CN113861238B - Method for synthesizing phosphine chiral center secondary/tertiary phosphine oxide compound through palladium/chiral ligand catalysis - Google Patents
Method for synthesizing phosphine chiral center secondary/tertiary phosphine oxide compound through palladium/chiral ligand catalysis Download PDFInfo
- Publication number
- CN113861238B CN113861238B CN202111222445.0A CN202111222445A CN113861238B CN 113861238 B CN113861238 B CN 113861238B CN 202111222445 A CN202111222445 A CN 202111222445A CN 113861238 B CN113861238 B CN 113861238B
- Authority
- CN
- China
- Prior art keywords
- phosphine oxide
- formula
- phosphine
- chiral
- aryl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 title claims abstract description 85
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 title claims abstract description 46
- 229910000073 phosphorus hydride Inorganic materials 0.000 title claims abstract description 42
- 239000003446 ligand Substances 0.000 title claims abstract description 28
- 238000000034 method Methods 0.000 title claims abstract description 24
- 229910052763 palladium Inorganic materials 0.000 title claims abstract description 23
- 238000006555 catalytic reaction Methods 0.000 title claims abstract description 13
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 5
- -1 phosphine oxide compound Chemical group 0.000 title claims description 35
- AUONHKJOIZSQGR-UHFFFAOYSA-N oxophosphane Chemical group P=O AUONHKJOIZSQGR-UHFFFAOYSA-N 0.000 claims abstract description 28
- 238000006243 chemical reaction Methods 0.000 claims abstract description 22
- 239000003054 catalyst Substances 0.000 claims abstract description 18
- 230000000996 additive effect Effects 0.000 claims abstract description 12
- 239000000654 additive Substances 0.000 claims abstract description 11
- 239000003960 organic solvent Substances 0.000 claims abstract description 7
- 125000003118 aryl group Chemical group 0.000 claims description 35
- 125000000217 alkyl group Chemical group 0.000 claims description 28
- 125000001072 heteroaryl group Chemical group 0.000 claims description 26
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 18
- 125000003107 substituted aryl group Chemical group 0.000 claims description 17
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- 239000002168 alkylating agent Substances 0.000 claims description 14
- 229940100198 alkylating agent Drugs 0.000 claims description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 7
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 6
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 6
- 125000001589 carboacyl group Chemical group 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 125000004185 ester group Chemical group 0.000 claims description 6
- 125000001624 naphthyl group Chemical group 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 229910052710 silicon Inorganic materials 0.000 claims description 6
- 239000010703 silicon Substances 0.000 claims description 6
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims description 6
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical group [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
- WPFGFHJALYCVMO-UHFFFAOYSA-L rubidium carbonate Chemical group [Rb+].[Rb+].[O-]C([O-])=O WPFGFHJALYCVMO-UHFFFAOYSA-L 0.000 claims description 5
- 229910000026 rubidium carbonate Inorganic materials 0.000 claims description 5
- 235000010290 biphenyl Nutrition 0.000 claims description 4
- 239000004305 biphenyl Substances 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 125000005561 phenanthryl group Chemical group 0.000 claims description 4
- MDDUHVRJJAFRAU-YZNNVMRBSA-N tert-butyl-[(1r,3s,5z)-3-[tert-butyl(dimethyl)silyl]oxy-5-(2-diphenylphosphorylethylidene)-4-methylidenecyclohexyl]oxy-dimethylsilane Chemical group C1[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)C(=C)\C1=C/CP(=O)(C=1C=CC=CC=1)C1=CC=CC=C1 MDDUHVRJJAFRAU-YZNNVMRBSA-N 0.000 claims description 4
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical group OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 claims description 3
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 3
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 229930192474 thiophene Natural products 0.000 claims description 3
- 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
- 239000006259 organic additive Substances 0.000 claims 1
- 238000000746 purification Methods 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 49
- 230000015572 biosynthetic process Effects 0.000 abstract description 13
- 238000003786 synthesis reaction Methods 0.000 abstract description 13
- MPQXHAGKBWFSNV-UHFFFAOYSA-N oxidophosphanium Chemical group [PH3]=O MPQXHAGKBWFSNV-UHFFFAOYSA-N 0.000 abstract description 7
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 4
- 239000000758 substrate Substances 0.000 abstract description 4
- 230000002152 alkylating effect Effects 0.000 abstract description 3
- 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-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 42
- 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 13
- 238000001228 spectrum Methods 0.000 description 10
- 239000011734 sodium Substances 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 3
- 150000002894 organic compounds Chemical class 0.000 description 3
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 3
- SUSQOBVLVYHIEX-UHFFFAOYSA-N phenylacetonitrile Chemical compound N#CCC1=CC=CC=C1 SUSQOBVLVYHIEX-UHFFFAOYSA-N 0.000 description 3
- 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 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 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
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 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 description 2
- 125000006165 cyclic alkyl group Chemical group 0.000 description 2
- 239000006260 foam Substances 0.000 description 2
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical group [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 2
- 229910052808 lithium carbonate Inorganic materials 0.000 description 2
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 2
- MXQOYLRVSVOCQT-UHFFFAOYSA-N palladium;tritert-butylphosphane Chemical compound [Pd].CC(C)(C)P(C(C)(C)C)C(C)(C)C.CC(C)(C)P(C(C)(C)C)C(C)(C)C MXQOYLRVSVOCQT-UHFFFAOYSA-N 0.000 description 2
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical group [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 235000011181 potassium carbonates Nutrition 0.000 description 2
- 150000003222 pyridines Chemical class 0.000 description 2
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 description 1
- VYXHVRARDIDEHS-UHFFFAOYSA-N 1,5-cyclooctadiene Chemical compound C1CC=CCCC=C1 VYXHVRARDIDEHS-UHFFFAOYSA-N 0.000 description 1
- 239000004912 1,5-cyclooctadiene Substances 0.000 description 1
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 1
- CSIFGMFVGDBOQC-UHFFFAOYSA-N 3-iminobutanenitrile Chemical compound CC(=N)CC#N CSIFGMFVGDBOQC-UHFFFAOYSA-N 0.000 description 1
- PKPBCVSCCPTDIU-UHFFFAOYSA-N B.P Chemical group B.P PKPBCVSCCPTDIU-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- RFFFKMOABOFIDF-UHFFFAOYSA-N Pentanenitrile Chemical compound CCCCC#N RFFFKMOABOFIDF-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 238000005273 aeration Methods 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- TWKVUTXHANJYGH-UHFFFAOYSA-L allyl palladium chloride Chemical class Cl[Pd]CC=C.Cl[Pd]CC=C TWKVUTXHANJYGH-UHFFFAOYSA-L 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- AYJRCSIUFZENHW-DEQYMQKBSA-L barium(2+);oxomethanediolate Chemical compound [Ba+2].[O-][14C]([O-])=O AYJRCSIUFZENHW-DEQYMQKBSA-L 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 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 description 1
- 230000007547 defect Effects 0.000 description 1
- 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 description 1
- 239000007789 gas Substances 0.000 description 1
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- USFPINLPPFWTJW-UHFFFAOYSA-N tetraphenylphosphonium Chemical compound C1=CC=CC=C1[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 USFPINLPPFWTJW-UHFFFAOYSA-N 0.000 description 1
- JABYJIQOLGWMQW-UHFFFAOYSA-N undec-4-ene Chemical compound CCCCCCC=CCCC JABYJIQOLGWMQW-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 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 phosphine chiral center secondary/tertiary phosphine oxide compounds by palladium/chiral ligand catalysis, which comprises the steps of carrying out kinetic resolution reaction on racemized secondary phosphine oxide shown in a formula I and an alkylating reagent shown in a formula II under the catalysis of a palladium catalyst/chiral ligand Xiao-Phos in the presence of an organic solvent and an additive to obtain phosphine chiral center secondary phosphine oxide shown in a formula III and phosphine chiral center tertiary phosphine oxide shown in a formula IV. The invention has the advantages of stable and easily obtained raw materials, simple method and wide substrate application range, provides a high-efficiency and atom-economical route for the kinetic resolution of the racemic secondary phosphine oxide and the preparation of the phosphine chiral center compound, and has wide subsequent synthesis application of the two products with high optical activity, so that 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 phosphine chiral center secondary phosphine oxide and phosphine chiral center tertiary phosphine oxide by using a palladium/chiral ligand catalytic system to catalyze asymmetric alkylation of a secondary phosphine oxide compound with high enantioselectivity and realizing efficient kinetic resolution of racemic secondary phosphine oxide.
Background
Organic compounds containing phosphine chiral centers find very important applications in the field of asymmetric catalysis (chem. Soc. Rev.2016,45,5771-5794; chem. Rec.2016,16, 2655-2669). Construction of phosphine chiral tertiary phosphine compounds by asymmetric catalysis has been widely developed (Eur. J. Org. Chem.2020, 3351-3366), however, preparation of phosphine chiral central secondary phosphine compounds (secondary phosphine oxides, secondary phosphine boranes) is still mainly obtained by chiral prosthetic group resolution (Synthesis 2021, doi: 10.1055/a-1582-0169), and there is little to obtain such compounds by asymmetric catalysis. The phosphine chiral center secondary phosphine compound is taken as a key phosphine chiral center organic compound synthon, can be quickly introduced into a designated 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 racemic secondary phosphine oxide with certain configuration stability is used as an initial phosphine reagent, a kinetic resolution strategy is introduced into an asymmetric catalytic system, and the phosphine chiral secondary phosphine oxide with higher practicability can be obtained with high enantioselectivity while the phosphine chiral center compound is efficiently constructed, so that the implementation and application value of the reaction can be remarkably improved, and the atom economy is improved.
Disclosure of Invention
In order to solve the defects existing in the prior art, the invention aims to provide a method for synthesizing phosphine chiral center secondary/tertiary phosphine oxide compounds by palladium/chiral ligand catalysis, 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 dynamic 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 phosphine chiral center tertiary phosphine oxide compound shown in a formula IV, wherein the reaction formula is as follows:
in formula III and formula IV: * Represents chirality, and is R or S;
R 1 、R 2 are respectively and independently selected from C 1 ～C 12 An alkyl, benzyl or substituted benzyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl group; r is R 3 Selected from C 1 ～C 12 Alkyl, 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 the alkyl group includes straight chain, branched chain and cycloalkyl; the aryl is an aromatic ring such as phenyl, naphthyl, biphenyl, phenanthryl or anthracyl; the heteroaryl is thiophene, furan, pyridine, indole and the like; in the substituted benzyl, the substituted aryl and the substituted heteroaryl, the substituents are all selected from halogen and C 1 ～C 12 Alkyl, C of (2) 1 ～C 10 Alkoxy, C 1 ～C 10 Silicon oxy, C 1 ～C 10 Alkanoyl, C 1 ～C 10 Ester group, C 1 ～C 10 One or more of sulfonate, amino, hydroxyl, trifluoromethyl, nitro, cyano and aryl.
The specific synthesis method is as follows: the method comprises the steps of using a palladium catalyst and a chiral ligand Xiao-Phos as catalysts, adding a racemized secondary phosphine oxide compound, an alkylating agent and an additive into an organic solvent, reacting at a temperature of 10-80 ℃ for 10-120 hours, and purifying after the reaction is finished to obtain phosphine chiral center secondary phosphine oxide and phosphine chiral center tertiary phosphine oxide compound.
In the present invention, 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 tetrafluoroborate, (1, 5-cyclooctadiene) palladium dichloride, bis (tri-t-butylphosphine) palladium, palladium acetate, bis (tri-t-butylphosphine) palladium, diacetonitrile palladium chloride, and tetra-triphenylphosphine palladium.
In the invention, the chiral ligand is chiral tert-butylsulfinamide monophosphine ligand Xiao-Phos shown in the formula V or an enantiomer thereof,
in formula V: r is R 4 Selected from C 1 ～C 12 An alkyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl group; r is R 5 Selected from hydrogen, C 1 ～C 12 An alkyl, benzyl or substituted benzyl, aryl or substituted aryl group; r is R 6 Selected from C 1 ～C 12 An alkanyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl group;
wherein the alkyl group includes straight chain, branched chain and cycloalkyl; the aryl is an aromatic ring such as phenyl, naphthyl, biphenyl, phenanthryl or anthracyl; the heteroaryl is thiophene, furan, pyridine, indole and the like; in the substituted benzyl, the substituted aryl and the substituted heteroaryl, the substituents are all selected from halogen and C 1 ～C 12 Alkyl, C of (2) 1 ～C 10 Alkoxy, C 1 ～C 10 Silicon oxy, C 1 ～C 10 Alkanoyl, C 1 ～C 10 Ester group, C 1 ～C 10 One or more of sulfonate, amino, 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-Diazo heterobisspirocycles [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 C 1 ～C 12 Alkyl, C of (2) 1 ～C 10 Alkoxy, C 1 ～C 10 Silicon oxy, C 1 ～C 10 Alkanoyl, C 1 ～C 10 Ester group, C 1 ～C 10 One or more of sulfonate, amino, hydroxyl, trifluoromethyl, nitro, cyano, aryl and heteroaryl; r is R 7 、R 8 、R 9 Are independently selected from hydrogen, C 1 ～C 12 Or substituted benzyl, aryl or substituted aryl.
Said R is 7 、R 8 、R 9 Alkyl groups include straight chain, branched, and cyclic alkyl groups; aryl is an aromatic ring such as phenyl, naphthyl, biphenyl, phenanthryl or anthracyl; in the substituted benzyl and the substituted aryl, the substituents are selected from halogen and C 1 ～C 12 Alkyl, C of (2) 1 ～C 10 Alkoxy, C 1 ～C 10 Silicon oxy, C 1 ～C 10 Alkanoyl, C 1 ～C 10 Ester group, C 1 ～C 10 One or more of sulfonate, amino, hydroxyl, trifluoromethyl, nitro, cyano, aryl and heteroaryl.
In the present invention, the organic solvent may be one or any mixture 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, benzotrifluoride, chloroform, and acetone.
In the invention, the method comprises the following steps: the molar ratio of the racemized secondary phosphine oxide, the alkylating agent, the palladium catalyst, the chiral ligand and the additive is (1-6) 1 (0.03-0.1) 0.09-0.20 (2-4).
In the present invention, the reaction temperature is 10 to 80 ℃.
As a preferred embodiment, the method for simultaneously preparing phosphine chiral center secondary/tertiary phosphine oxide compounds by palladium/chiral ligand catalysis comprises the following steps:
R 1 、R 2 are independently preferably selected from C 1 ～C 12 Alkyl, aryl or substituted aryl of (a); r is R 3 Preferably selected from aryl or substituted aryl, heteroaryl or substituted heteroaryl; LG is preferably selected from alkyl or aryl substituted phosphonate, alkyl or aryl substituted phosphite; n is preferably 1 or 2;
wherein the alkyl group includes straight chain, branched chain and cycloalkyl; the aryl is an aromatic ring such as phenyl, naphthyl and the like; the heteroaryl is pyridine and the like; in the substituted aryl and the substituted heteroaryl, the substituents are selected from halogen and C 1 ～C 12 Alkyl, C of (2) 1 ～C 10 Alkoxy, C 1 ～C 10 Silicon oxy, C 1 ～C 10 Alkanoyl, C 1 ～C 10 Ester group, C 1 ～C 10 One or more of sulfonate, amino, 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 adducts, palladium acetate, and tetraphenylphosphine palladium.
In the present invention, the chiral tert-butylsulfonamide monophosphine ligand Xiao-Phos is preferably of the structure:
or an enantiomer thereof.
In the present invention, the additive is preferably selected from lithium carbonate, potassium carbonate, rubidium carbonate, cesium carbonate, and,One or two or more of them;
wherein R is 7 、R 8 、R 9 Are independently selected from hydrogen, C 1 ～C 12 Alkyl, benzyl or substituted benzyl, arylA group or a substituted aryl group.
Said R is 7 、R 8 、R 9 Alkyl groups include straight chain, branched, and cyclic alkyl groups; aryl is an aromatic ring such as phenyl, naphthyl and the like; in the substituted benzyl and substituted aryl, the substituents are all selected from C 1 ～C 12 Alkyl, C of (2) 1 ～C 10 One or more of alkoxy, trifluoromethyl, aryl, heteroaryl.
In the present invention, the reaction solvent is preferably selected from one or any mixture of methylene chloride, dichloroethane, acetonitrile, benzonitrile, benzyl cyanide, anisole, ethylene glycol dimethyl ether, 1, 4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, and acetone.
In the invention, the feeding ratio of the method is preferably as follows: the molar ratio of the racemized secondary phosphine oxide, the alkylating agent, the palladium catalyst, the chiral ligand and the additive is (2-4) 1 (0.03-0.06): 0.09-0.18): 2-4.
In the present invention, the reaction temperature is preferably 40 to 55 ℃.
As a further preferred embodiment, the method for simultaneously preparing the phosphine chiral center secondary/tertiary phosphine oxide compound through palladium/chiral ligand catalysis 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 tert-butylsulfinamide monophosphine ligand Xiao-Phos is optimally selected fromOr 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: according to the invention, a palladium catalyst is used together with a chiral ligand Xiao-Phos as a catalyst, a route which is efficient and has atom economy is provided for the kinetic resolution of the racemic secondary phosphine oxide and the preparation of the phosphine chiral center compound, and the obtained phosphine chiral center secondary phosphine oxide with high optical activity and the phosphine chiral center tertiary phosphine oxide compound are widely applied to the subsequent synthesis, so that the synthesis method provided by the invention has high practical application value.
Detailed Description
The present invention will be further described in detail with reference to the following specific examples. The procedures, conditions, experimental methods, etc. for carrying out the present invention are common knowledge and common knowledge in the art, except for the following specific references, 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 15 mL-volume tube, tris (dibenzylideneacetone) dipalladium (0.01 mmol,5 mol%), (S, R) S ) X6 (0.03 mmol,15 mol%). The double gauntlets were connected, the gas was evacuated three times under argon and racemic secondary phosphine I-1 (0.4 mmol), alkylating reagent II-2 (0.2 mmol), rubidium carbonate (0.44 mmol) and acetonitrile (2.0 mL) were added while maintaining aeration. The reaction system was closed, and the reaction mixture was reacted at 55 ℃. After the reaction is finished, the reaction system is filtered through a small amount of silica gel and concentrated, and the obtained concentrate is separated and purified to obtain a target compound III-1 and a target compound IV-1 respectively.
The obtained concentrated crude product was separated and purified by column chromatography to obtain the objective compound III-1 as a white solid, 28.2mg, yield 39%, ee value 91%. [ alpha ]] D 20 = -37.9 (c=0.33, chloroform). The spectrum of the resulting product is consistent with that reported 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 objective compound IV-1 as a white solid, 48.6mg, a yield of 45%, and an ee value of 93%. [ alpha ]] D 20 -96.6 (c=0.33, chloroform). 1 H NMR(500MHz,CDCl 3 )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)； 13 C NMR(125MHz,CDCl 3 )δ(ppm):132.0(d,J C-P ＝7.8Hz),131.9(d,J C-P ＝6.6Hz),131.3(d,J C-P ＝2.6Hz),130.1(d,J C-P ＝5.0Hz),129.8(d,J C-P ＝87.0Hz),128.3(d,J C-P ＝2.1Hz),128.0(d,J C-P ＝10.6Hz),126.5(d,J C-P ＝2.4Hz),33.3(d,J C-P ＝67.5Hz),31.3(d,J C-P ＝58.4Hz),24.7； 31 P NMR(202MHz,CDCl 3 )δ(ppm):46.2；HRMS-ESI + (m/z):found[M+Na] + 295.1215,calc’d[C 17 H 21 NaOP] + requires 295.1222.
Example 2: synthesis of products III-2 and IV-2
Experimental procedure for example 2 referring to example 1, the corresponding target compounds III-2 and IV-2 were finally obtained by using the racemic secondary phosphine oxide shown in formula I-2 and the remaining procedures as in example 1.
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 ]] 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 obtain the objective compound IV-2 as a white solid, 47.8mg, yield 42%, ee value 96%. [ alpha ]] D 20 = -68.6 (c=0.33, chloroform). 1 H NMR(500MHz,CDCl 3 )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)； 13 C NMR(125MHz,CDCl 3 )δ(ppm):145.2(d,J C-P ＝3.1Hz),132.5(d,J C-P ＝10.1Hz),132.5(d,J C-P ＝7.4Hz),132.3(d,J C-P ＝11.3Hz),131.0(d,J C-P ＝2.8Hz),130.2(d,J C-P ＝5.0Hz),128.1(d,J C-P ＝1.9Hz),126.9(d,J C-P ＝84.8Hz),126.3(d,J C-P ＝2.3Hz),124.3(d,J C-P ＝11.5Hz),34.8(d,J C-P ＝66.3Hz),32.4(d,J C-P ＝59.0Hz),24.8,21.8(d,J C-P ＝2.0Hz)； 31 P NMR(202MHz,CDCl 3 )δ(ppm):51.5；HRMS-ESI + (m/z):found[M+Na] + 309.1372,calc’d[C 18 H 23 NaOP] + requires 309.1379.
Example 3: synthesis of products III-3 and IV-3
Experimental procedure for example 3 referring to example 1, the racemic secondary phosphine oxide shown in formula I-3 was used, and the remaining procedure was the same as in example 1, to finally obtain the corresponding target compounds III-3 and IV-3.
The obtained concentrated crude product was separated and purified by column chromatography to obtain the objective compound III-3 as a white solid, 33.2mg, yield 42%, ee value 93%. [ alpha ]] 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 obtain the objective compound IV-3 as a white solid, 48.1mg, yield 42%, ee value 93%. [ alpha ]] D 20 -89.9 (c=0.33, chloroform). 1 H NMR(500MHz,CDCl 3 )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)； 13 C NMR(125MHz,CDCl 3 )δ(ppm):137.8(d,J C-P ＝10.5Hz),132.8(d,J C-P ＝7.3Hz),132.1(d,J C-P ＝2.6Hz),132.0(d,J C-P ＝7.8Hz),130.1(d,J C-P ＝5.0Hz),129.4(d,J C-P ＝87.0Hz),128.7(d,J C-P ＝8.3Hz),128.3(d,J C-P ＝2.0Hz),127.7(d,J C-P ＝11.4Hz),126.4(d,J C-P ＝2.4Hz),33.3(d,J C-P ＝67.3Hz),31.3(d,J C-P ＝58.3Hz),24.7,21.3； 31 P NMR(202MHz,CDCl 3 )δ(ppm):46.6；HRMS-ESI + (m/z):found[M+Na] + 309.1378,calc’d[C 18 H 23 NaOP] + requires 309.1379.
Example 4: synthesis of products III-4 and IV-4
Experimental procedure for example 4 referring to example 1, the corresponding target compounds III-4 and IV-4 were finally obtained by using the racemic secondary phosphine oxide shown in formula I-4 and the remaining procedures as in example 1.
The obtained concentrated crude product was separated and purified by column chromatography to obtain the objective compound III-4 as a white solid, 30.8mg, yield 39%, ee value 94%. [ alpha ]] 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 obtained concentrated crude product was separated and purified by column chromatography to give the objective compound IV-4 as a white solid, 49.3mg, yield 43%, ee value 91%. [ alpha ]] D 20 = -111.5 (c=0.33, chloroform). 1 H NMR(600MHz,CDCl 3 )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)； 13 C NMR(150MHz,CDCl 3 )δ(ppm):141.6(d,J C-P ＝2.3Hz),132.0(d,J C-P ＝7.8Hz),131.9(d,J C-P ＝7.8Hz),130.1(d,J C-P ＝4.8Hz),128.7(d,J C-P ＝11.3Hz),128.2(d,J C-P ＝1.4Hz),126.4(d,J C-P ＝2.0Hz),126.2(d,J C-P ＝89.7Hz),33.3(d,J C-P ＝67.5Hz),31.3(d,J C-P ＝58.4Hz),24.6,21.4； 31 P NMR(242MHz,CDCl 3 )δ(ppm):46.5；HRMS-ESI + (m/z):found[M+Na] + 309.1376,calc’d[C 18 H 23 NaOP] + requires 309.1379.
Example 5: synthesis of products III-5 and IV-5
Experimental procedure for example 5 referring to example 1, the corresponding target compounds III-5 and IV-5 were finally obtained by the same procedure as in example 1 using racemic secondary phosphine oxide represented by formula I-5.
The obtained concentrated crude product was separated and purified by column chromatography to obtain the objective compound III-5 as a white solid, 35.6mg, yield 38%, ee value 97%. [ alpha ]] 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 obtain the objective compound IV-5 as a white solid, 54.6mg, yield 43%, ee value 92%. [ alpha ]] D 20 = -151.2 (c=0.33, chloroform). 1 H NMR(500MHz,CDCl 3 )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)； 13 C NMR(125MHz,CDCl 3 )δ(ppm):134.4(d,J C-P ＝6.5Hz),134.3(d,J C-P ＝2.3Hz),132.2(d,J C-P ＝11.6Hz),131.8(d,J C-P ＝7.9Hz),130.0(d,J C-P ＝5.0Hz),128.7,128.2(d,J C-P ＝2.0Hz),127.8,127.6,127.3(d,J C-P ＝10.6Hz),126.9(d,J C-P ＝84.6Hz),126.6(d,J C-P ＝9.0Hz),126.6,126.4(d,J C-P ＝2.4Hz),33.5(d,J C-P ＝67.6Hz),31.2(d,J C-P ＝58.4Hz),24.7； 31 P NMR(202MHz,CDCl 3 )δ(ppm):46.5；[α] D 20 ＝-151.2(c＝0.33,CHCl 3 )；HRMS-ESI + (m/z):found[M+Na] + 345.1373,calc’d[C 21 H 23 NaOP] + requires 345.1379.
Example 6: synthesis of products III-6 and IV-6
Experimental procedure for example 6 referring to example 1, the corresponding target compounds III-6 and IV-6 were finally obtained by the same procedure as in example 1, using racemic secondary phosphine oxide represented by formula I-6 and alkylating agent represented by formula II-2.
The obtained concentrated crude product was separated and purified by column chromatography to obtain the objective compound III-6 as a colorless oily compound, 23.2mg, yield 32%, ee value 38%. [ alpha ]] D 20 -5.9 (c=0.33, chloroform). The spectrum of the resulting product is consistent with that reported in the literature (J.Am. Chem. Soc.2019,141, 20556-20564).
The obtained concentrated crude product was separated and purified by column chromatography to obtain the objective compound IV-6 as a white solid, 28.1mg, yield 26%, ee value 91%. [ alpha ]] D 20 =21.6 (c=0.33, chloroform). 1 H NMR(500MHz,CDCl 3 )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)； 13 C NMR(125MHz,CDCl 3 )δ(ppm):141.7(d,J C-P ＝7.9Hz),132.0(d,J C-P ＝7.3Hz),131.8(d,J C-P ＝3.3Hz),131.7(d,J C-P ＝3.9Hz),131.5(d,J C-P ＝2.6Hz),129.6(d,J C-P ＝5.0Hz),129.6(d,J C-P ＝89.6Hz),128.3(d,J C-P ＝2.5Hz),126.6(d,J C-P ＝3.0Hz),125.4(d,J C-P ＝11.4Hz),38.7(d,J C-P ＝61.0Hz),30.5(d,J C-P ＝68.9Hz),21.4(d,J C-P ＝2.9Hz),15.6(d,J C-P ＝15.1Hz),15.1(d,J C-P ＝4.0Hz)； 31 P NMR(202MHz,CDCl 3 )δ(ppm):40.4；HRMS-EI + (m/z):found[M] + 272.1327,calc’d[C 17 H 21 OP] + requires 272.1325.
Example 7: synthesis of products III-7 and IV-7
Experimental procedure for example 7 referring to example 1, the corresponding target compounds III-7 and IV-7 were finally obtained by the same procedure as in example 1, using racemic secondary phosphine oxide represented by formula I-7 and alkylating agent represented by formula II-2.
The obtained concentrated crude product was separated and purified by column chromatography to obtain the objective compound III-7 as a colorless oily compound, 29.2mg, yield 40%, ee value 95%. [ alpha ]] 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 obtained concentrated crude product was separated and purified by column chromatography to obtain the objective compound IV-7 as a colorless oily compound, 45.7mg, yield 42%, ee value 95%. [ alpha ]] D 20 = -2.1 (c=0.33, chloroform). 1 H NMR(500MHz,CDCl 3 )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)； 13 C NMR(125MHz,CDCl 3 )δ(ppm):142.3(d,J C-P ＝7.4Hz),132.1(d,J C-P ＝9.6Hz),132.0(d,J C-P ＝7.3Hz),131.7(d,J C-P ＝10.5Hz),131.2(d,J C-P ＝2.6Hz),129.7(d,J C-P ＝4.9Hz),128.3(d,J C-P ＝87.4Hz),128.1(d,J C-P ＝2.4Hz),126.4(d,J C-P ＝2.6Hz),125.1(d,J C-P ＝11.1Hz),36.2(d,J C-P ＝59.4Hz),27.1(d,J C-P ＝68.6Hz),21.4(d,J C-P ＝2.3Hz),15.7(d,J C-P ＝2.9Hz),15.3(d,J C-P ＝3.1Hz)； 31 P NMR(202MHz,CDCl 3 )δ(ppm):46.6；[α] D 20 ＝-2.1(c＝0.33,CHCl 3 )；HRMS-EI + (m/z):found[M] + 272.1325,calc’d[C 17 H 21 OP] + requires 272.1325.
Example 8: synthesis of products III-8 and IV-8
Experimental procedure for example 8 referring to example 1, the corresponding target compounds III-8 and IV-8 were finally obtained by the same procedure as in example 1, using racemic secondary phosphine oxide represented by formula I-8 and alkylating agent represented by formula II-2.
The obtained concentrated crude product was separated and purified by column chromatography to obtain the objective compound III-8 as a colorless oily compound, 37.4mg, yield 42%, ee value 68%. [ alpha ]] 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 obtained concentrated crude product was separated and purified by column chromatography to obtain the objective compound IV-8 as a white solid, 46.7mg, yield 37%, ee value 96%. [ alpha ]] D 20 -11.1 (c=0.33, chloroform). 1 HNMR(500MHz,CDCl 3 )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)； 13 C NMR(125MHz,CDCl 3 )δ(ppm):142.3(d,J C-P ＝7.5Hz),132.2(d,J C-P ＝9.4Hz),132.1(d,J C-P ＝6.3Hz),131.7(d,J C-P ＝10.4Hz),131.2(d,J C-P ＝2.6Hz),129.7(d,J C-P ＝5.0Hz),128.3(d,J C-P ＝87.0Hz),128.2(d,J C-P ＝2.4Hz),126.4(d,J C-P ＝2.8Hz),125.1(d,J C-P ＝11.1Hz),37.7(d,J C-P ＝68.6Hz),35.8(d,J C-P ＝59.6Hz),26.4(d,J C-P ＝5.9Hz),26.2(d,J C-P ＝5.4Hz),25.7(d,J C-P ＝1.3Hz),25.2(d,J C-P ＝3.0Hz),25.1(d,J C-P ＝3.3Hz),21.5(d,J C-P ＝2.4Hz)； 31 P NMR(202MHz,CDCl 3 )δ(ppm):44.0；HRMS-EI + (m/z):found[M] + 312.1639,calc’d[C 20 H 25 OP] + 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 the secondary phosphine oxide compound and the tertiary phosphine oxide compound of the phosphine chiral center can be obtained in high yield and high stereoselectivity.
The experimental methods of examples 9-25 refer to example 1, except that "(1) the compound of formula II-1 in example 1 is replaced with an equivalent molar amount of alkylating agent; (2) The chiral ligand is (S, R) S ) -X6 or (S, R) S ) -X10"; (3) different reaction time periods "; the rest operation steps are the same as in example 1, and the corresponding phosphine chiral center secondary phosphine oxide compound and tertiary phosphine oxide compound are finally obtained, and the reaction formula is as follows:
in the above reaction formula, the substituent R in the structural formula IV 3 All are the same as those in the structural formula II.
The molecular structural formulas of the alkylating agents used in examples 9 to 25 are shown in Table 1 as II-3 to II-19, respectively.
The reaction results are shown in Table 1.
In Table 1 of the present application, two corresponding target compounds, namely, a phosphine chiral center secondary phosphine oxide of the structural formula III-1 and a phosphine chiral center tertiary phosphine oxide of the structural formula IV, can be prepared by matching a racemic secondary phosphine oxide of the structural formula I-1 with different alkylating agents shown as the structural formula II. For example, the experimental procedure of example 9 of the present application was conducted with reference to example 1, except that "the compound of formula II-1 of example 1 was replaced with an equivalent molar amount of the compound of formula II-3 and the reaction time was changed to 39 hours", and the remaining operation steps were the same as those of example 1, to finally obtain the corresponding compounds III-1 and IV-9, the reaction results of which are summarized in Table 1, 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
Experimental procedure for example 26 referring to example 1, an alkylating agent and chiral ligand (S, R) as shown in formulas II-20 are used S ) X10 and the remaining operating steps are the same as in example 1, the corresponding target compounds III-1 and IV-26 being finally obtained.
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, yield 42%, ee value 78%. The spectrum of the resulting product is consistent with that reported 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 as white foam solid, 0.99g, yield of 27%, dr value of>20:1, ee value 99%. [ alpha ]] D 20 = -1.8 (c=0.33, chloroform). 1 H NMR(500MHz,CDCl 3 )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)； 13 C NMR(125MHz,CDCl 3 )δ(ppm):133.2(dd,J C-P ＝4.8Hz,J C-P ＝2.6Hz),132.9(dd,J C-P ＝8.9Hz,J C-P ＝5.4Hz),132.2(dd,J C-P ＝11.4Hz,J C-P ＝7.8Hz),131.9(d,J C-P ＝8.1Hz),131.7(d,J C-P ＝7.8Hz),131.3(d,J C-P ＝2.4Hz),131.1(d,J C-P ＝2.4Hz),131.0(dd,J C-P ＝89.3Hz,J C-P ＝1.6Hz),130.9(dd,J C-P ＝89.8Hz,J C-P ＝3.6Hz),130.4(dd,J C-P ＝7.3Hz,J C-P ＝1.8Hz),129.2(dd,J C-P ＝87.1Hz,J C-P ＝4.1Hz),128.3(dd,J C-P ＝11.3Hz,J C-P ＝1.4Hz),127.9(d,J C-P ＝10.9Hz),127.9(d,J C-P ＝10.6Hz),33.6(d,J C-P ＝70.3Hz),33.2(d,J C-P ＝67.6Hz),31.0(d,J C-P ＝57.8Hz),24.9,24.5； 31 P NMR(202MHz,CDCl 3 )δ(ppm):46.7,38.6；HRMS-ESI + (m/z):found[M+Na] + 475.1923,calc’d[C 27 H 34 NaO 2 P 2 ] + requires 475.1926.
Example 27: synthesis of products III-1 and IV-27
Experimental procedure for example 27 referring to example 1, an alkylating agent and chiral ligand (S, R) as shown in formula II-21 are used S ) X10 and the remaining operating steps are the same as in example 1, the corresponding target compounds III-1 and IV-27 being finally obtained.
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, a yield of 41% and an ee value of 84%. The spectrum of the resulting product is consistent with that reported 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-27 as white foam solid, 1.05g, the yield is 36%, and the dr value is>20:1, ee value of99％。[α] D 20 -90.8 (c=0.33, chloroform). 1 HNMR(500MHz,CDCl 3 )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)； 13 C NMR(125MHz,CDCl 3 )δ(ppm):132.1(dd,J C-P ＝5.3Hz,J C-P ＝5.3Hz),131.9(dd,J C-P ＝8.1Hz,J C-P ＝1.5Hz),131.8(d,J C-P ＝7.8Hz),131.1(d,J C-P ＝2.4Hz),129.6(d,J C-P ＝87.3Hz),128.2(dd,overlapping peaks),128.2(dd,overlapping peaks),127.9(d,J C-P ＝10.8Hz),33.2(d,J C-P ＝67.4Hz),31.1(d,J C-P ＝58.5Hz),24.6； 31 P NMR(202MHz,CDCl 3 )δ(ppm):46.5；HRMS-ESI + (m/z):found[M+Na] + 489.2084,calc’d[C 28 H 36 NaO 2 P 2 ] + requires 489.2083.
Example 28
According to the invention, palladium catalysts can be respectively matched with chiral ligands Xiao-Phos which are corresponding isomers as catalysts, and the chiral phosphine oxide compound with high optical activity can be respectively obtained by carrying out kinetic resolution on the racemic secondary phosphine oxide, so that the synthetic method provided by the invention has high practical application value.
Experimental procedure of example 28 referring to example 1, the difference is that "chiral ligand (S, R) in example 1 S ) -X6 is replaced by its corresponding isomer (R, S S ) -X6"; the rest of the operation steps are the same as in example 1, and the corresponding phosphine chiral center secondary phosphine oxide compound Enantiomer-III-1 and tertiary phosphine oxide compound Enantiomer-IV-1 are finally obtained, and the reaction formula is as follows:
separating and purifying the obtained concentrated crude product by column chromatography to obtain the targetCompound Enantiomer-III-1, characterization data are consistent with 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 the target compound Enantiomer-IV-1, and the characterization data is consistent with the compound IV-1, [ alpha ]] D 20 = +96.6 (c=0.33, chloroform).
The invention can be used for constructing phosphine chiral center secondary phosphine oxide and phosphine chiral center tertiary phosphine oxide compounds which are mutually corresponding isomers, has wide substrate applicability, can smoothly react by changing chiral ligands used in examples 2-27 into corresponding isomers, and can obtain phosphine chiral center secondary phosphine oxide compounds and tertiary phosphine oxide compounds which are mutually enantiomer with products in examples 2-27 with high yield and high stereoselectivity.
The protection of the present invention is not limited to the above embodiments. Variations and advantages that would occur to one skilled in the art are included within the invention without departing from the spirit and scope of the inventive concept, and the scope of the invention is defined by the appended claims.
Claims (4)
1. A method for synthesizing phosphine chiral center secondary/tertiary phosphine oxide compound by palladium/chiral ligand catalysis is characterized in that in the presence of organic solvent and additive, racemic secondary phosphine oxide shown in formula I and alkylating agent shown in formula II are subjected to dynamic resolution reaction under the catalysis of palladium catalyst/chiral ligand Xiao-Phos to obtain phosphine chiral center secondary phosphine oxide shown in formula III and phosphine chiral center tertiary phosphine oxide compound shown in formula IV, wherein the chemical reaction formula is shown in formula (a):
in formula III and formula IV: * Represents chirality, and is R or S;
R 1 、R 2 are respectively and independently selected from C 1 ～C 12 Alkyl, benzyl or substituted benzyl, aryl or substituted aryl groups of (a)A group, heteroaryl or substituted heteroaryl; r is R 3 Selected from C 1 ～C 12 Alkyl, benzyl or substituted benzyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, ferrocene; LG is selected from alkyl or aryl substituted phosphonate groups; n is 1;
wherein the alkyl group includes straight chain, branched chain and cycloalkyl; the aryl is phenyl, naphthyl, biphenyl, phenanthryl or anthracyl; the heteroaryl is thiophene, furan, pyridine and indole; in the substituted benzyl, the substituted aryl and the substituted heteroaryl, the substituents are all selected from halogen and C 1 ～C 12 Alkyl, C of (2) 1 ～C 10 Alkoxy, C 1 ～C 10 Silicon oxy, C 1 ～C 10 Alkanoyl, C 1 ～C 10 Ester group, C 1 ～C 10 One or more of sulfonate, amino, hydroxyl, trifluoromethyl, nitro, cyano and aryl;
the palladium catalyst is tris (dibenzylideneacetone) dipalladium;
the chiral ligand Xiao-Phos is selected from the following structures:
the additive is rubidium carbonate;
the organic solvent is acetonitrile.
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 agent and an additive are added into an organic solvent, the reaction temperature is 10-80 ℃, the reaction time is 10-120 hours, and the phosphine chiral center secondary phosphine oxide and the phosphine chiral center tertiary phosphine oxide compound are obtained through purification after the reaction.
3. The method according to claim 1 or 2, characterized in that the method has a feed ratio of: the molar ratio of the racemized secondary phosphine oxide, the alkylating agent, the palladium catalyst, the chiral ligand and the additive is (1-6) 1 (0.03-0.1) 0.09-0.20 (2-4).
4. The process according to claim 1 or 2, wherein the temperature of the reaction is between 10 and 80 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111222445.0A CN113861238B (en) | 2021-10-20 | 2021-10-20 | Method for synthesizing phosphine chiral center secondary/tertiary phosphine oxide compound through palladium/chiral ligand catalysis |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111222445.0A CN113861238B (en) | 2021-10-20 | 2021-10-20 | Method for synthesizing phosphine chiral center secondary/tertiary phosphine oxide compound through palladium/chiral ligand catalysis |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113861238A CN113861238A (en) | 2021-12-31 |
| CN113861238B true CN113861238B (en) | 2024-03-12 |
Family
ID=78996859
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111222445.0A Active CN113861238B (en) | 2021-10-20 | 2021-10-20 | Method for synthesizing phosphine chiral center secondary/tertiary phosphine oxide compound through palladium/chiral ligand catalysis |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113861238B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101253183A (en) * | 2005-07-29 | 2008-08-27 | 巴斯夫欧洲公司 | Process for preparing optically active diphosphanes |
| CN104119382A (en) * | 2014-07-15 | 2014-10-29 | 同济大学 | 1,3-disubstituted-allylphosphine oxide compounds and preparation method thereof |
| CN110078763A (en) * | 2019-04-24 | 2019-08-02 | 华东师范大学 | A kind of chirality phosphine oxide compound and its synthetic method and application |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9512155B2 (en) * | 2011-08-19 | 2016-12-06 | Nanyang Technological University | Chiral phosphines for palladium-catalyzed asymmetric α-arylation of ester enolates to produce tertiary stereocenters in high enantioselectivity |
-
2021
- 2021-10-20 CN CN202111222445.0A patent/CN113861238B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101253183A (en) * | 2005-07-29 | 2008-08-27 | 巴斯夫欧洲公司 | Process for preparing optically active diphosphanes |
| CN104119382A (en) * | 2014-07-15 | 2014-10-29 | 同济大学 | 1,3-disubstituted-allylphosphine oxide compounds and preparation method thereof |
| CN110078763A (en) * | 2019-04-24 | 2019-08-02 | 华东师范大学 | A kind of chirality phosphine oxide compound and its synthetic method and application |
Non-Patent Citations (4)
| Title |
|---|
| Palladium-catalyzed benzylic substitution of benzyl carbonates with phosphorus nucleophiles;Yusuke Makida等;Chem. Lett.;第46卷(第12期);1814–1817 * |
| Palladium-catalyzed phosphorylation of benzyl ammonium triflates with P(O)H compounds;Long Liu等;Tetrahedron;第76卷;131020 * |
| Qiang Dai, Lu Liu,and Junliang Zhang.Palladium/Xiao-Phos-Catalyzed Kinetic Resolution of sec-Phosphine Oxides by P-Benzylation.Angew. Chem. Int. Ed..2021,第60卷27247 –27252. * |
| 基于钯/Xiao-Phos催化体系构建磷手性膦氧化合物的方法研究;戴强;中国博士学位论文全文数据库工程科技Ⅰ辑(第12期);B014-6 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN113861238A (en) | 2021-12-31 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0916637B1 (en) | Process for preparating optically active compounds | |
| CN106892945A (en) | A kind of N-heterocyclic carbine-palladium complex, its preparation method and application | |
| US9096626B2 (en) | Monophosphorus ligands and their use in cross-coupling reactions | |
| CN112321627B (en) | Axis chiral arylethynyl silane compound and preparation method thereof | |
| US7485744B2 (en) | Iron-catalyzed allylic alkylation | |
| CN113861238B (en) | Method for synthesizing phosphine chiral center secondary/tertiary phosphine oxide compound through palladium/chiral ligand catalysis | |
| US10125082B2 (en) | Method for coupling a first compound to a second compound | |
| CN108467408B (en) | Diaryl phosphorus compound with hydroxyphenyl functional group and preparation method thereof | |
| CN114989178B (en) | Spiro [ beta-lactam-3, 3' -oxindole ] derivative and preparation method and application thereof | |
| CN114539097B (en) | Polysubstituted alkenyl cyanide and synthetic method thereof | |
| CN116496316A (en) | Method for synthesizing fluorine alkenyl phosphorus | |
| EP3204351A1 (en) | Method for coupling a fluorosulfonate compound with an amine compound | |
| US20090054689A1 (en) | Phosphoramidite ligand and production method of allylic amine using the same | |
| CN116199713A (en) | Chiral alpha-aminophosphonic acid derivative and preparation method thereof | |
| CN112209947A (en) | Chiral indoxazinone compound and synthesis method thereof | |
| US10221203B2 (en) | Chiral dihydrobenzooxaphosphole ligands and synthesis thereof | |
| CN113754544B (en) | Preparation method of polysubstituted (E) -trifluoromethyl olefin | |
| CN112624998A (en) | Azacyclolactone compound and preparation method thereof | |
| EP3484842B1 (en) | Halogen-containing metathesis catalysts and methods thereof | |
| CN113845550B (en) | Flexible large-steric-hindrance N-heterocyclic carbene palladium complex containing halogenated benzene ring, preparation method and application thereof | |
| CN114832862B (en) | Catalytic composition for coupling reaction and application of catalytic composition in preparation of isoquinoline-1, 3-dione compounds | |
| CN116396185B (en) | Preparation method of N-allyl aryl hydrazine compound | |
| CN114591369B (en) | Phosphoramidite ligand and preparation method and application thereof | |
| CN110028487B (en) | Preparation method of thiochromanone compound | |
| CN117024354B (en) | Preparation method of Rui Mi Buti Ni |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |