteroaryl.
5. The method of claim 1 or 2, wherein the additive is selected from the group consisting of lithium carbonate, sodium carbonate, potassium carbonate, rubidium carbonate, cesium carbonate, barium carbonate, potassium bicarbonate, sodium bicarbonate, pyridine or substituted pyridine,
1, 8-diazohetero-bis-spiro [5.4.0 ]]One or more than two of undec-7-ene;
wherein, the substituents in the substituted pyridine are all selected from halogen and C1～C12Alkyl of (C)1～C10Alkoxy group of (C)1～C10Siloxane group of (A), C1～C10Alkanoyl of (2), C1～C10Ester group of (1), C1～C10One or more than two of sulfonate, amido, hydroxyl, trifluoromethyl, nitryl, cyano, aryl and heteroaryl; r7、R8、R9Are respectively and independently selected from hydrogen and C1～C12Alkyl, benzyl or substituted benzyl, aryl or substituted aryl.
6. The method of claim 5, wherein R is7、R8、R9In (1), the alkyl group includes straight chain, branched chain and cycloalkyl; aryl is phenyl, naphthyl, biphenyl, phenanthryl or anthryl and other aromatic rings; in the substituted benzyl and the substituted aryl, the substituents are selected from halogen and C1～C12Alkyl of (C)1～C10Alkoxy group of (C)1～C10Siloxane group of (A), C1～C10Alkanoyl of (2), C1～C10Ester group of (1), C1～C10One or more of sulfonate, amido, hydroxyl, trifluoromethyl, nitro, cyano, aryl and heteroaryl.
7. The method according to claim 1 or 2, wherein the organic solvent is selected from one of dichloromethane, dichloroethane, acetonitrile, propionitrile, butyronitrile, valeronitrile, benzonitrile, phenylacetonitrile, diethyl ether, dibutyl ether, methyl tert-butyl ether, anisole, ethylene glycol dimethyl ether, ethyl acetate, 1, 4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, xylene, benzene, chlorobenzene, fluorobenzene, trifluorotoluene, chloroform, acetone, or any mixture thereof.
8. The method according to claim 1 or 2, characterized in that the batch ratio of the method is: the mole ratio of the racemized secondary phosphine oxide to the alkylating reagent to the palladium catalyst to the chiral ligand to the additive is (1-6) to 1, (0.03-0.1) to (0.09-0.20) to (2-4).
9. The method according to claim 1 or 2, wherein the reaction temperature is 10 to 80 ℃.
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