CN113735899A - 一种具有膦手性和轴手性化合物的合成方法 - Google Patents
一种具有膦手性和轴手性化合物的合成方法 Download PDFInfo
- Publication number
- CN113735899A CN113735899A CN202110970035.8A CN202110970035A CN113735899A CN 113735899 A CN113735899 A CN 113735899A CN 202110970035 A CN202110970035 A CN 202110970035A CN 113735899 A CN113735899 A CN 113735899A
- Authority
- CN
- China
- Prior art keywords
- chirality
- phosphine
- ligand
- compound
- reaction
- 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.)
- Granted
Links
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 title claims abstract description 57
- 229910000073 phosphorus hydride Inorganic materials 0.000 title claims abstract description 30
- 150000001875 compounds Chemical class 0.000 title claims abstract description 21
- 238000001308 synthesis method Methods 0.000 title claims abstract description 6
- -1 diaryl phosphine oxide compound Chemical class 0.000 claims abstract description 43
- 238000006243 chemical reaction Methods 0.000 claims abstract description 42
- 239000003446 ligand Substances 0.000 claims abstract description 35
- 239000003054 catalyst Substances 0.000 claims abstract description 15
- 239000007800 oxidant agent Substances 0.000 claims abstract description 12
- 230000001590 oxidative effect Effects 0.000 claims abstract description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 10
- 230000009471 action Effects 0.000 claims abstract description 7
- 239000003960 organic solvent Substances 0.000 claims abstract description 7
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 238000004809 thin layer chromatography Methods 0.000 claims description 7
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 6
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- OVOVDHYEOQJKMD-UHFFFAOYSA-N 2,4-dimethylpentan-1-ol Chemical compound CC(C)CC(C)CO OVOVDHYEOQJKMD-UHFFFAOYSA-N 0.000 claims description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical group C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 claims description 3
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 3
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 3
- BGNGWHSBYQYVRX-UHFFFAOYSA-N 4-(dimethylamino)benzaldehyde Chemical compound CN(C)C1=CC=C(C=O)C=C1 BGNGWHSBYQYVRX-UHFFFAOYSA-N 0.000 claims description 3
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 3
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 3
- 125000004861 4-isopropyl phenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 3
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 3
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 claims description 3
- 229910001958 silver carbonate Inorganic materials 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- VPSULBJUKFCKKU-UHFFFAOYSA-N CC1=C(C(=C(C1(C)[Ir])C)C)C Chemical group CC1=C(C(=C(C1(C)[Ir])C)C)C VPSULBJUKFCKKU-UHFFFAOYSA-N 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 239000003208 petroleum Substances 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 239000000758 substrate Substances 0.000 abstract description 14
- 229910052751 metal Inorganic materials 0.000 abstract description 6
- 239000002184 metal Substances 0.000 abstract description 6
- 230000015572 biosynthetic process Effects 0.000 abstract description 5
- 229910052741 iridium Inorganic materials 0.000 abstract description 5
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 abstract description 5
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- AUONHKJOIZSQGR-UHFFFAOYSA-N oxophosphane Chemical compound P=O AUONHKJOIZSQGR-UHFFFAOYSA-N 0.000 abstract description 4
- 238000010499 C–H functionalization reaction Methods 0.000 abstract description 3
- 238000006254 arylation reaction Methods 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 230000009467 reduction Effects 0.000 abstract description 3
- 150000001408 amides Chemical class 0.000 abstract description 2
- 239000012295 chemical reaction liquid Substances 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 148
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 59
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 51
- 238000004128 high performance liquid chromatography Methods 0.000 description 50
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 50
- 239000011734 sodium Substances 0.000 description 27
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 26
- 238000005160 1H NMR spectroscopy Methods 0.000 description 26
- 239000007787 solid Substances 0.000 description 26
- 238000004679 31P NMR spectroscopy Methods 0.000 description 25
- 238000010568 chiral column chromatography Methods 0.000 description 25
- 239000000243 solution Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 5
- 238000006555 catalytic reaction Methods 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 150000003003 phosphines Chemical class 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-MZWXYZOWSA-N benzene-d6 Chemical compound [2H]C1=C([2H])C([2H])=C([2H])C([2H])=C1[2H] UHOVQNZJYSORNB-MZWXYZOWSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- 150000001499 aryl bromides Chemical class 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 229910052723 transition metal Inorganic materials 0.000 description 2
- 150000003624 transition metals Chemical class 0.000 description 2
- QKZWXPLBVCKXNQ-UHFFFAOYSA-N (2-methoxyphenyl)-[2-[(2-methoxyphenyl)-phenylphosphanyl]ethyl]-phenylphosphane Chemical compound COC1=CC=CC=C1P(C=1C=CC=CC=1)CCP(C=1C(=CC=CC=1)OC)C1=CC=CC=C1 QKZWXPLBVCKXNQ-UHFFFAOYSA-N 0.000 description 1
- BAYAKMPRFGNNFW-UHFFFAOYSA-N 2,4-dimethylpentan-3-ol Chemical compound CC(C)C(O)C(C)C BAYAKMPRFGNNFW-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000012317 TBTU Substances 0.000 description 1
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- BEQVQKJCLJBTKZ-UHFFFAOYSA-N diphenylphosphinic acid Chemical compound C=1C=CC=CC=1P(=O)(O)C1=CC=CC=C1 BEQVQKJCLJBTKZ-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- OIRDBPQYVWXNSJ-UHFFFAOYSA-N methyl trifluoromethansulfonate Chemical compound COS(=O)(=O)C(F)(F)F OIRDBPQYVWXNSJ-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- GUQRKZPMVLRXLT-UHFFFAOYSA-N n-cyclohexylhydroxylamine Chemical compound ONC1CCCCC1 GUQRKZPMVLRXLT-UHFFFAOYSA-N 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- WQIQNKQYEUMPBM-UHFFFAOYSA-N pentamethylcyclopentadiene Chemical compound CC1C(C)=C(C)C(C)=C1C WQIQNKQYEUMPBM-UHFFFAOYSA-N 0.000 description 1
- ZFJMTDFOGDGPTF-UHFFFAOYSA-N phosphanium;chloride;hydrochloride Chemical compound P.Cl.Cl ZFJMTDFOGDGPTF-UHFFFAOYSA-N 0.000 description 1
- 238000006894 reductive elimination reaction Methods 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- HSYLTRBDKXZSGS-UHFFFAOYSA-N silver;bis(trifluoromethylsulfonyl)azanide Chemical compound [Ag+].FC(F)(F)S(=O)(=O)[N-]S(=O)(=O)C(F)(F)F HSYLTRBDKXZSGS-UHFFFAOYSA-N 0.000 description 1
- 229910000144 sodium(I) superoxide Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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)
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/22—Organic complexes
- B01J31/2282—Unsaturated compounds used as ligands
- B01J31/2295—Cyclic compounds, e.g. cyclopentadienyls
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/58—[b]- or [c]-condensed
- C07D209/72—4,7-Endo-alkylene-iso-indoles
- C07D209/76—4,7-Endo-alkylene-iso-indoles with oxygen atoms in positions 1 and 3
-
- 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
- C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
- C07F9/32—Esters thereof
-
- 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
- C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
- C07F9/32—Esters thereof
- C07F9/3205—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/3229—Esters of aromatic acids (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
- C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
- C07F9/32—Esters thereof
- C07F9/3258—Esters thereof the ester moiety containing a substituent or a structure which is considered as characteristic
- C07F9/3264—Esters with hydroxyalkyl compounds
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/02—Compositional aspects of complexes used, e.g. polynuclearity
- B01J2531/0261—Complexes comprising ligands with non-tetrahedral chirality
- B01J2531/0266—Axially chiral or atropisomeric ligands, e.g. bulky biaryls such as donor-substituted binaphthalenes, e.g. "BINAP" or "BINOL"
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/80—Complexes comprising metals of Group VIII as the central metal
- B01J2531/82—Metals of the platinum group
- B01J2531/825—Osmium
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本案涉及一种具有膦手性和轴手性化合物的合成方法,在有机溶剂体系中,以二芳基膦氧类化合物和二芳基炔为基本原料,在铱催化剂、氧化剂和手性酰胺配体的作用下合成,反应液经后处理得到膦手性和轴手性的类化合物。本发明反应中使用的二芳基膦氧简单易合成,底物的普适性较好,反应操作简便效率高。配体的合成也比较方便,在反应中配体与金属结合,在底物的膦氧导向下对苯环上的C‑H键进行选择性活化,实现了分子间碳氢键活化芳基化反应,以中等以上收率和较高的对映选择性合成具有膦手性和轴手性的化合物。所得的产物可以作为医药中间体或者手性配体;产物进一步还原后得到的三价膦也可以充当手性膦配体。
Description
技术领域
本发明涉及手性膦化合物合成技术领域,具体涉及一种具有膦手性和轴手性化合物的合成方法。
背景技术
膦化合物被广泛应用于催化、医药、材料化学等多个领域,尤其是手性膦化合物作为一种性能优良的配体,在作为有机催化剂或与过渡金属共同催化的不对称催化过程中表现出了极好的对映选择性。自从Knowles及其同事在20世纪70年代成功制备了膦手性配体DIPAMP以来,各种各样合成手性膦化合物的方法被开发出来。从最初通过手性拆分或不同的手性辅助基团等方法获得纯的对映异构手性膦化合物,到最近几年通过不对称催化或动力学拆分的方式得到手性膦化合物或手性膦配体。各种例子相继报道,但总体来看,立体选择性更高、底物使用性更广的催化体系并不是很多。
buchwald膦配体过渡金属催化的偶联反应中体现很好的效果,制备具有膦手性和轴手性的buchwald膦配体可以为不对称催化提供机会,但这方面的研究仍鲜有报道。
发明内容
针对现有技术中的不足之处,本发明提供一种自制的手性酰胺类化合物作为配体,与铱催化剂、氧化剂共同作用实现二芳基膦氧化合物不对称碳氢键活化芳基化制得具有膦手性和轴手性的化合物,其具有反应步骤短、原子经济效益好等特点。
为实现上述目的,本发明提供如下技术方案:
一种具有膦手性和轴手性化合物的合成方式,在有机溶剂中,使用式1)所示二芳基膦氧与式2)所示二芳基乙炔在催化剂、氧化剂、配体L的作用下生成具有膦手性和轴手性的式3)所示目标化合物;
其中,R1所在苯环任选自3-甲基苯基、4-甲基苯基、3-甲氧基苯基、4-甲氧基苯基、4-异丙基苯基、4-叔丁基苯基、3-叔丁基苯基、3-苯基苯基、4-苯基苯基、4-氯苯基、4-氟苯基、4-N,N-二甲基胺基苯基、4-三甲基硅基苯基、2-萘基、3,4-二甲基苯基和3-甲基-4-甲氧基苯基中的一种;
R2所在苯环任选自4-甲基苯基、4-甲氧基苯基、4-氯苯基、4-溴苯基和3,5-二甲基苯基中的一种;
R3任选自叔丁基、环己基、1-金刚烷基和2,4-二甲基戊醇基;
所述配体L是手性酰胺类化合物,其结构通式为R1选自-H、-CH3、-CH2CH(CH3)2、-OCH3、-OCH2CH3、-OCH(CH3)2、-OCH(CH3)3、-OCH(CH2CH3)2、中的一种;表示含芳环的取代基。
进一步优选地,所述有机溶剂为四氢呋喃;所述催化剂为五甲基环戊二烯基铱三乙腈二六氟锑酸;所述氧化剂为碳酸银。
进一步优选地,所述二芳基膦氧、二芳基乙炔、催化剂、氧化剂和配体L的摩尔比是1:3:0.15:1.1:0.3。
进一步优选地,所述合成方法的具体条件是在氮气下将有机溶剂、二芳基膦氧、二芳基乙炔、催化剂、氧化剂和配体L全部添加到密封管中,在90℃下反应12h;通过薄层层析或柱层析提纯法,所用展开剂为乙酸乙酯-石油醚的混合溶剂。
本发明的有益效果是:本发明由二芳基膦氧化合物出发,在铱催化剂和氧化剂以及手性酰胺化合物作为配体的存在下,实现了分子间碳氢键活化芳基化反应,以中等以上收率和较高的对映选择性合成具有膦手性和轴手性的化合物。反应中使用的二芳基膦氧简单易合成,底物的普适性较好,反应操作简便效率高。配体的合成也比较方便,在反应中配体与金属结合,在底物的膦氧导向下对苯环上的C-H键进行选择性活化,进而得到具有手性的化合物。所得的产物可以作为医药中间体或者手性配体;产物进一步还原后得到的三价膦也可以充当手性膦配体。
具体实施方式
下面将结合实施例对本发明的技术方案进行清楚、完整地描述,显然,所描述的实施例是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
此外,下面所描述的本发明不同实施方式中所涉及的技术特征只要彼此之间未构成冲突就可以相互结合。
本发明一种手性酰胺类化合物的合成方法,其合成路线如下所示:
上述反应方程式中涉及到的原料,如无特别说明均为本领域常规选择,部分原料通过自制所得。
一、配体L通过如下合成方法制得。
取100mL圆底烧瓶,将手性酸(10mmol)溶于30mL无水二氯甲烷,加入两滴N,N-二甲基甲酰胺,滴加草酰氯(15mmol),在40℃下反应3h,然后将挥发物抽干得到酰氯粗品。取100mL圆底烧瓶,将环己基羟胺(10mmol)与三乙胺(15mmol)溶于无水二氯甲烷(20mL)。将上一步制得的酰氯溶于10mL二氯甲烷,再滴加进胺溶液。室温反应3小时。拉干反应溶液,通过薄层色谱法或柱层析法分离得到产物。白色固体,80%收率。
1H NMR(400MHz,CDCl3)δ10.07(s,1H),4.71(s,1H),3.79(s,1H),2.80(s,2H),2.00–1.89(m,2H),1.81–1.72(m,2H),1.70–1.18(m,14H),1.10(s,9H).13C NMR(101MHz,CDCl3)δ180.1,178.9,165.9,83.2,64.9,48.5,48.3,42.2,39.5,39.4,35.7,30.5,28.2,25.5,24.7,24.7,23.7,23.6.HRMS(ESI,m/z)calcd for C21H32N2NaO4[M+Na]+:399.2254,found 397.2261.
二、制备二芳基膦氧化合物,其可通过如下合成方法制得。
制备步骤为:在氮气条件下,在100mL的Schlenk瓶中将芳基溴(11mmol)溶于无水四氢呋喃(15mL)。在-78℃下,将叔丁基锂(22mmol,1.3M的戊烷溶液)滴加到芳基溴溶液中,搅拌反应混合物30min,得到白色悬浮液。然后在-78℃下,将二氯化膦(5mmol)的THF(5.0mL)溶液缓慢加入到芳基锂的溶液中。完全加入后,放置在室温下搅拌反应1h。在0℃将H2O2(2.0mL)缓慢滴加入反应液中,搅拌1h,分离有机层,用水、盐水和Na2SO3进行洗涤。有机层在MgSO4上干燥,减压过滤后浓缩。用闪速柱层析法在硅胶上进行纯化。
其中,R1所在苯环任选自3-甲基苯基、4-甲基苯基、3-甲氧基苯基、4-甲氧基苯基、4-异丙基苯基、4-叔丁基苯基、3-叔丁基苯基、3-苯基苯基、4-苯基苯基、4-氯苯基、4-氟苯基、4-N,N-二甲基胺基苯基、4-三甲基硅基苯基、2-萘基、3,4-二甲基苯基和3-甲基-4-甲氧基苯基中的一种。
R2所在苯环任选自4-甲基苯基、4-甲氧基苯基、4-氯苯基、4-溴苯基和3,5二甲基苯基中的一种。
R3任选自叔丁基、环己基、1-金刚烷基和2,4-二甲基戊醇基中的一种。
当R3为2,4-二甲基戊醇基时,其制备方法如下:
将二苯基次膦酸(5mmol),TBTU(5mmol),Et3N(5.0mmol),2,4-二甲基戊烷-3-醇(10mmol)溶解在DCE中(10mL),在氮气下室温搅拌12h。通过柱层析法纯化得到产物。以下是本发明中制得的具体结构式的二芳基膦氧化合物,即底物1。
三、所用二芳基炔即底物2均可由试剂公司购买,本发明所用底物2的结构式如下:
以底物1a与底物2a合成过程为例,机理解释如下:
首先,催化剂上的配位乙腈掉落形成两个六氟锑酸根配位的铱络合物,在配体L的作用下形成中间体A,然后金属与底物膦氧的氧进行配位,金属铱在膦氧导向及配体的作用下对底物1a进行C-H键活化得到C。其中配体的氮原子与金属结合,在氧的作用下使之结合的更牢,与氧相连的环己基提供位阻与催化剂的五甲基环戊二烯形成优势构象,进而控制手性。底物2a的炔基插入C-Ir键,形成中间体D。中间体D的Ir-O键断开形成中间体E,金属Ir继续对二芳基炔的一个苯环进行活化形成中间体F,底物2的炔基插入C-Ir键形成中间体G或G/,接着还原消除生成产物3a和Cp*Ir(I)。通过氧化剂碳酸银将Ir的价态升高,然后与配体L结合生成中间体A,完成催化循环。
实施例1:
从1a出发,与2a反应制得白色固体3a,56%产率,>20:1dr,92%ee。使用DaicelIE-H手性柱色谱柱,采用高效液相色谱法测定其ee值。(HPLC:IE-H,254nm,正己烷/异丙醇=97:3,流速1.0mL/min,30℃,tr(次)=20.3min,tr(主)=18.3min).[α]D 25=-113°(c0.100,CH2Cl2).
1H NMR(400MHz,CDCl3)δ7.70–7.60(m,2H),7.53–7.24(m,11H),7.18–7.11(m,2H),7.04–6.96(m,1H),6.93(d,J=7.6Hz,1H),6.84–6.68(m,5H),6.64–6.52(m,2H),6.45(d,J=7.6Hz,1H),5.91(t,J=7.6Hz,1H),1.11(d,J=14.8Hz,9H).13C NMR(101MHz,CDCl3)δ148.5(d,J=5.4Hz),140.5,139.7(d,J=13.3Hz),138.5(d,J=15.6Hz),137.8,137.4(d,J=3.3Hz),136.8(d,J=3.2Hz),135.62(d,J=10.9Hz),136.6(d,J=2.2Hz),135.6(d,J=11.0Hz),133.2,133.1,132.7(d,J=12.2Hz),132.1,132.0,131.8,131.6,131.2,130.9,130.6,130.28(d,J=89.9Hz),128.2(d,J=11.4Hz),128.0(d,J=90.4Hz),127.3(d,J=11.5Hz),127.1(d,J=9.9Hz),126.3(d,J=9.5Hz),126.2,126.1(d,J=12.2Hz),126.0(d,J=14.8Hz),125.3(d,J=17.9Hz),125.0,36.0(d,J=71.1Hz),26.0.HRMS(ESI,m/z)calcdfor C44H35Cl2NaOP[M+Na]+:703.1695,found 703.1687.31P NMR(162MHz,CDCl3)δ39.0.
实施例1-2:同实施例1,区别在于将反应中的配体L替换为(制备方法同上),收率50%,13:1dr,55%ee。相较于实施例同样可以合成具有轴手性和膦手性的化合物,但ee值较低,即该结构的配体在该催化反应中的效率较低。
实施例2:
从1b出发,与2a反应制得白色固体3b,50%产率,>20:1dr,88%ee。使用DaicelAD-H手性柱色谱柱,采用高效液相色谱法测定其ee值。(HPLC:AD-H,254nm,正己烷/异丙醇99:1,流速1.0mL/min,30℃,tr(minor)=10.3min,tr(major)=8.5min).[α]D 25=-66°(c0.11,CH2Cl2).
1H NMR(400MHz,CDCl3)δ7.79–7.71(m,1H),7.66–7.60(m,1H),7.52–7.39(m,4H),7.39–7.30(m,2H),7.30–7.07(m,5H),7.06–6.96(m,3H),6.93(d,J=7.6Hz,1H),6.82–6.69(m,4H),6.66–6.61(m,1H),6.52(dd,J=11.0,5.6Hz,2H),5.93(t,J=7.5Hz,1H),1.11(d,J=14.8Hz,9H).13C NMR(101MHz,CDCl3)δ164.3(dd,J=253.3Hz,2.8Hz),163.2(dd,J=255.7Hz,3.3Hz),149.8(dd,J=8.0Hz,6.5Hz),140.5,139.8,139.6,138.5,138.3,137.5,136.8,134.2,134.1,134.0,133.7(dd,J=12.7Hz,8.5Hz),132.0,131.6(d,J=1.4Hz),131.6,131.3,131.0,130.5,127.9(dd,J=91.7Hz,3.5Hz),127.2(dd,J=12.4Hz,8.3Hz),126.3,126.17(d,J=7.3Hz),125.9(d,J=10.9Hz),125.7(d,J=92.2Hz),125.2(d,J=20.9Hz),125.0(d,J=3.4Hz),122.7(dd,J=20.1Hz,11.2Hz),115.1(dd,J=21.0Hz,11.9Hz),113.4(dd,J=21.0Hz,12.5Hz),36.0(d,J=71.5Hz),26.0.HRMS(ESI,m/z)calcdfor C44H35F2NaOP[M+Na]+:671.2286,found 671.2287.31P NMR(162MHz,CDCl3)δ38.8.
实施例3:
从1c出发,与2a反应制得白色固体3c,41%产率,14:1dr,88%ee。使用Daicel IE-H手性柱色谱柱,采用高效液相色谱法测定其ee值。(HPLC:IE-H,254nm,正己烷/异丙醇80:20,流速1.0mL/min,30℃,tr(次)=12.5min,tr(主)=14.0min).[α]D 25=-125°(c 0.090,CH2Cl2).
1H NMR(400MHz,CDCl3)δ7.67–7.56(m,3H),7.45–7.34(m,3H),7.34–7.27(m,2H),7.22–7.09(m,4H),6.91(d,J=8.4Hz,1H),6.83–6.49(m,12H),6.01(t,J=7.6Hz,1H),2.94(d,J=26.8Hz,12H),1.12(d,J=14.0Hz,9H).13C NMR(101MHz,CDCl3)δ151.4(d,J=2.3Hz),150.4(d,J=2.3Hz),146.9(d,J=5.8Hz),141.1,140.7,140.1,139.8(d,J=2.5Hz),138.4,137.2(d,J=15.4Hz),133.2(d,J=9.2Hz),132.77(d,J=12.5Hz),132.75,132.3,131.9(d,J=7.0Hz),131.5,131.3,131.2,130.4,128.3,127.2,127.0,126.6,126.1(d,J=10.0Hz),125.9(d,J=8.5Hz),125.3,124.9,124.7,124.4(d,J=1.9Hz),118.9(d,J=100.2Hz),118.4(d,J=10.0Hz),116.5(d,J=99.6Hz),110.9(d,J=11.5Hz),109.0(d,J=12.2Hz),40.0,39.9,36.1(d,J=72.3Hz),26.3.HRMS(ESI,m/z)calcd for C48H47N2NaOP[M+Na]+:721.3318,found 721.3319.31P NMR(162MHz,CDCl3)δ39.9.
实施例4:
从1d出发,与2a反应制得白色固体3d,72%产率,>20:1dr,91%ee。使用DaicelIE-H手性柱色谱柱,采用高效液相色谱法测定其ee值。(HPLC:IE-H,254nm,正己烷/异丙醇95:5,流速1.0mL/min,30℃,tr(次)=20.2min,tr(主)=18.5min).[α]D 25=-163°(c 0.140,CH2Cl2).
1H NMR(400MHz,CDCl3)δ7.68(dd,J=10.4,8.0Hz,1H),7.65–7.60(m,1H),7.52–7.40(m,4H),7.35–7.29(m,2H),7.27–7.08(m,8H),6.94(d,J=7.5Hz,1H),6.82–6.65(m,6H),6.57(d,J=7.6Hz,1H),6.53–6.47(m,1H),5.84(t,J=7.6Hz,1H),2.36(d,J=10.0Hz,6H),1.13(d,J=14.4Hz,9H).13C NMR(101MHz,CDCl3)δ146.3(d,J=5.1Hz),140.9,140.7(d,J=2.8Hz),140.4,140.1(d,J=2.7Hz),139.9,138.6(d,J=2.5Hz),138.5,137.5(d,J=3.1Hz),136.2(d,J=10.4Hz),132.6,132.13,132.0(d,J=8.3Hz),131.9(d,J=20.2Hz),131.7(d,J=11.8Hz),131.5,131.4,131.1,130.5,129.2(d,J=91.1Hz),128.5(d,J=11.3Hz),127.8,127.2(d,J=9.0Hz),126.88(d,J=91.8Hz),126.86,126.4(d,J=11.8Hz),126.2(d,J=15.3Hz),126.0,125.4,124.9(d,J=21.9Hz),124.6(d,J=8.7Hz),35.9(d,J=70.6Hz),26.2,21.4,21.2.HRMS(ESI,m/z)calcd for C46H41NaOP[M+Na]+:663.2787,found 663.2781.31P NMR(162MHz,CDCl3)δ39.6.
实施例5:
从1e出发,与2a反应制得白色固体3e,72%产率,>20:1dr,90%ee。使用DaicelIE-H手性柱色谱柱,采用高效液相色谱法测定其ee值。(HPLC:IE-H,254nm,正己烷/异丙醇95:5,流速1.0mL/min,30℃,tr(次)=16.6min,tr(主)=18.0min).[α]D 25=-95°(c 0.14,CH2Cl2).
1H NMR(400MHz,CDCl3)δ7.64–7.57(m,2H),7.51–7.04(m,14H),6.92(d,J=7.2Hz,1H),6.83–6.63(m,6H),6.55(d,J=8.0Hz,1H),6.53–6.48(m,1H),5.86(t,J=7.6Hz,1H),2.43(s,3H),2.30(s,3H),1.13(d,J=14.4Hz,9H).13C NMR(101MHz,CDCl3)δ143.3(d,J=4.8Hz),140.9,140.3,140.0,138.5,138.3(d,J=2.3Hz),137.7,137.5,137.3(d,J=10.8Hz),135.4(d,J=10.8Hz),134.9(d,J=11.5Hz),132.7(d,J=8.9Hz),132.6,132.3(d,J=11.2Hz),132.20,132.1(d,J=89.4Hz),131.8,131.5,131.4,131.3(d,J=2.7Hz),131.09,131.0(d,J=2.9Hz),130.6,129.7(d,J=89.3Hz),128.8(d,J=8.4Hz),127.7,127.5(d,J=11.6Hz),127.2(d,J=3.3Hz),126.8,126.2,126.0(d,J=8.8Hz),125.9,125.5,125.0,124.9(d,J=22.8Hz),124.5(d,J=14.1Hz),35.9(d,J=70.0Hz),26.3,21.51,21.46.HRMS(ESI,m/z)calcd for C46H41NaOP[M+Na]+:663.2787,found663.2787.31P NMR(162MHz,CDCl3)δ39.8.
实施例6:
从1f出发,与2a反应制得白色固体3f,63%产率,14:1dr,92%ee。使用Daicel IE-H手性柱色谱柱,采用高效液相色谱法测定其ee值。(HPLC:IE-H,254nm,正己烷/异丙醇=80:20,流速1.0mL/min,30℃,tr(次)=10.5min,tr(主)=9.5min).[α]D 25=-95°(c 0.12,CH2Cl2).
1H NMR(400MHz,CDCl3)δ7.74–7.67(m,1H),7.64–7.58(m,1H),7.54–7.49(m,1H),7.48–7.39(m,3H),7.36–7.30(m,2H),7.26–7.08(m,5H),6.95–6.88(m,3H),6.85–6.65(m,8H),6.59(d,J=7.6Hz,1H),6.57–6.51(m,1H),3.79(d,J=19.2Hz,6H),1.11(d,J=14.4Hz,9H).13C NMR(101MHz,CDCl3)δ161.3(d,J=2.7Hz),160.3(d,J=2.7Hz),148.3(d,J=6.0Hz),140.8,140.2,139.8,138.5,138.3(d,J=2.1Hz),137.7,137.4,133.6(d,J=9.4Hz),133.2(d,J=12.3Hz),132.4,132.1,131.8(d,J=3.7Hz),131.42,131.36,131.1,130.4,127.7,127.2(d,J=12.8Hz),126.8,126.2(d,J=17.4Hz),126.0,125.0(d,J=28.8Hz),124.8(d,J=6.6Hz),123.9(d,J=95.2Hz),121.8(d,J=95.4Hz),120.0(d,J=11.3Hz),113.2(d,J=11.9Hz),112.5(d,J=2.3Hz),55.33,55.23,36.0(d,J=71.8Hz),26.2.HRMS(ESI,m/z)calcd for C46H41NaO3P[M+Na]+:695.2686,found 695.2677.31P NMR(162MHz,CDCl3)δ39.3.
实施例7:
从1g出发,与2a反应制得白色固体3g,60%产率,13:1dr,91%ee。使用Daicel IE-H手性柱色谱柱,采用高效液相色谱法测定其ee值。(HPLC:IE-H,254nm,正己烷/异丙醇=80:20,流速1.0mL/min,30℃,tr(次)=7.9min,tr(主)=12.9min).[α]D 25=-95°(c 0.14,CH2Cl2).
1H NMR(400MHz,CDCl3)δ7.66–7.57(m,1H),7.49–7.40(m,2H),7.36–7.28(m,4H),7.26–7.20(m,2H),7.18–6.89(m,8H),6.82–6.62(m,6H),6.54–6.46(m,2H),5.87(t,J=7.6Hz,1H),3.85(s,3H),3.75(s,3H),1.15(d,J=14.4Hz,9H).13C NMR(101MHz,CDCl3)δ159.0(d,J=13.5Hz),156.7(d,J=14.5Hz),140.9,140.3,139.9,138.5,138.3(d,J=4.5Hz),138.0,137.6,136.5(d,J=11.9Hz),133.2(d,J=88.3Hz),133.0,131.9,131.8(d,J=5.2Hz),131.5,131.4,131.1,130.6(d,J=89.2Hz),130.5,128.9(d,J=2.8Hz),127.6,127.2(d,J=6.3Hz),126.9,126.2(d,J=15.7Hz),126.0(d,J=5.6Hz),125.6,125.1,124.8(d,J=7.7Hz),124.6,124.2(d,J=8.1Hz),117.7(d,J=12.6Hz),116.93,116.89(d,J=11.0Hz),115.2(d,J=2.6Hz),55.32,55.30,36.0(d,J=70.0Hz),26.2.HRMS(ESI,m/z)calcd for C46H41NaO3P[M+Na]+:695.2686,found695.2690.31P NMR(162MHz,CDCl3)δ39.4.
实施例8:
从1h出发,与2a反应制得白色固体3h,66%产率,15:1dr,92%ee。使用Daicel ID-H手性柱色谱柱,采用高效液相色谱法测定其ee值。(HPLC:ID-H,254nm,正己烷/异丙醇95:5,流速1.0mL/min,30℃,tr(次)=8.1min,tr(主)=6.4min).[α]D 25=-213°(c 0.200,CH2Cl2).
1H NMR(400MHz,CDCl3)δ7.71(dd,J=10.4,8.0Hz,1H),7.66–7.61(m,1H),7.55–7.41(m,4H),7.37–7.31(m,2H),7.28-7.06(m,8H),6.94(d,J=7.2Hz,1H),6.83–6.58(m,6H),6.43(td,J=7.4,1.6Hz,2H),5.74(t,J=7.4Hz,1H),2.97–2.85(m,J=6.8Hz,2H),1.30–1.19(m,12H),1.13(d,J=14.4Hz,9H).13C NMR(101MHz,CDCl3)δ151.4(d,J=2.7Hz),150.7(d,J=2.6Hz),146.3(d,J=5.1Hz),140.9,140.2,139.9,139.0(d,J=2.6Hz),138.5,137.6,137.5,133.8(d,J=10.5Hz),132.6,132.2,132.0(d,J=6.0Hz),131.9(d,J=7.8Hz),131.7(d,J=11.7Hz),131.43,131.37,131.0,130.5,129.4(d,J=91.1Hz),127.8,127.2(d,J=6.9Hz),127.0(d,J=92.0Hz),126.8,126.1(d,J=20.2Hz),126.0(d,J=2.1Hz),125.9,125.2(d,J=21.9Hz),124.8,124.6(d,J=23.8Hz),123.8(d,J=12.0Hz),36.3,35.6,33.9(d,J=21.0Hz),26.1,23.90,23.87,23.7,23.1.HRMS(ESI,m/z)calcd for C50H49NaOP[M+Na]+:719.3413,found719.3399.31P NMR(162MHz,CDCl3)δ39.1.
实施例9:
从1i出发,与2a反应制得白色固体3i,75%产率,18:1dr,95%ee。使用Daicel IE-H手性柱色谱柱,采用高效液相色谱法测定其ee值。(HPLC:ID-H,254nm,正己烷/异丙醇97:3,流速1.0mL/min,30℃,tr(次)=12.7min,tr(主)=14.8min).[α]D 25=-145°(c 0.230,CH2Cl2).
1H NMR(400MHz,CDCl3)δ7.83(dd,J=11.6,2.0Hz,1H),7.67–7.59(m,2H),7.53–7.41(m,4H),7.38-7.21(m,6H),7.19–7.04(m,3H),6.93(d,J=7.6Hz,1H),6.80–6.68(m,3H),6.68–6.55(m,3H),6.46–6.34(m,2H),5.65(t,J=7.6Hz,1H),1.39(s,9H),1.27(s,9H),1.12(d,J=14.4Hz,9H).13C NMR(101MHz,CDCl3)δ150.3(d,J=10.2Hz),148.1(d,J=10.7Hz),143.4(d,J=5.0Hz),140.9,140.0,139.9,138.6(d,J=2.6Hz),138.4,137.7,137.4,135.2(d,J=10.9Hz),131.92,131.90,131.8,131.51(d,J=88.7Hz),131.46,131.4,131.0,130.3,129.4(d,J=90.1Hz),129.2(d,J=7.9Hz),128.8(d,J=8.5Hz),128.3(d,J=11.9Hz),127.6,127.5(d,J=11.4Hz),127.4(d,J=2.7Hz),127.2(d,J=4.5Hz),127.0(d,J=2.7Hz),126.8,126.2,126.0(d,J=7.3Hz),125.7,125.3,125.0,124.7(d,J=9.0Hz),124.4,35.74(d,J=69.5Hz),34.8,34.6,31.32,31.26,26.1.HRMS(ESI,m/z)calcd for C52H53NaOP[M+Na]+:747.3726,found 747.3724.31P NMR(162MHz,CDCl3)δ39.3.
实施例10:
从1j出发,与2a反应制得白色固体3j,75%产率,18:1dr,92%ee。使用Daicel IE-H手性柱色谱柱,采用高效液相色谱法测定其ee值。(HPLC:IE-H,254nm,正己烷/异丙醇95:5,流速1.0mL/min,30℃,tr(次)=9.5min,tr(主)=10.7min).[α]D 25=-160°(c 0.160,CH2Cl2).
1H NMR(400MHz,CDCl3)δ7.76–7.70(m,1H),7.67–7.62(m,1H),7.54–7.45(m,4H),7.42–7.39(m,1H),7.33(dt,J=9.6,4.4Hz,5H),7.27–7.22(m,1H),7.13(h,J=6.8,6.4Hz,3H),6.94(d,J=7.6Hz,1H),6.80–6.58(m,6H),6.43(s,2H),5.71(t,J=7.2Hz,1H),1.31(d,J=12.8Hz,18H),1.14(d,J=14.4Hz,9H).13C NMR(101MHz,CDCl3)δ153.5(d,J=2.7Hz),152.8(d,J=2.7Hz),145.9(d,J=4.9Hz),140.9,140.3,139.9,139.2(d,J=2.4Hz),138.4,137.6,137.3,133.0(d,J=10.4Hz),132.6,132.0,131.9,131.9,131.8,131.5(d,J=11.4Hz),131.4,131.1,130.4,129.1(J=91.1Hz),127.8,127.1(J=5.7Hz),126.8,126.7(d,J=89.0Hz),126.1(d,J=19.2Hz),125.9(d,J=14.6Hz),125.1(d,J=2.0Hz),124.7,124.6(J=3.2Hz),124.3,122.1(J=11.6Hz),36.2,35.5,34.7(J=5.7Hz),31.0(J=21.1Hz),26.1.HRMS(ESI,m/z)calcd for C52H53NaOP[M+Na]+:747.3726,found747.3730.31P NMR(162MHz,CDCl3)δ38.9.
实施例11:
从1k出发,与2a反应制得白色固体3k,66%产率,>20:1dr,92%ee。使用DaicelIE-H手性柱色谱柱,采用高效液相色谱法测定其ee值。(HPLC:IE-H,254nm,正己烷/异丙醇95:5,流速1.0mL/min,30℃,tr(次)=6.7min,tr(主)=7.3min).[α]D 25=-129°(c 0.230,CH2Cl2).
1H NMR(400MHz,CDCl3)δ7.77(dd,J=10.4,7.6Hz,1H),7.67–7.62(m,1H),7.56–7.44(m,8H),7.37–7.30(m,2H),7.28–7.21(m,1H),7.18–7.08(m,3H),6.93(d,J=7.6Hz,1H),6.83–6.57(m,6H),6.45–6.35(m,2H),5.66(t,J=7.6Hz,1H),1.15(d,J=14.4Hz,9H),0.27(d,J=7.2Hz,18H).13C NMR(101MHz,CDCl3)δ145.0(d,J=4.2Hz),143.5(d,J=1.9Hz),143.0(d,J=2.3Hz),140.8,140.7(d,J=10.1Hz),140.2,139.9,138.9(d,J=2.5Hz),138.5,137.7,137.5,132.67,132.65,132.6,132.8(d,J=88.6Hz),131.9,131.8(d,J=6.1Hz),131.39,131.36,131.1(d,J=2.7Hz),131.0,130.6(d,J=11.0Hz),130.5,130.04(d,J=11.3Hz),130.0(d,J=89.3Hz),127.8,127.2(d,J=4.6Hz),126.8,126.2,126.0(d,J=4.1Hz),125.8,125.3,125.1,124.8,124.7,124.5,35.9(d,J=70.0Hz),26.1,-1.3,-1.4.HRMS(ESI,m/z)calcd for C50H53NaOPSi2[M+Na]+:779.3265,found779.3251.31P NMR(162MHz,CDCl3)δ39.0.
实施例12:
从1l出发,与2a反应制得白色固体3l,92%产率,17:1dr,90%ee。使用Daicel IE-H手性柱色谱柱,采用高效液相色谱法测定其ee值。(HPLC:IE-H,254nm,正己烷/异丙醇85:15,流速1.0mL/min,30℃,tr(次)=12.5min,tr(主)=16.2min).[α]D 25=-388°(c 0.330,CH2Cl2).
1H NMR(400MHz,CDCl3)δ7.96–7.88(m,1H),7.69(d,J=2.4Hz,1H),7.66–7.52(m,10H),7.48–7.30(m,9H),7.25–7.04(m,5H),6.97(d,J=7.6Hz,1H),6.81–6.57(m,7H),6.47(t,J=7.6Hz,1H),5.87(t,J=7.6Hz,1H),1.21(d,J=14.8Hz,9H).13C NMR(101MHz,CDCl3)δ146.8(d,J=5.1Hz),143.2(d,J=2.7Hz),142.3(d,J=2.8Hz),140.8,140.2,140.1,139.8,139.4,138.5,138.4(d,J=2.4Hz),137.8(d,J=10.9Hz),134.1(d,J=10.6Hz),132.4(d,J=8.3Hz),132.39,132.3(d,J=11.5Hz),132.1,131.8(d,J=2.0Hz),131.5,131.2(d,J=33.0Hz),130.9(d,J=89.9Hz),130.5,128.9(d,J=3.5Hz),128.6(d,J=90.4Hz),128.1,127.9,127.6,127.2,127.1,126.9,126.4(d,J=11.2Hz),126.2(d,J=14.6Hz),126.0(d,J=5.7Hz),125.6,124.92(d,J=41.1Hz),124.9(d,J=6.3Hz),124.1(d,J=11.9Hz),36.0(d,J=76.3Hz),26.2.HRMS(ESI,m/z)calcd for C56H45NaOP[M+Na]+:787.3100,found 787.3091.31P NMR(162MHz,CDCl3)δ39.5.
实施例13:
从1m出发,与2a反应制得白色固体3m,63%产率,10:1dr,90%ee。使用Daicel IG-H手性柱色谱柱,采用高效液相色谱法测定其ee值。(HPLC:IG-H,254nm,正己烷/异丙醇97:3,流速1.0mL/min,30℃,tr(次)=9.3min,tr(主)=12.5min).[α]D 25=-23°(c 0.15,CH2Cl2).
1H NMR(400MHz,CDCl3)δ8.08(dd,J=11.2,2.0Hz,1H),7.86(d,J=10.8Hz,1H),7.74(d,J=8.0Hz,1H),7.70–7.30(m,18H),7.28–7.22(m,1H),7.18–7.03(m,3H),6.95(d,J=7.6Hz,1H),6.79–6.60(m,6H),6.55(d,J=7.6Hz,1H),6.33(t,J=7.6Hz,1H),5.77(t,J=7.6Hz,1H),1.20(d,J=14.4Hz,9H).13C NMR(101MHz,CDCl3)δ145.5(d,J=4.8Hz),140.7,140.5(d,J=10.7Hz),140.3,139.9(d,J=16.7Hz),139.8,138.5,138.2(d,J=11.4Hz),138.0(d,J=2.3Hz),137.8(d,J=3.9Hz),136.2(d,J=10.6Hz),132.6(d,J=88.2Hz),132.3,132.1,131.8(d,J=2.3Hz),131.5,131.3,131.0,130.8(d,J=8.0Hz),130.6(d,J=8.4Hz),130.4,130.2(d,J=11.7Hz),129.2(d,J=2.7Hz),128.9(d,J=27.7Hz),128.7(d,J=2.7Hz),128.4(d,J=11.4Hz),127.7(d,J=31.9Hz),127.6,127.2,127.0,126.9(d,J=17.3Hz),126.2(d,J=16.6Hz),125.95(d,J=15.5Hz),125.5,125.1,124.8,124.7,36.1(d,J=69.5Hz),26.3.HRMS(ESI,m/z)calcd for C56H45NaOP[M+Na]+:787.3100,found 787.3089.31P NMR(162MHz,CDCl3)δ39.6.
实施例14:
从1n出发,与2a反应制得白色固体3n,56%产率,13:1dr,86%ee。使用Daicel IE-H手性柱色谱柱,采用高效液相色谱法测定其ee值。(HPLC:IE-H,254nm,正己烷/异丙醇85:15,流速1.0mL/min,30℃,tr(次)=17.0min,tr(主)=11.4min).[α]D 25=-186°(c 0.160,CH2Cl2).
1H NMR(400MHz,CDCl3)δ8.47(d,J=12.4Hz,1H),8.10(d,J=12.0Hz,1H),7.99–7.91(m,2H),7.86–7.74(m,4H),7.68–7.43(m,8H),7.35–7.22(m,3H),7.20–7.06(m,3H),6.91(d,J=7.6Hz,1H),6.76–6.63(m,5H),6.51(t,J=7.2Hz,2H),6.16–6.2(m,1H),5.33(t,J=7.6Hz,1H),1.23(d,J=14.4Hz,9H).13C NMR(101MHz,CDCl3)δ141.3(d,J=5.5Hz),140.8,140.1,139.9,138.5,138.2(d,J=1.6Hz),138.1,137.8,134.4(d,J=9.8Hz),134.0(d,J=2.4Hz),133.9(d,J=7.6Hz),133.4(d,J=2.3Hz),133.2(d,J=11.2Hz),133.1,132.3(d,J=12.2Hz),132.0,131.93,131.88,131.5,131.4,131.1,130.7,130.4(d,J=2.9Hz),129.5(d,J=88.9Hz),129.0,128.4,128.3(d,J=87.6Hz),128.2,127.8,127.7,127.5,127.3,127.2,127.19(d,J=8.9Hz),126.9,126.7,126.4,126.2,126.1(d,J=5.3Hz),125.6(d,J=31.6Hz),124.781(d,J=60.2Hz),124.779,36.3(d,J=70.5Hz),26.4.HRMS(ESI,m/z)calcd for C52H41NaOP[M+Na]+:735.2787,found 735.2780.31P NMR(162MHz,CDCl3)δ40.3.
实施例15:
从1o出发,与2a反应制得白色固体3o,57%产率,13:1dr,90%ee。使用Daicel IE-H手性柱色谱柱,采用高效液相色谱法测定其ee值。(HPLC:IE-H,254nm,正己烷/异丙醇85:15,流速1.0mL/min,30℃,tr(次)=9.9min,tr(主)=7.1min).[α]D 25=-204°(c 0.160,CH2Cl2).
1H NMR(400MHz,CDCl3)δ7.62–7.56(m,1H),7.52(d,J=10.8Hz,1H),7.50–7.45(m,1H),7.40(d,J=8.1Hz,1H),7.34–7.27(m,3H),7.24–7.02(m,7H),6.92(d,J=7.5Hz,1H),6.81–6.61(m,6H),6.56(d,J=7.7Hz,1H),6.52–6.47(m,1H),5.83(t,J=7.6Hz,1H),2.33(s,3H),2.27(s,3H),2.25(s,3H),2.20(s,3H),1.13(d,J=14.4Hz,9H).13C NMR(101MHz,CDCl3)δ143.5(d,J=4.7Hz),141.0,140.4,140.0,139.3(d,J=2.6Hz),138.9(d,J=3.0Hz),138.5(d,J=3.6Hz),137.5(d,J=20.1Hz),136.5(d,J=10.6Hz),135.9(d,J=11.1Hz),133.7(d,J=11.8Hz),133.2(d,J=8.1Hz),132.9,132.8(d,J=2.0Hz),132.1,131.9,131.43,131.38,131.1,130.6,129.44(d,J=90.4Hz),129.40(d,J=8.3Hz),128.9(d,J=11.7Hz),127.9,127.2(d,J=9.1Hz),127.0(d,J=92.3Hz),126.7,126.2,126.0(d,J=6.5Hz),125.9,125.4,125.0,124.7(d,J=15.2Hz),124.4,35.9(d,J=70.1Hz),26.3,19.84,19.83,19.7,19.6.HRMS(ESI,m/z)calcd for C48H45NaOP[M+Na]+:691.3100,found691.3098.31P NMR(162MHz,CDCl3)δ39.7.
实施例16:
从1p出发,与2a反应制得白色固体3p,60%产率,12:1dr,91%ee。使用Daicel IE-H手性柱色谱柱,采用高效液相色谱法测定其ee值。(HPLC:IE-H,254nm,正己烷/异丙醇90:10,流速1.0mL/min,30℃,tr(次)=11.8min,tr(主)=10.9min).[α]D 25=-138°(c 0.100,CH2Cl2).
1H NMR(400MHz,CDCl3)δ7.64–7.59(m,1H),7.57–7.49(m,2H),7.39(d,J=7.6Hz,1H),7.35–7.28(m,3H),7.26–7.09(m,5H),6.91(d,J=7.6Hz,1H),6.80–6.65(m,8H),6.60–6.49(m,2H),5.92(t,J=7.6Hz,1H),3.84(s,3H),3.74(s,3H),2.27(s,3H),2.15(s,3H),1.13(d,J=14.4Hz,9H).13C NMR(101MHz,CDCl3)δ159.6(d,J=2.8Hz),158.6(d,J=2.8Hz),145.9(d,J=5.6Hz),140.9,140.4,139.9,138.7(d,J=2.7Hz),138.5,137.5(d,J=6.5Hz),134.2(d,J=9.2Hz),133.6(d,J=12.5Hz),132.7,132.1,131.9(d,J=3.2Hz),131.5,131.38,131.37,131.1,130.3,127.9,127.3,127.1,126.7,126.1(d,J=22.0Hz),126.0,125.9(d,J=11.5Hz),125.5,125.1,124.8(d,J=9.8Hz),124.57,123.9(d,J=2.0Hz),123.5(d,J=105.1Hz),121.09(d,J=95.0Hz),116.8(d,J=11.6Hz),109.0(d,J=12.3Hz),55.3(d,J=12.3Hz),36.0(d,J=71.2Hz),26.4,16.3.HRMS(ESI,m/z)calcd forC48H45NaO3P[M+Na]+:723.2999,found 723.2984.31P NMR(162MHz,CDCl3)δ39.6.
实施例17:
从1q出发,与2a反应制得白色固体3q,70%产率,18:1dr,96%ee。使用Daicel IE-H手性柱色谱柱,采用高效液相色谱法测定其ee值。(HPLC:IE-H,254nm,正己烷/异丙醇90:10,流速1.0mL/min,30℃,tr(次)=10.9min,tr(主)=14.3min).[α]D 25=-67°(c 0.19,CH2Cl2).
1H NMR(400MHz,Benzene-d6)δ7.60(d,J=8.4Hz,1H),7.49–7.38(m,3H),7.33(t,J=9.2Hz,1H),7.12–6.93(m,5H),6.92–6.60(m,12H),6.54–6.42(m,3H),6.34(t,J=7.6Hz,1H),6.19(t,J=7.2Hz,1H),5.74(t,J=7.6Hz,1H),1.59–1.47(m,6H),1.40(s,3H),1.14–1.00(m,6H).13C NMR(101MHz,Benzene-d6)δ147.1(d,J=4.9Hz),141.1,140.7,140.1,138.8,138.6(d,J=2.5Hz),138.3,138.1,135.4(d,J=10.2Hz),132.9,132.6,132.28(d,J=87.3Hz),132.26(d,J=7.6Hz),132.2(d,J=6.1Hz),131.9,131.6(d,J=10.9Hz),131.1,130.9,130.6,130.2(d,J=2.6Hz),129.9(d,J=88.2Hz),129.6(d,J=2.7Hz),128.1,127.8,127.7,127.5,126.7,126.3,126.1,126.0,125.7,125.19(d,J=12.2Hz),125.15(d,J=5.3Hz),124.9,124.6,38.9(d,J=71.4Hz),36.1,35.8,27.7,27.6.HRMS(ESI,m/z)calcd for C50H43NaOP[M+Na]+:713.2944,found 713.2940.31P NMR(162MHz,Benzene-d6)δ33.4.
实施例18:
从1r出发,与2a反应,用[Cp*IrCl2]2(8mol%)作催化剂,AgNTf2(32mol%),在60℃制得白色固体3r,60%产率,>20:1dr,76%ee。使用Daicel IE-H手性柱色谱柱,采用高效液相色谱法测定其ee值。(HPLC:IE-H,254nm,正己烷/异丙醇70:30,流速1.0mL/min,30℃,tr(次)=17.0min,tr(主)=26.9min).[α]D 25=-160°(c 0.100,CH2Cl2).
1H NMR(400MHz,CDCl3)δ7.90(dd,J=11.2,7.6Hz,1H),7.49–7.03(m,15H),7.00–6.56(m,10H),6.44(s,1H),1.95–1.85(m,1H),1.67–1.24(m,7H),1.15–0.94(m,3H).13C NMR(101MHz,CDCl3)δ143.4(d,J=7.2Hz),140.7,139.6(d,J=4.0Hz),138.5(d,J=18.8Hz),137.4,137.3(d,J=3.0Hz),135.0(d,J=10.1Hz),133.3(d,J=9.2Hz),132.7(d,J=2.3Hz),132.2(d,J=86.3Hz),131.7,131.3,131.26,131.25(d,J=80.9Hz),131.1(d,J=4.8Hz),131.0(d,J=8.6Hz),130.8(d,J=4.3Hz),130.4(d,J=2.6Hz),130.0(d,J=2.6Hz),127.5(d,J=10.2Hz),127.3(d,J=11.1Hz),127.2,126.6,126.52,126.50,126.48,126.45,126.2,125.4(d,J=17.0Hz),125.2(d,J=10.4Hz),37.4(d,J=72.2Hz),26.2(d,J=13.4Hz),25.6,24.8.HRMS(ESI,m/z)calcd for C46H39NaOP[M+Na]+:661.2631,found 661.2629.31P NMR(162MHz,CDCl3)δ36.0.
实施例19:
从1s出发,与2b反应制得白色固体3s,69%产率,15:1dr,92%ee。使用Daicel IE-H手性柱色谱柱,采用高效液相色谱法测定其ee值。(HPLC:IE-H,254nm,正己烷/异丙醇85:15,流速1.0mL/min,30℃,tr(次)=7.8min,tr(主)=10.1min).[α]D 25=-145°(c 0.170,CH2Cl2).
1H NMR(400MHz,CDCl3)δ7.79–7.72(m,1H),7.52–7.22(m,11H),7.09(ddd,J=20.8,8.4,2.0Hz,2H),6.97–6.85(m,2H),6.80(d,J=7.8Hz,1H),6.58(d,J=8.0Hz,2H),6.55–6.47(m,2H),6.47–6.40(m,1H),6.34(d,J=7.6Hz,1H),5.57(d,J=7.6Hz,1H),2.35(s,3H),2.29(s,3H),2.00(s,3H),1.84(s,3H),1.11(d,J=14.4Hz,9H).13C NMR(101MHz,CDCl3)δ146.9(d,J=4.9Hz),138.7,138.1,137.9(d,J=2.6Hz),137.3(d,J=13.2Hz),137.1(d,J=7.1Hz),135.8(d,J=10.3Hz),135.0,134.3,133.7,133.3,132.213(d,J=89.2Hz),132.205,131.9,131.84,131.77(d,J=9.4Hz),131.7,131.2,130.8(d,J=17.1Hz),130.4,130.34(d,J=2.7Hz),130.3,129.8(d,J=2.7Hz),129.7(d,J=90.0Hz),127.9(d,J=11.7Hz),127.5(d,J=11.0Hz),127.4,126.9,126.8,126.7,126.1,125.8,125.3(d,J=11.7Hz),35.9(d,J=70.2Hz),26.2,21.8,21.2,21.0,20.9.HRMS(ESI,m/z)calcd for C48H45NaOP[M+Na]+:691.3100,found 691.3091.31P NMR(162MHz,CDCl3)δ39.5.
实施例20:
从1t出发,与2c反应制得白色固体3t,59%产率,18:1dr,90%ee。使用Daicel IE-H手性柱色谱柱,采用高效液相色谱法测定其ee值。(HPLC:IE-H,254nm,正己烷/异丙醇85:15,流速1.0mL/min,30℃,tr(次)=7.0min,tr(主)=5.8min).[α]D 25=-218°(c 0.150,CH2Cl2).
1H NMR(400MHz,CDCl3)δ7.80(t,J=11.6Hz,1H),7.69(d,J=1.6Hz,1H),7.58–7.27(m,13H),6.98(dd,J=8.4,2.0Hz,1H),6.91(dd,J=8.4,2.0Hz,1H),6.83–6.74(m,3H),6.47(ddd,J=14.4,8.0,2.0Hz,2H),6.23(dd,J=8.4,2.0Hz,1H),5.80(dd,J=8.4,2.0Hz,1H),1.10(d,J=14.4Hz,9H).13C NMR(101MHz,CDCl3)δ145.2(d,J=4.5Hz),139.4(d,J=2.4Hz),138.9,138.10,138.0,137.6,136.6,135.9,135.4(d,J=9.8Hz),133.7,133.2(d,J=6.3Hz),132.7,132.3,132.2(d,J=11.1Hz),131.64,131.6(d,J=89.0Hz),131.56,131.1,131.0(d,J=2.5Hz),130.9,130.3(d,J=2.7Hz),130.0(d,J=9.4Hz),129.5(d,J=89.3Hz),129.4(d,J=6.3Hz),129.0,128.7(d,J=8.9Hz),128.1(d,J=10.0Hz),126.2(d,J=11.3Hz),121.0,120.3,119.7(d,J=37.2Hz),36.5(d,J=70.5Hz),26.0.HRMS(ESI,m/z)calcd for C44H33Br4NaOP[M+Na]+:946.8895,found 946.8888.31P NMR(162MHz,CDCl3)δ40.0.
实施例21:
从1u出发,与2d反应制得白色固体3u,56%产率,14:1dr,90%ee。使用Daicel IE-H手性柱色谱柱,采用高效液相色谱法测定其ee值。(HPLC:IE-H,254nm,正己烷/异丙醇85:15,流速1.0mL/min,30℃,tr(次)=6.5min,tr(主)=5.4min).[α]D 25=-127°(c 0.130,CH2Cl2).
1H NMR(400MHz,CDCl3)δ7.83–7.76(m,1H),7.59–7.27(m,13H),7.15(dd,J=8.4,2.4Hz,1H),6.89–6.80(m,3H),6.76(dd,J=8.4,2.0Hz,1H),6.65(dd,J=8.4,2.4Hz,1H),6.56(dd,J=8.4,2.4Hz,1H),6.51(dd,J=8.4,2.0Hz,1H),6.28(dd,J=8.4,2.0Hz,1H),5.65(dd,J=8.4,2.4Hz,1H),1.10(d,J=14.4Hz,9H).13C NMR(101MHz,CDCl3)δ145.3(d,J=4.5Hz),139.2(d,J=2.5Hz),138.5,138.2,137.7,137.2,136.5,136.0,135.4(d,J=9.8Hz),133.4,132.9(d,J=5.7Hz),132.7,132.4,132.3,132.1(d,J=11.1Hz),131.8(d,J=8.2Hz),131.6(d,J=9.2Hz),131.49(d,J=89.2Hz),131.4(d,J=16.3Hz),131.03,130.98(d,J=2.7Hz),130.87,130.3(d,J=2.7Hz),129.36(d,J=88.3Hz),129.3,128.1(d,J=2.7Hz),128.0,127.0(d,J=11.5Hz),126.4,126.3,126.2,126.1,125.4,36.0(d,J=70.2Hz),26.0.HRMS(ESI,m/z)calcd for C44H33Cl4NaOP[M+Na]+:771.0915,found771.0903.31P NMR(162MHz,CDCl3)δ40.0.
实施例22:
从1v出发,与2e反应制得白色固体3v,49%产率,13:1dr,92%ee。使用Daicel IE-H手性柱色谱柱,采用高效液相色谱法测定其ee值。(HPLC:IE-H,254nm,正己烷/异丙醇70:30,流速1.0mL/min,30℃,tr(次)=9.8min,tr(主)=10.6min).[α]D 25=-83°(c 0.04,CH2Cl2).
1H NMR(400MHz,CDCl3)δ7.80–7.74(m,1H),7.56–7.28(m,10H),7.01–6.90(m,3H),6.82(dd,J=8.4,2.8Hz,2H),6.71(dd,J=8.4,2.8Hz,1H),6.56–6.50(m,2H),6.36(dt,J=8.8,2.0Hz,2H),6.30(dd,J=8.4,2.8Hz,1H),6.21(dd,J=8.4,2.8Hz,1H),5.32(dd,J=8.4,2.8Hz,1H),3.78(s,3H),3.69(s,3H),3.57(s,3H),3.42(s,3H),1.11(d,J=14.4Hz,9H).13C NMR(101MHz,CDCl3)δ157.5,156.8,156.5,156.2,146.9(d,J=4.7Hz),139.2,138.3(d,J=2.3Hz),136.6,135.8,135.7(d,J=10.0Hz),133.6(d,J=43.2Hz),133.0(d,J=3.7Hz),132.73,132.70(d,J=18.4Hz),132.2(d,J=88.9Hz),132.1(d,J=25.6Hz),131.9,131.8(d,J=11.5Hz),131.5,130.5(d,J=2.6Hz),130.0(d,J=2.6Hz),129.5(d,J=89.7Hz),129.1,128.0,127.7(d,J=10.8Hz),125.4(d,J=11.6Hz),116.8,112.8(d,J=33.7Hz),111.75(d,J=8.7Hz),111.65,110.7,105.56,55.1,55.0,54.8,54.5,35.9(d,J=70.0Hz),26.1.HRMS(ESI,m/z)calcd for C48H45NaO5P[M+Na]+:755.2897,found755.2893.31P NMR(162MHz,CDCl3)δ39.5.
实施例23:
从1w出发,与2f反应制得白色固体3w,75%产率,13:1dr,92%ee。使用Daicel OZ-H手性柱色谱柱,采用高效液相色谱法测定其ee值。(HPLC:OZ-H,254nm,正己烷/异丙醇98:2,流速1.0mL/min,30℃,tr(次)=4.5min,tr(主)=5.5min).[α]D 25=105°(c 0.160,CH2Cl2).
1H NMR(400MHz,CDCl3)δ7.73(dd,J=10.4,8.0Hz,1H),7.59–7.52(m,2H),7.50–7.27(m,6H),7.04(d,J=20.0Hz,2H),6.94(s,1H),6.65(s,2H),6.54(s,1H),6.26(d,J=17.6Hz,3H),6.13(d,J=12.8Hz,2H),2.27(s,3H),2.14(s,3H),2.11(s,3H),1.97(s,3H),1.91(s,3H),1.88(s,3H),1.85(s,3H),1.15(s,3H),1.10(d,J=14.4Hz,9H).13C NMR(101MHz,CDCl3)δ147.5(d,J=4.8Hz),143.0,140.7,140.4,140.0,137.8,137.5,137.0(d,J=2.5Hz),135.9,135.8,135.6,135.4,135.3,135.2,134.24,134.19,134.14,133.7,133.0,132.5(d,J=89.7Hz),132.0,131.9(d,J=5.8Hz),131.5,130.7(d,J=2.3Hz),130.2,130.0,129.8(d,J=2.7Hz),129.6,129.5,129.4(d,J=90.1Hz),129.1,128.9,128.5,127.8,127.7,126.8,126.4,125.9,125.5,125.2(d,J=11.8Hz),36.2(d,J=70.2Hz),25.4,21.3,21.1,21.0,20.80,20.75,20.2.HRMS(ESI,m/z)calcd for C52H53NaOP[M+Na]+:747.3726,found 747.3720.31P NMR(162MHz,CDCl3)δ39.7.
实施例24:
从1s出发,与2a反应制得白色固体3s,50%产率,>20:1dr,81%ee。使用DaicelIE-H手性柱色谱柱,采用高效液相色谱法测定其ee值。(HPLC:IE-H,254nm,正己烷/异丙醇80:20,流速1.0mL/min,30℃,tr(次)=10.1min,tr(主)=8.9min).[α]D 25=-28°(c 0.08,CH2Cl2).
1H NMR(400MHz,CDCl3)δ8.06–7.98(m,1H),7.56–7.51(m,1H),7.47–7.09(m,20H),6.89–6.64(m,9H),6.39(t,J=7.6Hz,1H),6.22(d,J=7.6Hz,1H),4.07(dt,J=9.9,5.2Hz,1H),1.89(dq,J=13.4,6.7Hz,2H),0.85(d,J=6.8Hz,3H),0.77(d,J=6.7Hz,4H),0.68(d,J=6.8Hz,3H),0.57(d,J=6.9Hz,3H).13C NMR(101MHz,CDCl3)δ143.20(d,J=13.2Hz),140.67,139.76(d,J=8.9Hz),138.57(d,J=9.2Hz),138.09,136.84(d,J=3.4Hz),134.19,133.97(d,J=12.7Hz),133.39(d,J=11.0Hz),133.21(d,J=8.8Hz),132.46(d,J=74.1Hz),131.71,131.61,131.54(d,J=7.0Hz),131.39,131.26(d,J=8.2Hz),131.03(d,J=2.5Hz),130.95,130.62(d,J=2.5Hz),127.77(d,J=32.3Hz),127.44(d,J=7.4Hz),127.28,126.56,126.50,126.42,126.25(d,J=7.7Hz),125.94,125.36(d,J=40.4Hz),125.03,86.65(d,J=7.6Hz),30.72(d,J=3.0Hz),30.15(d,J=3.3Hz),29.68,19.84,19.06,17.57.HRMS(ESI,m/z)calcd for C47H43NaO2P[M+Na]+:693.28923,found 693.2899.31P NMR(162MHz,CDCl3)δ39.4.
上述产物进一步还原可得到具有轴手性和膦手性的三价膦化合物,以化合物3l为例,其还原方程式如下:
将重结晶的化合物3l(0.05mmol)加入到反应瓶中,在氮气氛围下,向反应瓶中加入0.25mL乙腈,对体系降温至0℃,加入三氟甲磺酸甲酯(25μl,0.2mmol),并在0℃下搅拌4h。反应完成后旋转蒸发除去溶剂,再向反应管中加入无水THF(0.5mL),将混合物冷却至-78℃,加入氢化铝锂溶液(0.13mL,0.3mmol,2.4M in THF)。在-78℃下搅拌反应4h,并用薄层色谱法监测反应过程。将混合物加热至0℃,搅拌30分钟。用iPrOH(0.2mL)淬灭反应,通过硅胶柱层析进行纯化。制得白色固体4l,60%产率,94%ee。使用Daicel OD-H手性柱色谱柱,采用高效液相色谱法测定其ee值。(HPLC:OD-H,254nm,正己烷/异丙醇49:1,流速0.5mL/min,30℃,tr(次)=12.3min,tr(主)=14.3min).[α]D 25=63°(c 0.10,CH2Cl2).
1H NMR(400MHz,CDCl3)δ7.97(d,J=8.0Hz,1H),7.60–7.49(m,6H),7.45–7.26(m,10H),7.25–7.20(m,2H),7.20–7.14(m,2H),7.12–7.02(m,4H),7.00–6.94(m,2H),6.94–6.76(m,7H),6.68(d,J=8.4Hz,1H),6.47(ddd,J=8.4,6.8,1.2Hz,1H),1.12(d,J=12.8Hz,9H).13C NMR(101MHz,CDCl3)δ147.0,146.7,141.0,140.8,140.6,140.4,139.8(d,J=11.8Hz),138.6,138.4,137.71(d,J=3.7Hz),137.67(d,J=0.7Hz),136.2(d,J=21.8Hz),135.77,135.56,135.4(d,J=17.4Hz),132.8(d,J=1.6Hz),131.9(d,J=2.7Hz),131.8,131.6,131.6(d,J=5.6Hz),131.5,131.3,131.28(d,J=5.6Hz),131.27,128.7(d,J=2.5Hz),127.5,127.4(d,J=9.0Hz),127.2(d,J=4.9Hz),127.0(d,J=6.0Hz),126.4(d,J=2.6Hz),126.26,126.2,126.1,126.0(d,J=4.8Hz),125.4,125.1(d,J=7.2Hz),124.9,124.4,30.6(d,J=16.8Hz),29.1(d,J=16.0Hz).HRMS(ESI,m/z)calcd for C56H45NaP[M+Na]+:771.3151,found 771.3166.31P NMR(162MHz,CDCl3)δ3.7.
对比例1:
当使用酸作为配体时,所得产物收率仅40%,10:1dr,5%ee,与酰胺配体的结果相差较大。
尽管本发明的实施方案已公开如上,但其并不仅仅限于说明书和实施方式中所列运用,它完全可以被适用于各种适合本发明的领域,对于熟悉本领域的人员而言,可容易地实现另外的修改,因此在不背离权利要求及等同范围所限定的一般概念下,本发明并不限于特定的细节和这里示出与描述的示例。
Claims (5)
1.一种具有膦手性和轴手性化合物的合成方法,其特征在于,在有机溶剂中,使用式1)所示二芳基膦氧与式2)所示二芳基乙炔在催化剂、氧化剂及配体L的作用下生成具有膦手性和轴手性的式3)所示目标化合物;
其中,R1所在苯环任选自3-甲基苯基、4-甲基苯基、3-甲氧基苯基、4-甲氧基苯基、4-异丙基苯基、4-叔丁基苯基、3-叔丁基苯基、3-苯基苯基、4-苯基苯基、4-氯苯基、4-氟苯基、4-N,N-二甲基胺基苯基、4-三甲基硅基苯基、2-萘基、3,4-二甲基苯基和3-甲基-4-甲氧基苯基中的一种;
R2所在苯环任选自4-甲基苯基、4-甲氧基苯基、4-氯苯基、4-溴苯基和3,5-二甲基苯基中的一种;
R3任选自叔丁基、环己基、1-金刚烷基和2,4-二甲基戊醇基;
3.如权利要求1所述的具有膦手性和轴手性类化合物的合成方法,其特征在于,所述有机溶剂为四氢呋喃;所述催化剂为五甲基环戊二烯基铱三乙腈二六氟锑酸;所述氧化剂为碳酸银。
4.如权利要求1所述的具有膦手性和轴手性类化合物的合成方法,其特征在于,所述二芳基膦氧、二芳基乙炔、催化剂、氧化剂和配体L的摩尔比是1:3:0.15:1.1:0.3。
5.如权利要求1所述的具有膦手性和轴手性类化合物的合成方法,其特征在于,所述合成方法的具体条件是在氮气下将有机溶剂、二芳基膦氧、二芳基乙炔、催化剂、氧化剂和配体L全部添加到密封管中,在90℃下反应12h;通过薄层层析或柱层析提纯法,所用展开剂为乙酸乙酯-石油醚的混合溶剂。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202110970035.8A CN113735899B (zh) | 2021-08-23 | 2021-08-23 | 一种具有膦手性和轴手性化合物的合成方法 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202110970035.8A CN113735899B (zh) | 2021-08-23 | 2021-08-23 | 一种具有膦手性和轴手性化合物的合成方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN113735899A true CN113735899A (zh) | 2021-12-03 |
CN113735899B CN113735899B (zh) | 2023-02-21 |
Family
ID=78732364
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202110970035.8A Active CN113735899B (zh) | 2021-08-23 | 2021-08-23 | 一种具有膦手性和轴手性化合物的合成方法 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN113735899B (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115448949A (zh) * | 2022-10-25 | 2022-12-09 | 陕西师范大学 | 一种手性烯丙基膦化合物的合成方法 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104725427A (zh) * | 2015-02-03 | 2015-06-24 | 商丘师范学院 | 分子内c-h芳基化反应催化合成手性膦化合物及其制备方法 |
-
2021
- 2021-08-23 CN CN202110970035.8A patent/CN113735899B/zh active Active
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104725427A (zh) * | 2015-02-03 | 2015-06-24 | 商丘师范学院 | 分子内c-h芳基化反应催化合成手性膦化合物及其制备方法 |
Non-Patent Citations (2)
Title |
---|
PANJIE HU ET AL.: "Twofold C-H Activation-Based Enantio- and Diastereoselective C-H Arylation Using Diarylacetylenes as Rare Arylating Reagents", 《ANGEWANDTE CHEMIE INTERNATIONAL EDITION》 * |
PANJIE HU ET AL.: "Twofold C-H Activation-Based Enantio- and Diastereoselective C-H Arylation Using Diarylacetylenes as Rare Arylating Reagents", 《CHEMRXIV》 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115448949A (zh) * | 2022-10-25 | 2022-12-09 | 陕西师范大学 | 一种手性烯丙基膦化合物的合成方法 |
CN115448949B (zh) * | 2022-10-25 | 2024-03-22 | 陕西师范大学 | 一种手性烯丙基膦化合物的合成方法 |
Also Published As
Publication number | Publication date |
---|---|
CN113735899B (zh) | 2023-02-21 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US8552212B2 (en) | Chiral phosphorus ligands | |
Hayashi et al. | New chiral chelating phosphine complexes containing tricarbonyl (η6-arene) chromium for highly enantioselective allylic alkylation | |
de Graaf et al. | Chiral induction in the sysnthesis of 4, 4-dimethyl-1-phenylpenta-1, 2-diene (1-Ph-3-t-Bu-allene) catalyzed by chiral phosphine complexes of palladium | |
CN113735899B (zh) | 一种具有膦手性和轴手性化合物的合成方法 | |
Shi et al. | Trifluoromethanesulfonamide, diphenylphosphoramide and diphenylthiophosphoramide of (R)‐(+)‐1, 1′‐binaphthyl‐2, 2′‐diamine as chiral catalyst ligands for the titanium (IV) alkoxide‐promoted addition of diethylzinc to aldehydes | |
JP2010053049A (ja) | ジホスフィン化合物、その遷移金属錯体およびその遷移金属錯体を含む触媒並びにホスフィンオキシド化合物及びジホスフィンオキシド化合物 | |
CN106866730A (zh) | 一种钯催化亚胺膦酸酯不对称氢化合成手性胺基膦酸酯的方法 | |
US9707553B2 (en) | P-chirogenic organophosphorus compounds | |
JP2006527246A (ja) | 配位子 | |
JP4028625B2 (ja) | ホスフィン化合物およびそれを配位子とするロジウム錯体 | |
JP2000136193A (ja) | 光学活性ビスホスフィノメタン並びにそれらのロジウム又は銅錯体を用いる不斉合成 | |
JP2005523939A (ja) | フェロセニル配位子及び前記配位子の製造方法 | |
JP2002193984A (ja) | 二座有機リン配位子、それによって形成された錯化合物、該配位子の製造方法および該錯化合物の使用 | |
CA2567939A1 (en) | Chiral phosphorus compounds | |
CN114181256B (zh) | 手性双噁唑啉-炔基膦类配体及其制备和应用 | |
CN116554223A (zh) | 一种手性双膦骨架化合物、其制备方法及其应用 | |
JP5009613B2 (ja) | 不斉合成における使用のためのキラル配位子 | |
Shi et al. | C2‐Symmetric dialkoxyphosphoramide and dialkoxythiophosphoramide derivatives of (1R, 2R)‐1, 2‐diaminocyclohexane as chiral ligands for the titanium (IV) alkoxide‐promoted asymmetric addition reactions of diethylzinc to arylaldehydes | |
KR20010031959A (ko) | 강성 키랄 리간드를 포함하는 비대칭 합성용 촉매 | |
CN115477672A (zh) | 一种含有轴手性和膦中心手性化合物及其制备方法 | |
CN115819368A (zh) | 一种手性α-叔胺化合物的制备方法 | |
JP3376518B2 (ja) | ホスフィン化合物の製法及びその中間体並びにその製法 | |
CN114085250A (zh) | 一种含Ugi’s胺砌块的P-手性膦-噁唑啉配体金属络合物催化剂的制备及应用 | |
CN111868065A (zh) | C-大位阻p-手性源性有机磷化合物 | |
JP2021050232A (ja) | ホスフィノベンゼンボラン誘導体の製造方法、1,2−ビス(ジアルキルホスフィノ)ベンゼン誘導体の製造方法及び遷移金属錯体 |
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 |