CN111662331B - Phosphine ligand, preparation method thereof and application of phosphine ligand in catalytic synthesis of ortho-tetra-substituted biaryl - Google Patents
Phosphine ligand, preparation method thereof and application of phosphine ligand in catalytic synthesis of ortho-tetra-substituted biaryl Download PDFInfo
- Publication number
- CN111662331B CN111662331B CN201910165339.XA CN201910165339A CN111662331B CN 111662331 B CN111662331 B CN 111662331B CN 201910165339 A CN201910165339 A CN 201910165339A CN 111662331 B CN111662331 B CN 111662331B
- Authority
- CN
- China
- Prior art keywords
- compound
- alkyl
- substituted
- independently
- group
- 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
Images
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 System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
- C07F9/657163—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms the ring phosphorus atom being bound to at least one carbon atom
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
- B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
- B01J31/2442—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems
- B01J31/2461—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems and phosphine-P atoms as ring members in the condensed ring system or in a further ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/44—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by —CHO groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/30—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms
- C07C233/33—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/24—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfuric acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C305/00—Esters of sulfuric acids
- C07C305/26—Halogenosulfates, i.e. monoesters of halogenosulfuric acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/30—Preparation of ethers by reactions not forming ether-oxygen bonds by increasing the number of carbon atoms, e.g. by oligomerisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
- C07C43/225—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C47/00—Compounds having —CHO groups
- C07C47/52—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings
- C07C47/575—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings containing ether groups, groups, groups, or groups
-
- 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
- C07D209/80—[b, c]- or [b, d]-condensed
- C07D209/82—Carbazoles; Hydrogenated carbazoles
- C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/69—Two or more oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic System
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic System
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic System compounds of the platinum group
- C07F15/006—Palladium compounds
-
- 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
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
-
- 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 System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
-
- 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
-
- 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
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a phosphine ligand, a preparation method thereof and application of the phosphine ligand in catalytic synthesis of ortho-tetra-substituted biaryl. The phosphine ligand has a structure shown in a formula I. The phosphine ligand or the racemate thereof can be used as a metal ligand, and the ortho-tetra-substituted biaryl compounds with various functional groups can be obtained with high yield or high optical purity.
Description
Technical Field
The invention relates to a phosphine ligand, a preparation method thereof and application of the phosphine ligand in catalytic synthesis of ortho-tetra-substituted biaryl.
Background
Many natural products and drug molecules have biaryl structures with axial chirality, for example, in the large family of naphthalene isoquinoline alkaloids, such as Korupensamine a, korupensamine B, and Michellamine B. Both Korupensamine A and Korupensamine B have high antimalarial activity. Michellamine B has been used as a clinical drug because of its strong anti-HIV activity (j. Nat. Prod.1997,60,677, j. Med. Chem.1991,34,3402, chem.rev.2011,111, 563). Meanwhile, ortho-tetra-substituted chiral biaryl structures with axial chirality are also widely present in many natural products and drug molecules, for example, the chromone ester natural product gonadolide a. Gonytolide A has significant activity in stimulating innate immune responses in mammals (org. Lett.2011,13, 4624). Menadione dimer cardinalin 3 exhibits strong in vivo cytotoxicity against certain leukemia cells (j.chem.soc., perkin trans.1997,6,919 nat. Prod.lett.1994,5,211 aust.j.chem.1997,50, 1081). Gossypol is a natural product of polyphenols. Gossypol is marketed in china as a male contraceptive in the mid twentieth century (j.am.oil chem.soc.2006,83, 269). A range of biological activities of gossypol and its derivatives, including insect, malaria, tumor and virus inhibition activities, were subsequently reported (Future med. Chem.2017,9,11, science.1982,218,288, carbohydrar. Res.2011,346,2070, j.med. Chem.1998,41,3879, cancer res.1990,50,6936, bioorg.med.chem.lett.2012,22,1415, bioorg.med.chem.2016,24, 474.
The preparation method of the ortho-tetra-substituted biaryl compound with axial chirality mainly comprises the steps of resolving a racemic compound, inducing by using a chiral reagent or an auxiliary group, and carrying out asymmetric catalysis. The racemic compound is resolved at 50% consumption of starting material, and the chiral source is consumed by induction with a chiral reagent or an auxiliary group. Compared with the chiral catalyst, the asymmetric catalysis method has obvious high efficiency and economy by utilizing the chiral catalyst with catalytic amount.
Asymmetric coupling is one of the methods with highest efficiency and strongest practicability in the existing asymmetric catalysis method for synthesizing chiral biaryl. Although methods for synthesizing ortho-tetra-substituted biaryl compounds using asymmetric coupling have been studied (angelw. Chem. Int.ed.2017,56,4777, j.am.chem.soc.2002,124,13396, eur.j.org.chem.2014,6676, chem.eur.j.2006,12,9346, org.lett.2010,12, 1072), the existing methods still have many disadvantages, reaction substrate structure is single, functional group tolerance is poor, coupling efficiency or enantioselectivity is not high enough, and the like. For example, the following chiral phosphine ligands have been used for the synthesis of ortho-tetra-substituted 2,2 '-dimethyl-1, 1' -binaphthyl having axial chirality, and although some phosphine ligands can obtain a certain yield and ee value, the universality of substituents in the synthesis of ortho-tetra-substituted biaryl structures having axial chirality has not been studied in depth, and thus the obtained chiral ortho-tetra-substituted biaryl structures are relatively single.
In particular, there are fewer reports on chiral ortho-tetra-substituted biphenyl compounds containing an aldehyde group. The yield and enantioselectivity of the chiral ortho-tetra-substituted biphenyl compound containing aldehyde group reported at present are also general.
In view of the above, there is a need in the art to develop a more practical and efficient catalyst for efficiently synthesizing various functional groups of ortho-tetra-substituted biaryl compounds, especially ortho-tetra-substituted biaryl compounds with axial chirality.
Disclosure of Invention
The invention aims to overcome the defects of low yield, low optical purity or single substituent group type in the synthesis of ortho-tetra-substituted biaryl compounds in the prior art, and provides a phosphine ligand and a preparation method and application thereof. The phosphine ligand is applied to asymmetric Suzuki-Miyaura coupling reaction, and can obtain ortho-tetra-substituted biaryl compounds with various substituents at high yield, particularly ortho-tetra-substituted biaryl compounds with axial chirality at high selectivity, and the reaction conditions are mild.
The invention solves the technical problems through the following technical scheme.
The invention provides a phosphine ligand, which is a compound shown as a formula I or a racemate thereof:
wherein "-" indicates that the atom herein is a chiral atom; r 1 、R 3 And R 5 Independently of one another is hydrogen, C 1～10 Alkyl radical, C 1～10 Heteroalkyl group, C 3～30 Cycloalkyl radical, R 1-1a Substituted C 3～30 Cycloalkyl radical, C 6 ～ 30 Aryl or R 1-1b Substituted C 6 ～ 30 An aryl group; said C is 1～10 The heteroatom in the heteroalkyl group is selected from one or more of O, S and N, and the number is 1,2, 3,4,5 or 6; when the number of the heteroatoms is more than one, the heteroatoms are the same or different;
R 2 and R 4 Independently is C 1～10 Alkyl radical, C 1～10 Heteroalkyl group, C 3～30 Cycloalkyl radical, R 2-1a Substituted C 3～30 Cycloalkyl radical, C 6 ～ 30 Aryl or R 2-1b Substituted C 6 ～ 30 An aryl group; said C is 1～10 The heteroatom in the heteroalkyl group is selected from one or more of O, S and N, and the number is 1,2, 3,4,5 or 6; when the number of the heteroatoms is more than one, the heteroatoms are the same or different;
each R 1-1a And each R 2-1a Independently of C 1～10 An alkyl group; r 1-1a And R 2-1a The number is 1 or more; when R is 1-1a And R 2-1a A plurality of R independently 1-1a And R 2-1a Independently the same or different;
each R 1-1b And each R 2-1b Independently is C 1～10 Alkyl radical, C 1～10 Alkoxy or C 6 ～ 30 An aryl group; when each R is 1-1b And each R 2-1b A plurality of R independently 1-1b And R 2-1b Independently the same or different;
R 6 and R 7 Independently H, C 1～10 Alkyl, hydroxy substituted C 1～10 Alkyl radical, C 3～30 Cycloalkyl or C 6 ～ 30 An aryl group;
R 8 is hydroxy, C 1～10 Alkyl, hydroxy substituted C 1～10 Alkyl radical, C 1～10 Alkoxy radical,
C 3～30 Cycloalkyl, mercapto or C 6 ～ 30 Aryl, wherein R 10 And R 11 Independently is H or C 1～4 An alkyl group;
R 9 is C 1～10 Alkyl radical, C 3～30 Cycloalkyl or C 6 ～ 30 And (4) an aryl group.
When said R is 1 、R 3 And R 5 Independently isC 1～10 When alkyl, said C 1～10 The alkyl group may be C 1～6 Alkyl, preferably C 1～3 An alkyl group. Said C is 1～3 The alkyl group may be methyl, ethyl, n-propyl or isopropyl, preferably methyl or isopropyl.
When said R is 1 、R 3 And R 5 Independently is C 1～10 When it is heteroalkyl, said C 1～10 The heteroalkyl group may be C 1～6 A heteroalkyl group.
When said R is 1 、R 3 And R 5 Independently is C 3～30 When a cycloalkyl group is present, C is 3～30 Cycloalkyl radicals may be C 3～10 A cycloalkyl group.
When said R is 1 、R 3 And R 5 Independently is R 1-1a Substituted C 3～30 When cycloalkyl is present, said R 1-1a Substituted C 3～30 C in cycloalkyl 3～30 Cycloalkyl radicals may be C 3～10 A cycloalkyl group.
When said R is 1 、R 3 And R 5 Independently is C 6 ～ 30 Aryl is said to C 6 ～ 30 Aryl may be C 6～14 And (4) an aryl group.
When said R is 1 、R 3 And R 5 Independently is R 1-1b Substituted C 6 ～ 30 When aryl is said to R 1-1b Substituted C 6 ～ 30 C in aryl 6 ～ 30 Aryl may be C 6～14 And (4) an aryl group.
When said R is 2 And R 4 Independently is C 1～10 When alkyl, said C 1～10 The alkyl group may be straight chain C 1～10 Alkyl or branched C 3～10 Alkyl, preferably branched C 3～10 An alkyl group. Wherein, the straight chain C 1～10 The alkyl group may be straight-chain C 1～6 Alkyl, preferably straight-chain C 1～3 An alkyl group. The branched chain C 3～10 The alkyl group may be branched C 3～6 Alkyl, preferably branched C 3～5 An alkyl group. The branched chain C 3～5 The alkyl group may be isopropyl group,
Preferably isopropyl or
When said R is 2 And R 4 Independently is C 3～30 When a cycloalkyl group is present, C is 3～30 Cycloalkyl radicals may be C 3～10 Cycloalkyl, preferably C 3～6 A cycloalkyl group.
When said R is 2 And R 4 Independently is R 2-1a Substituted C 3～30 When being cycloalkyl, R 2-1a Substituted C 3～30 C in cycloalkyl 3～30 Cycloalkyl can be C 3～10 Cycloalkyl, preferably C 3～6 A cycloalkyl group. Said C is 3～6 Cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, with cyclopentyl being preferred.
When said R is 2 And R 4 Independently is R 2-1a Substituted C 3～30 When cycloalkyl is present, said R 2-1a Substituted C 3～30 R in cycloalkyl 2-1a The number may be 1,2, 3 or 4, preferably 4. When said R is 2-1a When the number of the substitution is plural, R is 2-1a Preferably the same.
When said R is 2-1a Is C 1～10 When alkyl, said C 1～10 The alkyl group may be C 1～6 Alkyl, preferably C 1～3 An alkyl group. Said C is 1～3 The alkyl group can be methyl, ethyl, n-propyl or isopropyl, preferably methyl.
When said R is 2 And R 4 Independently is R 2-1a Substituted C 3～30 When cycloalkyl is present, said R 2-1a Substituted C 3～30 Cycloalkyl can be C 1～3 Alkyl substituted C 3～6 Cycloalkyl, further preferred
When said R is 2 And R 4 Independently is C 6 ～ 30 Aryl is said to C 6 ～ 30 Aryl may be C 6～20 Aryl, preferably C 6～14 Aryl, more preferably phenyl.
When said R is 1 、R 2 、R 3 、R 4 And R 5 Independently is R 2-1b Substituted C 6 ～ 30 At aryl radical, the said R 2-1b Substituted C 6 ～ 30 C in aryl 6 ～ 30 Aryl may be C 6～20 Aryl, preferably C 6～14 And (4) an aryl group.
When said R is 6 And R 7 Independently is C 1～10 When alkyl, said C 1～10 The alkyl group may be C 1～6 Alkyl, preferably C 1～3 An alkyl group. Said C is 1～3 The alkyl group may be methyl, ethyl, n-propyl or isopropyl.
When said R is 6 And R 7 Independently is hydroxy-substituted C 1～10 When alkyl, said hydroxy group is substituted C 1～10 C in alkyl 1～10 The alkyl group may be C 1～6 Alkyl, preferably C 1～3 An alkyl group. Said C is 1～3 The alkyl group may be methyl, ethyl, n-propyl or isopropyl, preferably methyl.
When said R is 6 And R 7 Independently is C 3～30 When a cycloalkyl group is said C 3～30 Cycloalkyl radicals may be C 3～10 A cycloalkyl group.
When said R is 6 And R 7 Independently C 6 ～ 30 Aryl is said to C 6 ～ 30 Aryl may be C 6 ～ 20 And (4) an aryl group.
When said R is 8 Is C 1～10 When alkyl, said C 1～10 The alkyl group may be C 1～6 Alkyl, preferably C 1～3 An alkyl group. Said C is 1～3 The alkyl group may be methyl, ethyl, n-propyl or isopropyl, preferably methyl.
When said R is 8 Is hydroxy-substituted C 1～10 When alkyl, said hydroxy group is substituted by C 1～10 C in alkyl 1～10 The alkyl group may be C 1～6 Alkyl, preferably C 1～3 An alkyl group. Said C is 1～3 The alkyl group may be methyl, ethyl, n-propyl or isopropyl, preferably methyl.
When said R is 8 Is hydroxy-substituted C 1～10 When alkyl, said hydroxy group is substituted C 1～10 The number of hydroxyl groups in the alkyl group may be 1.
When said R is 8 Independently is C 1～10 At alkoxy, the C 1～10 Alkoxy may be C 1～6 Alkoxy, preferably C 1～3 An alkoxy group. Said C is 1～3 The alkoxy group may be methoxy, ethoxy, n-propoxy or isopropoxy, with methoxy being preferred.
When said R is 8 Is composed of
When it is in use, the
(may be)
Preference is given to
When said R is 8 Is C 3～30 When a cycloalkyl group is present, C is 3～30 Cycloalkyl radicals may be C 3～10 A cycloalkyl group.
When said R is 8 Is C 6 ～ 30 Aryl is said to C 6 ～ 30 Aryl may be C 6 ～ 20 And (3) an aryl group.
When R is 9 Is C 1～10 When alkyl, said C 1～10 The alkyl group may be straight-chain C 1～10 Alkyl or branched C 3～10 Alkyl, preferably branched C 3～10 An alkyl group. Wherein, the straight chain C 1～10 The alkyl group may be straight-chain C 1～6 Alkyl, preferably straight-chain C 1～3 An alkyl group. The branched chain C 3～10 The alkyl group may be branched C 3～6 Alkyl, preferably branched C 3～4 An alkyl group. Said branch C 3～4 The alkyl group may be isopropyl group,
Or tert-butyl, which may also be tert-butyl.
When said R is 9 Is C 3～30 When a cycloalkyl group is present, C is 3～30 Cycloalkyl radicals may be C 3～10 A cycloalkyl group.
When said R is 9 Is C 6 ～ 30 Aryl is said to C 6 ～ 30 Aryl may be C 6 ～ 20 And (4) an aryl group.
When said R is 10 And R 11 Independently is C 1～4 When alkyl, said C 1～4 The alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl,
Or a tert-butyl group.
In one embodiment of the present invention, the compound represented by formula I is
In one embodiment of the invention, R 1 And R 5 Independently is C 1～10 An alkyl group.
In one embodiment of the invention, R 1 And R 5 The same is true.
In one embodiment of the invention, R 2 And R 4 Independently is C 1～10 Alkyl radical, C 3～30 Cycloalkyl radical, R 2-1a Substituted C 3～30 Cycloalkyl or C 6 ～ 30 And (4) an aryl group.
In one embodiment of the invention, R 2 And R 4 Independently is C 3～30 Cycloalkyl radical, R 2-1a Substituted C 3～30 A cycloalkyl group.
In one embodiment of the invention, R 2 And R 4 The same is true.
In one embodiment of the invention, R 3 Is hydrogen.
In one embodiment of the invention, R 6 And R 7 Independently H, C 1～10 Alkyl or hydroxy substituted C 1～10 An alkyl group.
In one embodiment of the invention, R 6 And R 7 Independently is C 1～10 An alkyl group.
In one embodiment of the invention, R 8 Is hydroxy, C 1～10 Alkyl radical, C 1～10 Alkoxy or
In one embodiment of the invention, R 8 Is a hydroxyl group.
In one embodiment of the invention, R 9 Is C 1～10 An alkyl group.
In one embodiment of the present invention, the substrate is,
is composed of
In one embodiment of the present invention, the substrate is,
is composed of
In one embodiment of the present invention, in the compound represented by formula I,
is composed of
In one embodiment of the present invention, in the compound represented by formula I,
is composed of
In one embodiment of the invention, R 1 And R 5 Independently is C 1～10 An alkyl group; r is 2 And R 4 Independently is C 1～10 Alkyl radical, C 3～30 Cycloalkyl radical, R 2-1a Substituted C 3～30 Cycloalkyl or C 6 ～ 30 An aryl group; r 3 Is hydrogen;
R 6 and R 7 Independently H, C 1～10 Alkyl or hydroxy substituted C 1～10 An alkyl group; r 8 Independently is hydroxy, C 1～10 Alkyl radical, C 1～10 Alkoxy or
And, R 9 Is C 1～10 An alkyl group.
In one embodiment of the invention, R 1 And R 5 Independently is C 1～10 An alkyl group; r 2 And R 4 Independently is C 3～30 Cycloalkyl or R 2-1a Substituted C 3～30 A cycloalkyl group; r 3 Is hydrogen; r 6 And R 7 Independently is C 1～10 An alkyl group; r 8 Independently is a hydroxyl group; and, R 9 Is C 1～10 An alkyl group.
The compound shown in the formula I is selected from any one of the following compounds:
the invention also provides a preparation method of the compound shown in the formula I or the racemate thereof, which comprises the following steps: in the presence of a reducing agent, carrying out a reduction reaction of a compound II in an organic solvent to obtain a compound I;
wherein, ", R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 And R 9 The definitions of (A) and (B) are as described above.
In the reduction reaction, the reducing agent can be a reducing agent conventional in the reaction in the field, and preferably a halogenated silane reducing agent and/or a polysilane reducing agent. The halosilane-based reducing agent may be trichlorosilane. The polysilane-based reducing agent may be polymethoxy-hydrosilane. The reducing agent may be used in conventional amounts, preferably in a molar ratio of the reducing agent to the compound II of from 1 to 10, for example 8.
Wherein, when the reducing agent is a halosilane reducing agent, the reduction reaction is preferably carried out in the presence of an acid-binding agent. The acid-binding agent can be a conventional acid-binding agent, preferably an inorganic weak base and/or an organic weak base, preferably an organic weak base, and further preferably a tertiary amine organic weak base. When the reducing agent is a polysilane-based reducing agent, the reduction reaction is preferably carried out in the presence of tetraisopropyl titanate.
In the reduction reaction, the organic solvent may be a conventional solvent in the art, preferably an aromatic hydrocarbon solvent and/or an ether solvent. The aromatic hydrocarbon solvent can be toluene or benzene, and can also be toluene. The amount of the organic solvent to be used is not particularly limited as long as the reaction is not affected.
In the reduction reaction, the temperature of the reduction reaction may be a temperature conventional in such reactions in the art, preferably 60 to 80 ℃, for example 70 ℃.
The compound II is preferably
In the reduction reaction, the monitoring method of the progress of the reduction reaction may be a monitoring method (e.g., TIC, HPLC, LC-MS) which is conventional in the art, and the disappearance or absence of the compound II as the end point of the reaction is generally used. The time for the reduction reaction is preferably 8 to 24 hours, for example 12 hours.
After the reduction reaction is finished, the method also comprises the following post-treatment steps: cooling the reaction solution after the reaction is finished to room temperature, adjusting the reaction solution to be neutral, extracting (the extraction solvent is preferably ethyl acetate), drying, concentrating and performing column chromatography (the eluent is preferably petroleum ether-ethyl acetate, and the volume ratio of the eluent is 20-10, such as 15.
The invention also provides a compound shown as the formula II or a racemate thereof:
wherein, ", R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 And R 9 The definitions of (A) and (B) are as described above.
The compound shown in the formula II or the racemate thereof is preferably any one of the following compounds:
the invention also provides a preparation method of the compound shown in the formula II or the racemate thereof, which comprises the following steps:
under the action of an alkaline reagent, carrying out the following reaction of a compound III and a compound A in an organic solvent to obtain a compound II;
wherein X is halogen; r 12a And R 12b Independently H, C 1～10 Alkyl, hydroxy substituted C 1～10 Alkyl radical, C 3～30 Cycloalkyl or C 6 ～ 30 An aryl group; r 13a And R 13b Independently is H or C 1～4 Alkyl radical, R 13a And R 13b Not H at the same time; r 14 Is C 1～10 Alkyl, hydroxy substituted C 1～10 Alkyl or C 1～10 An alkoxy group; ", R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 And R 9 The definitions of (A) and (B) are as described above.
In X, the halogen is Cl, br or I.
R 12a And R 12b In (A), the C 1～10 Alkyl independently can be C 1～6 Alkyl, preferably C 1～3 The alkyl group is more preferably a methyl group, an ethyl group, an n-propyl group or an isopropyl group, and still more preferably a methyl group, an ethyl group or an isopropyl group.
R 12a And R 12b In (1), the hydroxyl group substituted C 1～10 C in alkyl 1～10 The alkyl group independently can be C 1～6 Alkyl, preferably C 1～3 The alkyl group is more preferably a methyl group, an ethyl group, an n-propyl group or an isopropyl group, and still more preferably a methyl group.
R 12a And R 12b In (A), the C 3～30 Cycloalkyl radicals may be C 3～10 Cycloalkyl, preferably C 3～6 A cycloalkyl group.
R 12a And R 12b In (A), the C 6 ～ 30 Aryl may be C 6 ～ 18 Aryl, preferably C 6 ～ 14 And (4) an aryl group.
R 13a And R 13b In (A), the C 1～4 The alkyl groups independently can be methyl, ethyl, or n-propyl, isopropyl, n-butyl,
Or tert-butyl, preferably methyl.
R 14 In (1), the C 1～10 The alkyl group may be C 1～6 Alkyl, preferably C 1～3 The alkyl group is more preferably a methyl group, an ethyl group, an n-propyl group or an isopropyl group, and still more preferably a methyl group.
R 14 In (1), the C 1～10 Alkoxy can be C 1～6 Alkoxy, preferably C 1～3 The alkoxy group is more preferably a methoxy group, an ethoxy group, a n-propoxy group or an isopropoxy group, and still more preferably a methoxy group.
In the reaction, the basic agent may be a basic agent conventional in the art, preferably one or more of lithium diisopropylamide, lithium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, and sodium bis (trimethylsilyl) amide or sodium hydride, more preferably lithium diisopropylamide or lithium bis (trimethylsilyl) amide.
The molar ratio of the basic agent to the compound III in the reaction may be a ratio conventional in such reactions in the art, preferably 1.0 to 5.0, for example 4.0.
In the reaction, the organic solvent may be an organic solvent conventional in the art for such reactions, preferably one or more of aromatic hydrocarbon solvents (e.g., toluene), ether solvents (e.g., tetrahydrofuran, dioxane, diethyl ether) and halogenated hydrocarbon solvents (e.g., dichloromethane), more preferably ether solvents. The amount of the organic solvent to be used is not particularly limited as long as the reaction is not affected.
The molar ratio of said compound a to said compound III in said reaction may be a ratio conventional in such reactions in the art, preferably from 1 to 5.0, e.g. 2.0.
In the reaction, the temperature of the reaction may be a temperature conventional in the art, and is preferably-78 to 30 ℃.
The compound III is preferably
The compound A is preferably acetone or
The monitoring of the progress of the reaction may be any method conventional in the art (e.g. TIC, HPLC, LC-MS), generally with disappearance of compound III or absence of reaction as the end point of the reaction. The time for the reduction reaction is preferably 1 to 5 hours, for example, 2 hours.
After the reaction is finished, the method can further comprise the following post-treatment steps: the reaction solution after the completion of the reaction is cooled, quenched (the quenching reagent is saturated ammonium chloride), extracted (the extraction solvent is preferably ethyl acetate), washed with water (with saturated saline solution), dried, concentrated, and subjected to column chromatography (the eluent is preferably petroleum ether-ethyl acetate, and the volume ratio thereof is 1 to 5, for example, 2.
The invention also provides a compound shown as the formula III:
wherein R is 1 、R 2 、R 3 、R 4 、R 5 And R 9 All as described above.
The compound of formula III can be
The invention also provides an application of the compound or racemate shown as the formula I as a metal ligand in Suzuki-Miyaura coupling reaction: the Suzuki-Miyaura coupling reaction, which comprises the following steps: in the presence of a palladium catalyst, the compound I and an alkaline reagent, carrying out Suzuki-Miyaura coupling reaction on the compound C and the compound D in a solvent to obtain a compound E or a compound ent-E;
alternatively, the Suzuki-Miyaura coupling reaction comprising the steps of: carrying out Suzuki-Miyaura coupling reaction on a compound C and a compound D in a solvent in the presence of a palladium catalyst, the compound I racemate and a basic reagent to obtain a compound E and a compound ent-E;
wherein "
And
"and"
And
all indicate that the group has axial chirality; q is C or N; when Q is N, R 18 Is absent; x is halogen (e.g., cl, br, or I); m is
or-BF 3 K (e.g. K)
or-BF 3 K)；
R 15 、R 19 、R 20 And R 24 Independently F, C 1～10 Alkyl (e.g. C) 1～6 Alkyl radicals, also e.g. C 1～3 Alkyl, for example methyl), C 1～10 Alkoxy (e.g. C) 1～6 Alkoxy radicals, e.g. C 1～3 Alkoxy, for example methoxy), C 6～30 Aryl (e.g. C) 6～14 Aryl, further for example phenyl), R 15-1 Substituted C 6～30 Aryl (e.g. C) 6～14 Aryl), phenoxy, R 15-2 Substituted phenoxy, -CHO or-OSO 2 F；
R 16 、R 17 、R 18 、R 21 、R 22 And R 23 Independently H, F, C 1～10 Alkyl (e.g. C) 1～6 Alkyl radicals, again e.g. C 1～3 Alkyl, for example methyl), C 1～10 Alkoxy (e.g. C) 1～6 Alkoxy radicals, e.g. C 1～3 Alkoxy, further for example methoxy), C 6～30 Aryl (e.g. C) 6～14 Aryl, such as phenyl), R 16-1 Substituted C 6～30 Aryl (e.g. C) 6～14 Aryl), phenoxy, R 16-2 Substituted phenoxy, C 1～10 Silyl radical (C) 1～6 Silyl radicals, e.g. C 1～3 Silyl radicals, such as trimethylsilyl), NHPiv, -CHO or-OSO 2 F; or, R 16 、R 17 And R 18 Any two adjacent groups in (a) together with the carbon atom to which they are attached form
Or, R 21 、R 22 And R 23 Any two adjacent groups together with the carbon atom to which they are attached form
Or, R 15 And R 16 Together with the carbon atom to which they are attached form C 6-10 Aryl (e.g. C) 6～14 Aryl, such as phenyl), R 15-3 Substituted C 6-10 Aryl (e.g. C) 6～14 Aryl, such as phenyl), C 5-10 Cycloalkyl radical, C 3-10 Heteroaryl (e.g. C) 3～10 Heteroaryl, for example, pyridyl) or C 5-10 A heterocycloalkyl group; said C is 3-10 Heteroaryl and said C 5-10 The hetero atoms in the heterocycloalkyl group are selected from one or more of N, S and O, and the number of the hetero atoms is 1,2, 3 or 4;
or, R 18 And R 19 Together with the carbon atom to which they are attached form C 6-10 Aryl (e.g. C) 6～14 Aryl, such as phenyl), R 18-1 Substituted C 6-10 Aryl (e.g. C) 6～14 Aryl, further for example phenyl), C 5-10 Cycloalkyl radical, C 3-10 Heteroaryl (e.g. C) 3～10 Aryl, for example pyridyl) or C 5-10 A heterocycloalkyl group; said C is 3-10 Heteroaryl and said C 5-10 The hetero atoms in the heterocycloalkyl group are selected from one or more of N, S and O, and the number of the hetero atoms is 1,2, 3 or 4;
or, R 20 And R 21 Together with the carbon atom to which they are attached form C 6-10 Aryl (e.g. C) 6～14 Aryl, such as phenyl), R 20-1 Substituted C 6-10 Aryl (e.g. C) 6～14 Aryl, such as phenyl), C 5-10 Cycloalkyl radical, C 3-10 Heteroaryl (e.g. C) 3～10 Aryl, for example pyridyl) or C 5-10 A heterocycloalkyl group; said C is 3-10 Heteroaryl and said C 5-10 The hetero atoms in the heterocycloalkyl group are selected from one or more of N, S and O, and the number of the hetero atoms is 1,2, 3 or 4;
or, R 23 And R 24 Together with the carbon atom to which they are attached form C 6-10 Aryl (e.g. C) 6～14 Aryl, such as phenyl), R 23-1 Substituted C 6-10 Aryl radicals (e.g. C) 6～14 Aryl, such as phenyl), C 5-10 Cycloalkyl radical, C 3-10 Heteroaryl (e.g. C) 3～10 Aryl, for example pyridyl) or C 5-10 A heterocycloalkyl group; said C is 3-10 Heteroaryl and said C 5-10 The hetero atoms in the heterocycloalkyl group are selected from one or more of N, S and O, and the number of the hetero atoms is 1,2, 3 or 4;
R 15-1 、R 15-2 、R 16-1 、R 16-2 independently is C 1～10 Alkyl radical, C 1～10 Alkoxy, phenyl, nitro, -CHO or-OSO 2 F；
The R is 15-3 、R 18-1 、R 20-1 And R 23-1 Independently is phenyl, R 15-3-1 Substituted phenyl or
R 15-3-1 Independently is C 1～10 Alkyl or halogen substituted C 1～10 Alkyl (e.g. F-substituted C) 1～3 Alkyl, for example trifluoromethyl);
the R is 15-1 、R 15-2 、R 16-1 、R 16-2 、R 15-3 、R 18-1 、R 20-1 And R 23-1 And R 15-3-1 The number of (A) is one or more, and when a plurality of (A) is plural, the same or different.
In said use, the ee value of said compound E is preferably >86%, more preferably >90%; most preferably >93%.
In the application, the conditions and operation of the Suzuki-Miyaura coupling reaction can be the conventional conditions and operation of the reaction in the field, and the following conditions are preferred in the invention:
in the Suzuki-Miyaura coupling reaction, the palladium catalyst is preferably one or more of palladium chloride, palladium hydroxide, bis (acetonitrile) palladium chloride, tris (dibenzylideneacetone) dipalladium and palladium acetate, and is preferably tris (dibenzylideneacetone) dipalladium.
In the Suzuki-Miyaura coupling reaction, the molar ratio of the palladium catalyst to the compound C is preferably 0.0005 to 0.01, for example 0.001, and further for example 0.005.
In the Suzuki-Miyaura coupling reaction, the molar ratio of the compound shown in the formula I to the compound C is preferably 0.001-0.02, such as 0.002, and further such as 0.01.
In the Suzuki-Miyaura coupling reaction, the alkaline reagent is preferably inorganic weak base. The weak inorganic base is preferably one or more of an alkali metal carbonate, an alkali metal fluoride and an alkali metal phosphate, more preferably an alkali metal phosphate, and further preferably potassium phosphate.
In the Suzuki-Miyaura coupling reaction, the molar ratio of the basic agent to the compound C is preferably 1 to 5, for example 3.
In the Suzuki-Miyaura coupling reaction, the molar ratio of the compound D to the compound C is preferably 1 to 4, for example 2.
In the Suzuki-Miyaura coupling reaction, the dosage of the solvent is not specifically limited as long as the reaction is not affected.
In the Suzuki-Miyaura coupling reaction, the solvent is preferably a mixed solvent of an organic solvent and water. The organic solvent is preferably one or more of aromatic hydrocarbon solvents, alcohol solvents, amide solvents, ether solvents and sulfoxide solvents, and more preferably aromatic hydrocarbon solvents. The aromatic hydrocarbon solvent is preferably toluene. The alcohol solvent is preferably n-butanol and/or 3-pentanol. The amide solvent is preferably N, N-dimethylformamide. The ether solvent is preferably tetrahydrofuran and/or dioxane. The sulfoxide solvent is preferably dimethyl sulfoxide. The volume ratio of the organic solvent to water is preferably 10:1, e.g. 5.
In the Suzuki-Miyaura coupling reaction, the reaction temperature is preferably 40-100 ℃, and more preferably 55-80 ℃.
In the Suzuki-Miyaura coupling reaction, the compound C is preferably any one of the following compounds:
in the Suzuki-Miyaura coupling reaction, the compound D is preferably any one of the following compounds:
in the Suzuki-Miyaura coupling reaction, the monitoring of the progress of the reaction may be conventional in the art (e.g., TIC, HPLC, LC-MS), typically with disappearance of compound III or absence of reaction as the end point of the reaction. The reaction time is preferably 4 to 24 hours, more preferably 8 to 20 hours.
The invention also provides a compound shown as a formula E or an enantiomer ent-E thereof:
wherein "
And
"and"
And
all indicate that the group has axial chirality; q, R 15 、R 16 、R 17 、R 18 、R 19 、R 20 、R 21 、R 22 And R 23 And R 24 All as described above.
The compound shown in the formula E or the enantiomer thereof is preferably any one of the following compounds:
the invention also provides a compound shown as the formula Y:
wherein, ", R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 And R 9 The definitions of (A) and (B) are as described above.
The invention also provides an application of the compound shown as the formula Y as a catalyst in Suzuki-Miyaura coupling reaction:
the Suzuki-Miyaura coupling reaction, which comprises the following steps: under the catalysis of the compound Y and in the presence of an alkaline reagent, carrying out Suzuki-Miyaura coupling reaction on the compound C and the compound D in a solvent to obtain a compound E or a compound ent-E;
wherein "
And with
"and"
And
all indicate that the group has axial chirality; m, Q, R 15 、R 16 、R 17 、R 18 、R 19 、R 20 、R 21 、R 22 、R 23 And R 24 All as described above.
The invention also provides a single crystal of the compound shown as the formula Y-1, wherein the crystal system belongs to a monoclinic system, C 2 Space group, cell parameter of
α＝γ＝90°，β＝113.055(2)°；
Preferably, the single crystal parameters of the compound of formula Y-1 are as shown in table 1:
TABLE 1 Single Crystal parameters of the Compound of formula Y-1
The inventor has long-term and intensive research and finds that the phosphine ligand of the invention can synthesize a series of ortho-tetra-substituted biaryl compounds with high yield in asymmetric Suzuki-Miyaura coupling reaction (especially coupling reaction with large steric hindrance). The adoption of the phosphine ligand with a single configuration can also obtain the ortho-tetra-substituted biaryl compound with high optical purity (ee value is more than 86 percent) in high yield, high substrate compatibility (especially aldehyde group) to different functional groups and mild reaction conditions (without high temperature or strong alkali). The presently reported ortho-tetra-substituted biaryl compounds with axial chirality often require the prior availability of achiral or racemic biaryl compounds through resolution or desymmetrization strategies. The synthesis steps are relatively complicated; the chiral prosthetic group strategy requires a stoichiometric chiral source, and the chemical reaction economy is relatively low compared to asymmetric catalytic coupling; in the aspect of constructing the chiral ortho-tetra-substituted compound by using an asymmetric aromatic cyclization strategy, reaction substrates are complex and poor in practicability. (org.biomol.chem., 2006,4,3197, chem.soc.rev.,2015,44, 3418. The chiral biaryl compound obtained by the invention has higher optical purity, simple and easily obtained raw materials, and strong economical and practical properties. The present invention has been completed on the basis of this finding.
In the present invention, the term "chiral atom" means that when different substituents are attached to the atom C or P, the atom C or P is referred to as a chiral atom. The "R-S configuration" in the present invention is a term in the nomenclature of the R-S system in the nomenclature of chiral atoms. The specific nomenclature of the R-S system is as follows: when a, b, C, d attached to the central C or P atom are different groups, the molecule is chiral. Assuming that the four substituents in the molecule are arranged in the CIP order rule in the order a > b > c > d, if the smallest d group is placed at the position furthest from the viewer, the other three groups are viewed in a-b-c order, with the observation that a → b → c is clockwise, then the configuration of this carbon center is defined as R (latin rectangle); otherwise, S (Latin Sinister) is assumed.
In the present invention, the term "alkyl" is not particularly specified, and is a saturated, straight-chain or branched, monovalent hydrocarbon group, such as C, each of the specified number of carbon atoms 1 -C 10 Alkyl refers to alkyl groups having 1 to 10 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl, isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl, t-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl).
In the present invention, the terms "alkoxy" or "phenoxy" both refer to an alkyl or phenyl group attached to the rest of the molecule through an oxygen bridge.
In the present invention, the term "cycloalkyl" or "cycloalkane" refers to a non-aromatic, saturated or unsaturated cyclic hydrocarbon group having the specified number of ring carbon atoms, and cycloalkyl groups may be monocyclic or polycyclic (e.g., bicyclic and tricyclic), may be bicyclic, spirocyclic and bridged. Cycloalkyl groups optionally contain one or more double or triple bonds therein. Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl. Cycloalkyl also includes polycyclic cycloalkyl structures, wherein the polycyclic structure optionally includes a saturated or partially unsaturated cycloalkyl fused to a saturated or partially unsaturated cycloalkyl or heterocyclyl or aryl or heteroaryl ring. Bicyclic carbocycles having 7 to 12 atoms may be arranged, for example, as bicyclo [ 4.5 ], [ 5.5 ], [ 5.6 ] or [ 6.6 ] systems or as bridged ring systems, for example, bis [2.2.1] heptane, bicyclo [2.2.2] octane and bicyclo [3.2.2] nonane.
In the present invention, the term "heterocycle" refers to a non-aromatic, saturated or partially unsaturated cyclic hydrocarbon group formed by replacing at least one ring carbon atom in a cycloalkane (as defined in the present invention) with a heteroatom selected from N, O and S.
In the present invention, the term "aryl" or "aromatic ring" refers to any stable monocyclic or polycyclic (e.g., bicyclic or tricyclic) carbocycle of up to 7 atoms in each ring, wherein at least one ring is aromatic. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, 2, 3-indanyl, biphenyl, phenanthryl, anthryl, or acenaphthenyl (acenaphthyl). It will be understood that where the aryl substituent is a bicyclic substituent and one of the rings is non-aromatic, the attachment is through an aromatic ring.
In the present invention, the term "heteroaryl" or "heteroaromatic ring" refers to a stable monocyclic or polycyclic (e.g., bicyclic or tricyclic) carbocyclic ring of up to 7 atoms in each ring, wherein at least one ring is aromatic and contains at least one heteroatom selected from O, N and S. Heteroaryl groups may be attached to other moieties in the molecule through heteroatoms or carbon atoms therein. Examples of heteroaryl groups include, but are not limited to, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furanyl.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows: the compound shown as the formula I or the racemate thereof is used as a metal ligand in Suzuki-Miyaura coupling reaction, and the tetra-substituted aryl compound can be obtained with high yield (the yield is more than 75%). The compound with single configuration shown in the formula I is used as a metal ligand in Suzuki-Miyaura coupling reaction, and the tetra-substituted aryl compound with axial chirality (ee value is more than 83%) can be obtained in high yield.
Drawings
FIG. 1 is an X-ray single crystal diffractogram of the compound represented by the formula Y-1 in example 7.
FIG. 2 is a partial enlarged view of the X-single crystal diffraction pattern of the compound represented by the formula Y-1 in example 7.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
Example 1 preparation of 2- ((2S, 3S) -3-tert-butyl-4- (2, 6-dimethoxy-3, 5-dicyclopentylphenyl) -2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-penta-nyl) -propanol (I-6, baryPhos)
Preparation of (S) -4- (2, 6-dimethoxyphenyl) -3-tert-butyl-2, 3-dihydrobenzo [ d ] [1,3] oxy, phospho-pentan-3-oxy (c)
A is converted to (S) -4- (2, 6-dimethoxyphenyl) -3-tert-butyl-2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphorus-penta-yoke-3-oxy (c) according to known literature procedures (org. Lett.2010,12,176, angelw.chem., int. Ed.2010,49, 5879).
Preparation of (S) -4- (3, 5-dibromo-2, 6-dimethoxyphenyl) -3-tert-butyl-2, 3-dihydrobenzo [ d ] [1,3] oxy, phospho-pentan-3-oxy (d)
C is converted to (S) -4- (3, 5-dibromo-2, 6-dimethoxyphenyl) -3-tert-butyl-2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphorus-pentan-3-oxy (d) (adv. Syn. Catal.2016,358, 3522) according to known literature procedures.
Preparation of (S) -4- (2, 6-dimethoxy-3, 5-dicyclopentylphenyl) -3-tert-butyl-2, 3-dihydrobenzo [ d ] [1,3] oxy, phospho-penta-3-oxy (III-1)
(S) -4- (3, 5-dibromo-2, 6-dimethoxyphenyl) -3-tert-butyl-2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphorus-pentan-3-oxy (d, 0.80g, 1.59mmol), cyclopentenylboronic acid pinacol ester (0.93g, 4.77mmol) and potassium phosphate (1.68g, 4.77mmol) were added to a 25mL Schlenk tube, and the air in the Schlenk tube was replaced with nitrogen gas by purging three times. 1, 4-dioxane (3 mL), deionized water (0.6 mL), tris (dibenzylideneacetone) dipalladium (44mg, 0.048mmol) and 2-dicyclohexylphosphine-2 ',6' -dimethoxybiphenyl (39mg, 0.096 mmol) were added in this order under nitrogen protection. The reaction was stirred at 80 ℃ for 10 hours and then cooled to room temperature. The reaction mixture was filtered through celite, and the filter residue was washed three times with ethyl acetate. The filtrates are combined and concentrated, and the crude product is purified by silica gel column chromatography, wherein the eluent is a mixed solvent of petroleum ether and ethyl acetate with the volume ratio of 1. The eluent containing the product (e) was concentrated and spin-dried to give a colorless oily liquid which solidified on standing to give a colorless waxy solid in 0.66g yield 87%.
To a methanol solution containing e (0.66g, 1.38mmol) was added 20% palladium on carbon hydroxide (0.10g, 15wt%). The reaction system was stirred under a hydrogen atmosphere of one atmosphere for 48 hours. The reaction mixture was filtered through celite and the catalyst was washed three times with ethyl acetate. The filtrates are combined and concentrated, and the crude product is purified by silica gel column chromatography, wherein the eluent is a mixed solvent of petroleum ether and ethyl acetate with the volume ratio of 1. The eluent containing product (f) was concentrated and dried to give a colourless foamy solid in a yield of 0.61g, 92%.
f: 1 H NMR(500MHz,CDCl 3 )δ7.45(t,J＝7.8Hz,1H),7.15(s,1H),6.98(dd,J＝7.3,3.1Hz,1H),6.93(dd,J＝8.3,2.9Hz,1H),4.49(dd,J＝13.7,2.3Hz,1H),4.34(dd,J＝13.7,10.7Hz,1H),3.58(s,3H),3.46(s,3H),3.35–3.17(m,2H),2.11(dt,J＝8.4,5.6Hz,1H),2.07–1.90(m,3H),1.89–1.48(m,12H),1.40–1.30(m,1H),0.94(d,J＝16.2Hz,8H)； 13 C NMR(126MHz,CDCl 3 )δ165.6(d,J＝19.1Hz),154.9,153.9,139.6(d,J＝5.9Hz),135.6,134.5,133.3(d,J＝1.4Hz),127.6(d,J＝2.0Hz),125.5,124.5(d,J＝8.2Hz),115.4(d,J＝90.2Hz),112.8(d,J＝5.4Hz),65.8(d,J＝60.7Hz),62.0(d,J＝81.4Hz),38.7,38.4,35.4,34.6,34.3,34.2,33.9,33.4,25.7,25.6,25.6,25.5,24.0； 31 P NMR(162MHz,CDCl 3 )δ62.4；HRMS(ESI)Calcd.for C 29 H 40 O 4 P[M+H] + :483.2664；Found:483.2660.
S4.preparation of 2- ((2S, 3S) -3-tert-butyl-4- (2, 6-dimethoxy-3, 5-dicyclopentylphenyl) -2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-pentan-3-oxy) -propanol (II-1)
A solution of lithium diisopropylamide in tetrahydrofuran (2.5 mol/L,1.66mL, 4.16mmol) was slowly added dropwise under nitrogen to a dry ice/acetone bath cooled solution of (S) -4- (2, 6-dimethoxy-3, 5-dicyclopentylphenyl) -3-tert-butyl-2, 3-dihydrobenzo [ d ] [1,3] oxy, phospho-pentan-3-oxy (f) (0.50g, 1.04mmol) in anhydrous tetrahydrofuran (8 mL). After stirring at-78 ℃ for 1 hour, dry freshly distilled acetone (0.61mL, 8.28mmol) was added to the reaction. The reaction was stirred at-78 ℃ for one hour and then slowly warmed to room temperature, followed by stirring at room temperature for an additional 1 hour. To the reaction solution was added a saturated ammonium chloride solution (15 mL), the aqueous layer was extracted with ethyl acetate (15 mL × 2), the combined organic phases were washed with a saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate =2: 1) to obtain 2- ((2s, 3s) -3-tert-butyl-4- (2, 6-dimethoxy-3, 5-dicyclopentylphenyl) -2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-pentylidene-3-oxy) -propanol (g, 0.48g, 85%) as a colorless oily liquid.
g: 1 H NMR(500MHz,CDCl 3 )δ7.47(t,J＝7.8Hz,1H),7.15(s,1H),7.00–6.92(m,2H),4.24–4.17(m,2H),3.57(s,3H),3.43(s,3H),3.38–3.29(m,1H),3.26–3.17(m,1H),2.13–1.47(m,15H),1.42(s,3H),1.36(s,3H),1.38–1.30(m,1H),0.98(d,J＝16.2Hz,9H)； 13 C NMR(126MHz,CDCl 3 )δ164.9(d,J＝19.5Hz),154.6,153.9,139.7(d,J＝5.5Hz),135.5,134.4,133.6(d,J＝1.7Hz),127.1(d,J＝2.0Hz),125.5,124.8(d,J＝8.3Hz),114.9,114.2,112.4(d,J＝5.4Hz),78.2(d,J＝60.2Hz),73.5(d,J＝2.0Hz),62.2,61.2,38.5(d,J＝11.2Hz),35.1(d,J＝74.2Hz),34.4(d,J＝13.2Hz),33.9(d,J＝70.4Hz),29.3,28.5(d,J＝5.7Hz),25.7,25.6,25.6,25.6,24.7(d,J＝2.8Hz),23.6； 31 P NMR(162MHz,CDCl 3 )δ65.7；HRMS(ESI)Calcd.for C 32 H 46 O 5 P[M+H] + :541.3083；Found:541.3085.
S5.preparation of 2- ((2S, 3S) -3-tert-butyl-4- (2, 6-dimethoxy-3, 5-dicyclopentylphenyl) -2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-penta-nyl) -propanol (6, baryPhos)
To a solution of 2- ((2S, 3S) -3-tert-butyl-4- (2, 6-dimethoxy-3, 5-dicyclopentylphenyl) -2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-penta-3-oxy) -propanol (g) (0.40g, 0.74mmol) in dry toluene (5 mL) cooled in an ice-water bath under nitrogen atmosphere was added triethylamine (1.65mL, 11.84mmol) and trichlorosilane (0.60mL, 5.93mmol) in that order. The reaction was stirred at 0 ℃ for 10 minutes and then heated to 70 ℃. The reaction mixture was stirred at 70 ℃ for 12 hours and then cooled to room temperature. Degassed 30% sodium hydroxide solution (15 mL) was slowly added dropwise to the reaction system under ice-water bath, and then the reaction system was warmed to room temperature and stirred for 2 hours. To the reaction solution was added ethyl acetate (10 mL), the organic phase was separated after sufficient shaking, the aqueous phase was extracted with ethyl acetate (10 mL × 4), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated at 20 ℃, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 15.
6: 1 H NMR(500MHz,CDCl 3 )δ7.30(t,J＝7.8Hz,1H),7.13(s,1H),6.99(dd,J＝7.3,3.0Hz,1H),6.92(d,J＝8.1Hz,1H),4.63(s,1H),3.69(s,3H),3.38–3.21(m,2H),3.18(s,3H),2.41(s,1H),2.14–2.02(m,2H),2.02–1.91(m,2H),1.90–1.75(m,4H),1.74–1.49(m,7H),1.43–1.34(m,1H),1.26(d,J＝7.4Hz,6H),0.73(d,J＝12.3Hz,9H)； 13 C NMR(126MHz,CDCl 3 )δ164.5,154.4,153.7,139.7(d,J＝17.4Hz),135.3,134.6,130.1,129.0,124.6(d,J＝3.1Hz),124.5,123.2(d,J＝4.0Hz),109.2,91.3(d,J＝30.4Hz),73.5(d,J＝19.4Hz),62.5,60.7,38.9,38.7(s),35.5,34.4,34.2,34.1,30.8,30.6,26.9,26.8,25.7,25.6,25.6,25.5,24.9,24.8； 31 P NMR(162MHz,CDCl 3 )δ-1.1；HRMS(ESI)Calcd.for C 32 H 46 O 4 P[M+H] + :525.3134；Found:525.3131.
Example 2 preparation of- ((2S, 3S) -3-tert-butyl-4- (2, 6-dimethoxy-3, 5-diisopropylphenyl) -2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-penta-nyl) -propanol (I-3)
2- ((2S, 3S) -3-tert-butyl-4- (2, 6-dimethoxy-3, 5-diisopropylphenyl) -2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-penta-nyl) -propanol was prepared by the preparation method of reference example 1.
1 H NMR(500MHz,CDCl 3 )δ7.31(t,J＝7.8Hz,1H),7.11(s,1H),7.00(dd,J＝7.3,3.0Hz,1H),6.92(d,J＝8.1Hz,1H),4.62(s,1H),3.69(s,3H),3.27(ddd,J＝28.8,13.7,6.8Hz,2H),3.17(s,3H),1.31(d,J＝6.9Hz,3H),1.29–1.21(m,12H),1.12(d,J＝6.8Hz,3H),0.72(d,J＝12.3Hz,9H)； 13 C NMR(126MHz,CDCl 3 )δ164.5,153.5,153.0,139.7(d,J＝17.5Hz),137.9,137.2,130.1,129.1(d,J＝1.1Hz),124.6(d,J＝16.4Hz),123.3,123.1(d,J＝4.3Hz),109.2,91.3(d,J＝30.6Hz),73.6(d,J＝19.4Hz),62.5,60.6,30.6(d,J＝19.0Hz),26.8(d,J＝51.6Hz),26.8(d,J＝15.0Hz),25.4(d,J＝7.0Hz),24.8(d,J＝8.1Hz),24.4,24.3,23.1(d,J＝38.4Hz)； 31 P NMR(121MHz,CDCl 3 )δ0.2.
Example 3 preparation of 3- ((2S, 3S) -3-tert-butyl-4- (2, 6-dimethoxy-3, 5-bis (3, 4-tetramethylcyclopentyl) phenyl) -2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-penta-nyl) -pentanol (I-7)
3- ((2S, 3S) -3-tert-butyl-4- (2, 6-dimethoxy-3, 5-bis (3, 4-tetramethylcyclopentyl) phenyl) -2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-penta-nyl) -pentanol was prepared by the preparation method of reference example 1.
1 H NMR(500MHz,CDCl 3 )δ7.35(s,1H),7.28(t,J＝8.0Hz,1H),6.95(dd,J＝7.4,3.3Hz,1H),6.88(d,J＝8.1Hz,1H),4.82(s,1H),3.68(s,3H),3.65–3.58(m,2H),3.16(s,3H),2.05(ddd,J＝31.8,13.1,9.9Hz,3H),1.95–1.88(m,3H),1.84(dd,J＝13.2,9.1Hz,1H),1.77–1.70(m,3H),1.69–1.61(m,4H),1.54(dd,J＝13.1,9.0Hz,1H),1.05–0.94(m,30H),0.73(d,J＝12.3Hz,9H)； 13 C NMR(126MHz,CDCl 3 )δ164.8,154.1,153.5,139.5(d,J＝17.7Hz),136.7,135.8,130.0,128.8,125.4,124.4(d,J＝14.9Hz),123.0(d,J＝4.5Hz),109.1,88.9(d,J＝29.5Hz),77.1(d,J＝14.3Hz),62.6,60.8,50.0,49.2,48.7,48.2,43.6,43.4,43.3,43.2,33.4,27.0,26.9,25.7,25.6,25.5,25.2,24.7,24.6,24.6,24.5； 31 P NMR(121MHz,CDCl 3 )δ-3.2.
EXAMPLE 4 preparation of (2S, 3S) -3-tert-butyl-4- (2, 6-dimethoxy-3, 5-diphenylphenyl) -2-isopropyl-2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-pentayoke (I-10)
3- ((2S, 3S) -3-tert-butyl-4- (2, 6-dimethoxy-3, 5-diphenylphenyl) -2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-penta-nyl) -pentanol (I-10) was prepared by the preparation method of reference example 1.
1 H NMR(500MHz,CDCl 3 )δ7.58-7.40(m,10H),7.35(s,1H),7.28(t,J＝8.0Hz,1H),6.95(dd,J＝7.4,3.3Hz,1H),6.88(d,J＝8.1Hz,1H),4.82(s,1H),3.68(s,3H),3.16(s,3H),1.90(s,3H),1.73(s,3H),0.72(d,J＝12.3Hz,9H)； 31 P NMR(121MHz,CDCl 3 )δ-2.9.
EXAMPLE 5 preparation of (2S, 3S) -3-tert-butyl-4- (2, 6-dimethoxy-3, 5-dicyclopentylphenyl) -2-isopropyl-2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-pentayoke (I-5)
S4. (S) -4- (2, 6-dimethoxy-3, 5-dicyclopentylphenyl) -3-tert-butyl-2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphorus-penta-n-yl-3-oxy (f) was prepared by the preparation method of reference example 1.
Preparation of (2S, 3S) -2-isopropyl-3-tert-butyl-4- (2, 6-dimethoxy-3, 5-dicyclopentylphenyl) -2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-penta-3-oxy (h)
A solution of lithium diisopropylamide in tetrahydrofuran (1.5 mol/L,0.5mL, 0.75mmol) was slowly added dropwise under a nitrogen atmosphere to a dry ice/acetone bath cooled solution of (S) -4- (2, 6-dimethoxy-3, 5-dicyclopentylphenyl) -3-tert-butyl-2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphorus-pentan-3-oxy (f) (0.18g, 0.38mmol) in anhydrous tetrahydrofuran (8 mL). After stirring at-78 ℃ for 1 hour, 2-iodoisopropane (0.12mL, 1.14mmol) was added to the reaction system. The reaction was stirred at-78 ℃ for one hour and then slowly warmed to room temperature, followed by stirring at room temperature for an additional 1 hour. To the reaction solution was added a saturated ammonium chloride solution (15 mL), the aqueous layer was extracted with ethyl acetate (15 mL × 2), the combined organic phases were washed with a saturated saline solution (20 mL), dried over anhydrous sodium sulfate, and concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate =3: 1) to obtain a colorless oily liquid (2s, 3s) -2-isopropyl-3-tert-butyl-4- (2, 6-dimethoxy-3, 5-dicyclopentylphenyl) -2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-penta-yoke-3-oxy (h, 0.1lg, 82%).
1 H NMR(500MHz,CDCl 3 )δ7.44(t,J＝7.8Hz,1H),7.14(s,1H),6.95–6.90(m,2H),4.14(dd,J＝6.5,4.7Hz,1H),3.56(s,3H),3.49(s,3H),3.37–3.29(m,1H),3.22(ddd,J＝17.3,9.6,7.6Hz,1H),2.33(qd,J＝13.4,6.7Hz,1H),2.15–1.98(m,4H),1.94(ddd,J＝11.9,7.6,3.8Hz,1H),1.89–1.74(m,4H),1.73–1.62(m,5H),1.55(ddt,J＝20.7,18.2,8.8Hz,2H),1.13(d,J＝6.7Hz,3H),1.09(d,J＝6.7Hz,3H),0.96(d,J＝15.8Hz,9H)； 13 C NMR(126MHz,CDCl 3 )δ164.4(d,J＝19.5Hz),154.7,153.8,139.8(d,J＝5.4Hz),135.4,134.3,133.1,127.5(d,J＝2.0Hz),125.4,124.4(d,J＝8.1Hz),115.5,114.8,112.2(d,J＝5.3Hz),78.8(d,J＝60.7Hz),61.8(d,J＝74.8Hz),38.6,38.4,35.4,34.7,34.6,34.4,33.9,33.3,29.8,25.7,25.7,25.6,23.8,20.0(d,J＝5.1Hz),18.1(d,J＝5.0Hz)； 31 P NMR(162MHz,CDCl 3 )δ60.7；HRMS(ESI)Calcd.for C 32 H 46 PO 4 [M+H] + :525.3134；Found:525.3131.
Preparation of (2S, 3S) -2-isopropyl-3-tert-butyl-4- (2, 6-dimethoxy-3, 5-dicyclopentylphenyl) -2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-penta-yoke (I-5)
To a solution of (2S, 3S) -2-isopropyl-3-tert-butyl-4- (2, 6-dimethoxy-3, 5-dicyclopentylphenyl) -2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-penta-yoke-3-oxy (h) (0.16g, 0.31mmol) in dry tetrahydrofuran (5 mL) cooled in an ice-water bath under a nitrogen atmosphere was added successively polymethylhydrosiloxane (1.0 g) and tetraisopropyl titanate (0.70mL, 2.36mmol). The reaction was stirred at 0 ℃ for 10 minutes and then heated to 70 ℃. The reaction mixture was stirred at 70 ℃ for 12 hours and then cooled to room temperature. Degassed 30% sodium hydroxide solution (10 mL) was slowly added dropwise to the reaction system under ice-water bath, and then the reaction system was raised to 60 ℃ and stirred for 30 minutes. After cooling to room temperature, ethyl acetate (10 mL) was added to the reaction mixture, the organic phase was separated after sufficient shaking, the aqueous phase was extracted with ethyl acetate (10 mL × 4), the organic phases were combined, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure at 20 ℃ to remove the organic solvent, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30) to obtain a white foamy solid (2s, 3s) -2-isopropyl-3-tert-butyl-4- (2, 6-dimethoxy-3, 5-dicyclopentylphenyl) -2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-pentayoke (I-5, 0.13g, 84%).
1 H NMR(500MHz,cdcl 3 )δ7.28(d,J＝7.8Hz,1H),7.12(s,1H),6.96(d,J＝6.9Hz,1H),6.88(d,J＝7.9Hz,1H),4.65(d,J＝4.9Hz,1H),3.66(s,3H),3.37(dt,J＝16.8,8.4Hz,1H),3.30–3.25(m,1H),3.25(s,3H),2.01(ddd,J＝31.1,16.3,9.7Hz,6H),1.89–1.54(m,10H),1.00(d,J＝8.7Hz,3H),0.98(d,J＝7.2Hz,3H),0.72(d,J＝11.9Hz,9H)； 13 C NMR(126MHz,cdcl 3 )δ164.5,154.4,153.7,139.6(d,J＝17.3Hz),135.2,134.4,129.7,129.0,124.5(d,J＝18.3Hz),124.4,123.0(d,J＝3.7Hz),109.0,89.1(d,J＝28.8Hz),62.3,60.8,38.8,38.7,35.5(s),34.4(s),34.3,34.2,34.1,33.9,30.6,30.5,27.0,26.9,25.8,25.6,25.6,25.5,18.8(d,J＝11.1Hz),18.0(d,J＝8.9Hz)； 31 P NMR(162MHz,CDCl 3 )δ0.8.
Example 6 preparation of 2- ((2R, 3R) -3-tert-butyl-4- (2, 6-dimethoxy-3, 5-dicyclopentylphenyl) -2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-penta-nyl) -propanol (I-ent 6)
By substituting the starting material a with the starting material ent-a, the enantiomer of ligand I-6, 2- ((2R, 3R) -3-tert-butyl-4- (2, 6-dimethoxy-3, 5-dicyclopentylphenyl) -2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-penta-yoke) -propanol (I-ent 6), was prepared by the method of preparation of reference example 1.
Example 7
Preparation of a Compound of formula Y-1
To aryl chloride 13ac (10.3mg, 0.052mmol) in degassed n-hexane, under nitrogen, was added palladium catalyst (cod) Pd (CH) 2 SiMe 3 ) 2 (20.0 mg, 0.052mmol) and ligand I-ent6 prepared in example 6 (27.0 mg, 0.052mmol). The mixture was stirred at room temperature for 1 hour to give a clear solution. The reaction was stirred at room temperature for 10 hours, and a white precipitate was precipitated. The mixture was filtered under nitrogen and the solid was washed three times with dry degassed n-hexane (3 ml each). The pale yellow solid obtained was dried in vacuo to give the polyaddition palladium complex in 29mg yield of 69%.
1 H NMR(400MHz,CDCl 3 )δ9.48(s,2H),7.35(t,J＝7.7Hz,2H),7.21(s,2H),7.12(d,J＝8.4Hz,2H),6.90(d,J＝8.1Hz,2H),6.84(dd,J＝7.3,3.2Hz,2H),6.46(d,J＝8.4Hz,2H),4.74(s,2H),3.79(s,6H),3.75(s,6H),3.68(s,3H),3.40–3.34(m,2H),3.33(s,6H),2.99(dd,J＝16.2,8.7Hz,2H),2.25–1.42(m,44H),0.77(d,J＝16.5Hz,18H)。
Single crystal preparation of a compound of formula Y-1
Growing the single crystal by volatilization: 25mg of Compound Y-1 was weighed into a 10mL test tube, dissolved in 0.5mL of methylene chloride, and then 2mL of n-hexane was added. Placing the test tube in a conical flask filled with n-hexane, sealing the conical flask, and crystallizing at 0 deg.C.
Detection method X-ray single crystal diffraction
The crystal system of the compound represented by the formula Y-1 is detected to belong to a monoclinic system, C 2 Space group, cell parameter of
α = γ =90 °, β =113.055 (2) °; the single crystal parameters are shown in Table 2; the X-ray single crystal diffraction thereof is shown in FIG. 1.
TABLE 2 Single Crystal parameters of the Compound of formula Y-1
The results of characterization of the X-ray single crystal diffraction showed that the configuration of Compound Y could be determined to be
According to the results of previous studies by the inventors (J.Am.chem.Soc.2014, 136,570-573, org.Lett.2012,14, 2258-2261),
in the structure, the substituent M on the phosphorus oxygen five-membered ring and the tertiary butyl on the P atom are positioned on two sides of the plane formed by nitrogen and carbon oxygen. After the determination of the stereoconfiguration of the raw material a in example 1, based on the results of previous studies by the inventors andexample 5 configuration of the product, it can be deduced that the configuration of the product of example 1 is
Example 8
An ortho-tetra-substituted biaryl compound E-15a having axial chirality (the reaction scheme is shown below) was prepared by asymmetric Suzuki-Miyaura coupling reaction involving a transition metal palladium catalyzed aryl halide 13a and potassium arylfluoroborate 14a using the compound 2- ((2S, 3S) -3-tert-butyl-4- (2, 6-dimethoxy-3, 5-dicyclopentylphenyl) -2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-penta-yoke) -propanol (I-6, baryPhos) prepared in example 1 as a chiral ligand.
The reaction steps are as follows: 2-bromo-3, 4-dimethoxybenzaldehyde (13a, 60mg, 0.24mmol), potassium 2-formyl-6-methoxyphenyltrifluoroborate (14a, 68mg, 0.28mmol) and potassium phosphate (156mg, 0.72mmol) were charged into a 10mL Schlenk tube, and the air in the Schlenk tube was replaced with nitrogen by purging three times. Degassed toluene (4 mL), deionized water (0.8 mL), tris (dibenzylideneacetone) dipalladium (2.2mg, 0.0024mmol) and chiral phosphine ligand 6 (2.6 mg, 0.0049mmol) were added in this order under nitrogen. The reaction was stirred at 60 ℃ for 15 hours and then cooled to room temperature. Saturated brine was added to the reaction system, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product is purified by silica gel column chromatography, and the eluent is a mixed solvent of petroleum ether and ethyl acetate with the volume ratio of 4. The eluent containing the product (15 a) was concentrated and dried to give (S) -5,6 '-trimethoxybiphenyl-2, 2' -dialdehyde (E-15 a) as a colorless waxy solid in a yield of 63mg and 86%.
The enantiomeric excess (ee) is determined by chiral high-pressure liquid phase, and the ee value is 92 percent; high-pressure liquid phase conditions: chiral AD-H column, 25 ℃, flow rate of 1mL/min, n-hexane/isopropanol: 70/30,210nm,6.70min (S), 9.67min (R); 1 H NMR(500MHz,CDCl 3 )δ9.70(s,1H),9.50(s,1H),7.85(d,J＝8.6Hz,1H),7.68(dd,J＝7.8,1.0Hz,1H),7.56(t,J＝7.8Hz,1H),7.23(dd,J＝8.2,0.8Hz,1H),7.11(d,J＝8.6Hz,1H),3.99(s,3H),3.76(s,3H),3.50(s,3H)； 13 C NMR(126MHz,CDCl 3 )δ191.2,190.2,157.6,157.3,146.6,135.7,131.3,129.8,128.5,125.6,125.5,120.0,115.6,111.9,77.3,77.0,76.7,60.2,56.0；HRMS(ESI)Calcd.for C 17 H 17 O 5 [M+H] + :301.1076；Found:301.1081.
example 9
With the compound 2- ((2S, 3S) -3-tert-butyl-4- (2, 6-dimethoxy-3, 5-dicyclopentylphenyl) -2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-penta-nyl) -propanol (I-6, baryPhos) prepared in example 1 as a chiral ligand, an ortho-tetra-substituted biaryl compound E-15b having axial chirality (the reaction scheme is shown below) was prepared by an asymmetric Suzuki-Miyaura coupling reaction involving a transition metal palladium-catalyzed aryl halide 13b and a potassium arylfluoroborate 14a, in accordance with the preparation method of example 8.
(S) -3-fluoro-6, 6 '-dimethoxybiphenyl-2, 2' -dialdehyde (15 b) as a white solid (78% yield); 90% ee.
The enantiomeric excess (ee) is determined by chiral high-pressure liquid phase, and the ee value is 90 percent; high pressure liquid phase conditions: chiral AD-H column, 25 ℃, flow rate of 1mL/min, n-hexane/isopropanol: 85/15,250nm,8.00min (S), 12.55min (R); 1 H NMR(400MHz,CDCl 3 )δ9.96(s,1H),9.68(s,1H),7.64(dd,J＝7.8,1.0Hz,1H),7.53(t,J＝8.0Hz,1H),7.26–7.14(m,3H),3.73(s,3H),3.68(s,3H)； 13 C NMR(126MHz,CDCl 3 )δ191.4,188.3,158.8,156.8(d,J＝6.4Hz),153.3(d,J＝2.3Hz),135.3,129.7,125.5(d,J＝74.2Hz),120.3,117.0(d,J＝10.4Hz),116.9(d,J＝2.9Hz),116.0(s),56.4(d,J＝2.8Hz),56.0(d,J＝3.2Hz)； 19 F NMR(376MHz,CDCl 3 )δ-128.7；HRMS(ESI)Calcd.for C 16 H 14 FO 4 [M+H] + :289.0876；Found:289.0870.
example 10
With the compound 2- ((2S, 3S) -3-tert-butyl-4- (2, 6-dimethoxy-3, 5-dicyclopentylphenyl) -2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-penta-nyl) -propanol (6, baryPhos) prepared in example 1 as a chiral ligand, an ortho-tetra-substituted biaryl compound E-15c having axial chirality (the reaction scheme is shown below) was prepared by asymmetric Suzuki-Miyaura coupling reaction involving a transition metal palladium-catalyzed aryl halide 13c and a potassium arylfluoroborate 14a, with reference to the preparation method of example 8.
(S) -5,6 '-trimethoxy-3-nitrophenyl-2, 2' -dialdehyde (E-15 c) white solid (84% yield); 90% ee.
The enantiomeric excess (ee) is determined by chiral high-pressure liquid phase, and the ee value is 90 percent; high-pressure liquid phase conditions: chiral AD-H column, flow rate 1mL/min at 25 ℃, n-hexane/isopropanol: 70/30,250nm,8.38min (S), 14.42min (R); 1 H NMR(600MHz,CDCl 3 )δ9.91(s,1H),9.78(s,1H),7.70(s,1H),7.61(dd,J＝7.7,1.1Hz,1H),7.56(t,J＝7.9Hz,1H),7.20(dd,J＝8.2,1.0Hz,1H),4.04(s,4H),3.78(s,4H),3.60(s,3H)； 13 C NMR(151MHz,CDCl 3 )δ191.2,187.5,130.2,122.1,116.0,107.9,77.2,77.0,76.8,56.5,56.0；HRMS(ESI)Calcd.for C 17 H 16 NO 7 [M+H] + :346.0927；Found:346.0929.
example 11
With the compound 2- ((2S, 3S) -3-tert-butyl-4- (2, 6-dimethoxy-3, 5-dicyclopentylphenyl) -2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-penta-nyl) -propanol (6, baryPhos) prepared in example 1 as a chiral ligand, an ortho-tetra-substituted biaryl compound E-15d having axial chirality (the reaction scheme is shown below) was prepared by an asymmetric Suzuki-Miyaura coupling reaction involving a transition metal palladium-catalyzed aryl halide 13d and a potassium arylfluoroborate 14a, in accordance with the preparation method of example 8.
(S) -6,6 '-dimethoxybiphenyl-2, 2' -dialdehyde (E-15 d) white solid (83% yield); 91% ee.
The enantiomeric excess (ee) is determined by chiral high-pressure liquid phase, and the ee value is 91 percent; high-pressure liquid phase conditions: chiral AD-H column, flow rate 1mL/min at 25 ℃, n-hexane/isopropanol: 70/30,250nm,8.67min (S), 17.82min (R); 1 H NMR(500MHz,CDCl 3 )δ9.66(s,2H),7.67(d,J＝7.8Hz,2H),7.54(t,J＝8.0Hz,2H),7.22(d,J＝8.2Hz,2H),3.73(s,6H)； 13 C NMR(126MHz,CDCl 3 )δ191.7,157.2,135.8,129.8,125.4,119.7,115.9,77.3,77.0,76.7,56.0；HRMS(ESI)Calcd.for C 16 H 14 NaO 4 [M+Na] + :293.0790；Found:293.0786.
example 12
With the compound 2- ((2S, 3S) -3-tert-butyl-4- (2, 6-dimethoxy-3, 5-dicyclopentylphenyl) -2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-penta-nyl) -propanol (6, baryPhos) prepared in example 1 as a chiral ligand, an ortho-tetra-substituted biaryl compound E-15E having axial chirality (the reaction scheme is shown below) was prepared by an asymmetric Suzuki-Miyaura coupling reaction involving a transition metal palladium-catalyzed aryl halide 13E and a potassium arylfluoroborate 14b, in accordance with the preparation method of example 8.
(S) -N- (2, 6 '-diformyl-2, 3',5, 6-tetramethoxybiphenyl-3-) tert-butanamide (E-15E) white solid (67% yield); 91% ee.
The enantiomeric excess (ee) is determined by chiral high-pressure liquid phase, and the ee value is 91 percent; high-pressure liquid phase conditions: chiral AD-H column, flow rate 1mL/min at 25 ℃, n-hexane/isopropanol: 70/30,230nm,6.01min (S), 7.01min (R); 1 H NMR(500MHz,CDCl 3 )δ12.06(s,1H),9.59(s,1H),9.38(s,1H),8.72(s,1H),7.84(d,J＝8.6Hz,1H),7.13(d,J＝8.7Hz,1H),4.03(s,3H),4.01(s,3H),3.67(s,3H),3.54(s,3H),1.36(s,9H)； 13 C NMR(126MHz,CDCl 3 )δ192.9,189.7,179.2,158.8,157.6,146.7,140.8,133.2,130.9,128.5,126.0,113.8,112.2,103.4,60.6,60.5,56.1,56.0,40.6,27.6；HRMS(ESI)Calcd.for C 23 H 28 NO 7 [M+H] + :430.1866；Found:430.1864.
example 13
With the compound 2- ((2S, 3S) -3-tert-butyl-4- (2, 6-dimethoxy-3, 5-dicyclopentylphenyl) -2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-penta-nyl) -propanol (6, baryPhos) prepared in example 1 as a chiral ligand, an ortho-tetra-substituted biaryl compound E-15f having axial chirality (the reaction scheme is shown below) was prepared by an asymmetric Suzuki-Miyaura coupling reaction involving a transition metal palladium-catalyzed aryl halide 13f and a potassium arylfluoroborate 14a, in accordance with the preparation method of example 8.
(S) -3,6 '-trimethoxy-4-phenylbiphenyl-2, 2' -dialdehyde (E-15 f) as a white solid (73% yield); 86% ee.
The enantiomeric excess (ee) is determined by chiral high-pressure liquid phase, and the ee value is 86 percent; high-pressure liquid phase conditions: chiral AD-H column, flow rate 1mL/min at 25 ℃, n-hexane/isopropanol: 70/30,250nm,7.20min (S), 8.68min (R); 1 H NMR(400MHz,CDCl 3 )δ10.21(s,1H),9.72(s,1H),7.65(t,J＝7.6Hz,3H),7.48(td,J＝7.8,1.7Hz,3H),7.44–7.39(m,1H),7.17(d,J＝8.2Hz,1H),7.15(s,1H),3.74(s,3H),3.68(s,3H),3.47(s,3H)； 13 C NMR(126MHz,CDCl 3 )δ192.0,191.0,156.6,153.5,153.3,137.1,136.7,135.3,130.2,129.1,129.0,128.6,128.0,127.7,122.8,119.6,118.2,115.9,62.5,56.3,56.0；HRMS(ESI)Calcd.for C 23 H 21 O 5 [M+H] + :377.1389；Found:377.1390.
example 14
With the compound 2- ((2S, 3S) -3-tert-butyl-4- (2, 6-dimethoxy-3, 5-dicyclopentylphenyl) -2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-penta-nyl) -propanol (6, baryPhos) prepared in example 1 as a chiral ligand, an ortho-tetra-substituted biaryl compound E-15g having axial chirality was prepared by an asymmetric Suzuki-Miyaura coupling reaction involving 13g of an aryl halide catalyzed by transition metal palladium and 14b of aryl potassium fluoroborate, according to the preparation method of example 8 (the reaction scheme is shown below).
(S) -5,5', 6' -tetramethoxybiphenyl-2, 2' -dialdehyde (E-15 g): white solid (80% yield); 91% ee.
The enantiomeric excess (ee) is determined by chiral high-pressure liquid phase, and the ee value is 91 percent; high-pressure liquid phase conditions: chiral AD-H column, flow rate 1mL/min at 25 ℃, n-hexane/isopropanol: 70/30,230nm,7.08min (S), 9.49min (R); 1 H NMR(400MHz,CDCl 3 )δ9.56(s,2H),7.85(d,J＝8.6Hz,2H),7.13(d,J＝8.6Hz,2H),4.01(s,6H),3.61(s,6H)； 13 C NMR(126MHz,CDCl 3 )δ189.9,157.5,146.5,131.3,128.4,125.9,111.9,77.3,77.0,76.7,60.4,56.0；HRMS(ESI)Calcd.for C 18 H 19 O 6 [M+H] + :331.1182；Found:331.1175.
example 15
With the compound 2- ((2S, 3S) -3-tert-butyl-4- (2, 6-dimethoxy-3, 5-dicyclopentylphenyl) -2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-penta-nyl) -propanol (6, baryPhos) prepared in example 1 as a chiral ligand, an ortho-tetra-substituted biaryl compound E-15h having axial chirality (the reaction scheme is shown below) was prepared by an asymmetric Suzuki-Miyaura coupling reaction involving a transition metal palladium-catalyzed aryl halide 13h and a potassium arylfluoroborate 14c, in accordance with the preparation method of example 8.
(S) -6' -benzyloxy-4, 5', 6-tetramethoxybiphenyl-2, 2' -dialdehyde (E-15 h): white solid (71% yield); 90% ee.
The enantiomeric excess (ee) is determined by chiral high-pressure liquid phase, and the ee value is 90 percent; high-pressure liquid phase conditions: chiral AD-H column, flow rate 1mL/min at 25 ℃, n-hexane/isopropanol: 70/30,250nm,6.15min (S), 8.32min (R); 1 H NMR(600MHz,CDCl 3 )δ9.61(s,1H),9.50(s,1H),7.87(d,J＝8.7Hz,1H),7.34(s,1H),7.22–7.11(m,4H),6.93(dd,J＝7.6,1.6Hz,2H),4.83(d,J＝11.2Hz,1H),4.78(d,J＝11.1Hz,1H),4.01(s,3H),3.98(s,3H),3.89(s,3H),3.61(s,3H)； 13 C NMR(151MHz,CDCl 3 )δ190.1,189.9,157.7,153.9,151.4,147.3,145.9,137.0,131.2,130.2,129.0,128.1(d,J＝11.0Hz),127.8,127.7,126.1,125.1,112.0,105.6,74.5,61.0,60.8,56.2,56.1；HRMS(ESI)Calcd.for C 25 H 24 NaO 7 [M+Na] + :459.1420；Found:459.1418.
example 16
With the compound 2- ((2S, 3S) -3-tert-butyl-4- (2, 6-dimethoxy-3, 5-dicyclopentylphenyl) -2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-penta-nyl) -propanol (6, baryPhos) prepared in example 1 as a chiral ligand, an ortho-tetra-substituted biaryl compound E-15i having axial chirality (the reaction scheme is shown below) was prepared by an asymmetric Suzuki-Miyaura coupling reaction involving a transition metal palladium-catalyzed aryl halide 13i and a potassium arylfluoroborate 14c, in accordance with the preparation method of example 8.
(S) -6-benzyloxy-5, 6 '-dimethoxybiphenyl-2, 2' -dialdehyde (E-15 i) as a white solid (80% yield); 93% ee.
The enantiomeric excess (ee) is determined by chiral high-pressure liquid phase, and the ee value is 93 percent; high-pressure liquid phase conditions: chiral AD-H column, flow rate 1mL/min at 25 ℃, n-hexane/isopropanol: 70/30,230nm,6.78min (S), 11.84min (R); 1 H NMR(600MHz,CDCl 3 )δ9.66(d,J＝4.7Hz,1H),9.56–9.46(m,1H),7.88(d,J＝8.6Hz,1H),7.66(d,J＝7.8Hz,1H),7.54(t,J＝8.0Hz,1H),7.2–7.10(m,5H),6.86(d,J＝7.0Hz,2H),4.84(d,J＝11.1Hz,1H),4.59(d,J＝11.1Hz,1H),4.00(s,3H),3.68(s,3H)； 13 C NMR(151MHz,CDCl 3 )δ191.3,190.3,157.8,157.2,145.4,136.8,135.9,131.8,129.8,128.6,128.1,127.7,125.6,125.6,119.8,115.5,111.9,74.6,56.0,55.9；HRMS(ESI)Calcd.for C 23 H 21 O 5 [M+H] + :377.1389；Found:377.1378.
example 17
With the compound 2- ((2S, 3S) -3-tert-butyl-4- (2, 6-dimethoxy-3, 5-dicyclopentylphenyl) -2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-penta-nyl) -propanol (6, baryPhos) prepared in example 1 as a chiral ligand, an ortho-tetra-substituted biaryl compound E-15j having axial chirality (the reaction scheme is shown below) was prepared by an asymmetric Suzuki-Miyaura coupling reaction involving a transition metal palladium-catalyzed aryl halide 13j and a potassium arylfluoroborate 14b, in accordance with the preparation method of example 8.
(S) -5,5', 6' -tetramethoxy-3-methylbiphenyl-2, 2' -dialdehyde (E-15 j) white solid (83% yield); 91% ee.
The enantiomeric excess (ee) is determined by chiral high-pressure liquid phase, and the ee value is 91 percent; high pressure liquid phase conditions: chiral AD-H column, 25 ℃, flow rate of 1mL/min, n-hexane/isopropanol: 70/30,230nm,5.89min (S), 8.02min (R); 1 H NMR(600MHz,CDCl 3 )δ9.71(s,1H),9.55(s,1H),7.83(d,J＝8.6Hz,1H),7.10(d,J＝8.6Hz,1H),6.86(s,1H),4.00(s,3H),3.99(s,3H),3.64(s,3H),3.56(s,3H),2.69(s,3H)； 13 C NMR(151MHz,CDCl 3 )δ191.6,190.1,157.5,156.0,146.4,144.5,138.7,133.1,132.6,128.4,126.0,125.7,115.3,111.8,60.5,60.4,56.0,55.8,21.7；HRMS(ESI)Calcd.for C 19 H 21 O 6 [M+H] + :345.1338；Found:345.1337.
example 18
With the compound 2- ((2S, 3S) -3-tert-butyl-4- (2, 6-dimethoxy-3, 5-dicyclopentylphenyl) -2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-penta-nyl) -propanol (6, baryPhos) prepared in example 1 as a chiral ligand, an ortho-tetra-substituted biaryl compound E-15k having axial chirality (the reaction scheme is shown below) was prepared by an asymmetric Suzuki-Miyaura coupling reaction involving a transition metal palladium-catalyzed aryl halide 13k and a potassium arylfluoroborate 14a, in accordance with the preparation method of example 8.
(S) -2- (2-formyl-6-methoxyphenyl) -1-methoxy-9-methyl-3-carbazecarboxaldehyde (E-15 k) white solid (90% yield); 91% ee.
The enantiomeric excess (ee) is determined by chiral high-pressure liquid phase, and the ee value is 91 percent; high-pressure liquid phase conditions: chiral AD-H column, flow rate 1mL/min at 25 ℃, n-hexane/isopropanol: 70/30,230nm,9.84min (S), 14.12min (R); 1 H NMR(400MHz,CDCl 3 )δ9.75(s,1H),9.70(s,1H),8.65(s,1H),8.17(d,J＝7.7Hz,1H),7.77(dd,J＝7.8,1.0Hz,1H),7.65–7.55(m,2H),7.47(d,J＝8.2Hz,1H),7.35(t,J＝7.1Hz,1H),7.27(d,J＝9.7Hz,1H),4.16(s,3H),3.79(s,3H),3.42(s,3H)； 13 C NMR(126MHz,CDCl 3 )δ191.78,191.1,157.7,143.4,142.5,136.7,135.9,130.0,127.4,127.2,126.7,126.4,125.5,123.4,120.7,119.7,117.8,115.5,109.3,61.2,56.0,31.3；HRMS(ESI)Calcd.for C 23 H 20 NO 4 [M+H] + :374.1392；Found:374.1385.
example 19
With the compound 2- ((2S, 3S) -3-tert-butyl-4- (2, 6-dimethoxy-3, 5-dicyclopentylphenyl) -2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-penta-nyl) -propanol (6, baryPhos) prepared in example 1 as a chiral ligand, an ortho-tetra-substituted biaryl compound E-15l having axial chirality (the reaction scheme is shown below) was prepared by asymmetric Suzuki-Miyaura coupling reaction involving palladium transition metal catalyzed aryl halide 13l and aryl potassium fluoroborate 14a, with reference to the preparation method of example 8.
(R) -6-methoxy-6 '-methylbiphenyl-2, 2' -dicarboxaldehyde (E-15 l) white solid (83% yield); 92% ee.
The enantiomeric excess (ee) is determined by chiral high-pressure liquid phase, and the ee value is 92 percent; high-pressure liquid phase conditions: chiral AD-H column, flow rate 1mL/min at 25 ℃, n-hexane/isopropanol: 70/30,250nm,5.76min (S), 9.13min (R); 1 H NMR(600MHz,CDCl 3 )δ9.64(d,J＝0.6Hz,1H),9.58(d,J＝0.7Hz,1H),7.90(dd,J＝7.7,0.7Hz,1H),7.68(dd,J＝7.8,1.0Hz,1H),7.59–7.55(m,2H),7.49(t,J＝7.6Hz,1H),7.27–7.24(m,1H),3.75(s,3H),2.01(s,3H)； 13 C NMR(151MHz,CDCl 3 )δ191.8,191.2,157.0,138.3,136.8,135.5,135.5,135.0,129.9,129.2,128.5,125.8,120.1,116.0,56.0,19.8；HRMS(ESI)Calcd.for C 16 H 14 NaO 3 [M+Na] + :277.0841；Found:277.0830.
example 20
With the compound 2- ((2S, 3S) -3-tert-butyl-4- (2, 6-dimethoxy-3, 5-dicyclopentylphenyl) -2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-penta-nyl) -propanol (6, baryPhos) prepared in example 1 as a chiral ligand, an ortho-tetra-substituted biaryl compound E-15m having axial chirality (the reaction scheme is shown below) was prepared by an asymmetric Suzuki-Miyaura coupling reaction involving a transition metal palladium-catalyzed aryl halide 13m and a potassium arylfluoroborate 14a, in accordance with the preparation method of example 8.
(S) -6-fluoro-6 '-methylbiphenyl-2, 2' -dicarboxaldehyde (E-15 m) white solid (86% yield); 91% ee.
The enantiomeric excess (ee) is determined by chiral high-pressure liquid phase, and the ee value is 91 percent; high-pressure liquid phase conditions: chiral AD-H column, flow rate 1mL/min at 25 ℃, n-hexane/isopropanol: 80/20,250nm,8.00min (S), 12.46min (R); 1 H NMR(500MHz,CDCl 3 )δ9.79(d,J＝1.2Hz,1H),9.68(s,1H),7.86(dd,J＝7.8,1.0Hz,1H),7.68(dd,J＝7.8,1.1Hz,1H),7.61(t,J＝8.0Hz,1H),7.59–7.54(m,1H),7.43–7.39(m,1H),7.26(dd,J＝8.2,0.9Hz,1H),3.76(s,3H)； 13 C NMR(126MHz,CDCl 3 )δ190.8,190.3(d,J＝3.7Hz),159.9(d,J＝247.0Hz),157.4,136.4(d,J＝2.3Hz),135.8,130.6,130.1(d,J＝8.3Hz),124.4(d,J＝17.6Hz),123.9(d,J＝3.3Hz),122.0,121.3,120.8(d,J＝23.0Hz),116.1,56.1； 19 F NMR(282MHz,CDCl 3 )δ-113.9；HRMS(EI)Calcd.for C 15 H 11 FO 3 [M] + :258.0692；Found:258.0690.
example 21
With the compound 2- ((2S, 3S) -3-tert-butyl-4- (2, 6-dimethoxy-3, 5-dicyclopentylphenyl) -2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-penta-nyl) -propanol (6, baryPhos) prepared in example 1 as a chiral ligand, an ortho-tetra-substituted biaryl compound E-15n having axial chirality (the reaction scheme is shown below) was prepared by an asymmetric Suzuki-Miyaura coupling reaction involving a transition metal palladium-catalyzed aryl halide 13n and a potassium arylfluoroborate 14b, in accordance with the preparation method of example 8.
(S) -3, 4-dimethoxy-2- (2-methoxynaphthyl-1-) benzaldehyde (E-15 n) as a white solid (90% yield); 93% ee.
The enantiomeric excess (ee) is determined by chiral high-pressure liquid phase, and the ee value is 93 percent; high pressure liquid phase conditions: chiral OD-H column, 25 ℃, flow rate of 1mL/min, n-hexane/isopropanol: 95/5,230nm,27.22min (S), 30.24min (R); 1 H NMR(400MHz,CDCl 3 )δ9.29(s,1H),7.97(d,J＝9.1Hz,1H),7.93(d,J＝8.7Hz,1H),7.87–7.81(m,1H),7.39(d,J＝9.1Hz,1H),7.36–7.31(m,2H),7.25–7.20(m,1H),7.14(d,J＝8.7Hz,1H),4.01(s,3H),3.85(s,3H),3.46(s,3H)； 13 C NMR(126MHz,CDCl 3 )δ191.3,158.0,154.5,147.1,135.03(s),134.0,130.3,128.7(d,J＝1.8Hz),128.0,127.0,124.7,124.4,123.7,115.8,112.7,111.5,77.3,77.0,76.8,60.5,56.3,55.9；HRMS(ESI)Calcd.for C 20 H 19 O 4 [M+H] + :323.1283；Found:323.1279.
example 22
With the compound 2- ((2S, 3S) -3-tert-butyl-4- (2, 6-dimethoxy-3, 5-dicyclopentylphenyl) -2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-penta-nyl) -propanol (6, baryPhos) prepared in example 1 as a chiral ligand, the ortho-tetra-substituted biaryl compound E-15o having axial chirality (the reaction scheme is shown below) was prepared by an asymmetric Suzuki-Miyaura coupling reaction involving a transition metal palladium-catalyzed aryl halide 13o and a potassium arylfluoroborate 14a, in accordance with the preparation method of example 8.
(S) -5- (2-formyl-6-methoxyphenyl) -6-methoxy-2-naphthaldehyde (E-15 o) white solid (84% yield); 89% ee.
The enantiomeric excess (ee) is determined by chiral high pressure liquid phase, and the ee value is 89%; high-pressure liquid phase conditions: chiral AD-H column, flow rate 1mL/min at 25 ℃, n-hexane/isopropanol: 70/30,250nm,7.14min (S), 8.14min (R); 1 H NMR(600MHz,CDCl 3 )δ10.11(s,1H),9.49(s,1H),8.35(d,J＝1.4Hz,1H),8.14(d,J＝9.0Hz,1H),7.79(dd,J＝8.8,1.6Hz,1H),7.73(dd,J＝7.8,0.9Hz,1H),7.59(t,J＝8.0Hz,1H),7.48(d,J＝9.1Hz,1H),7.31(d,J＝8.2Hz,1H),7.28(d,J＝8.8Hz,1H),3.87(s,3H),3.69(s,3H)； 13 C NMR(151MHz,CDCl 3 )δ192.3,191.9,157.7,157.2,137.2,135.8,135.0,132.3,132.2,129.5,127.7,125.8,123.7,119.4,116.6,116.5,113.6,56.4,56.1；HRMS(ESI)Calcd.for C 20 H 17 O 4 [M+H] + :321.1127；Found:321.1129.
example 22
With the compound 2- ((2S, 3S) -3-tert-butyl-4- (2, 6-dimethoxy-3, 5-dicyclopentylphenyl) -2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-penta-nyl) -propanol (6, baryPhos) prepared in example 1 as a chiral ligand, an ortho-tetra-substituted biaryl compound E-15p having axial chirality (the reaction scheme is shown below) was prepared by an asymmetric Suzuki-Miyaura coupling reaction involving a transition metal palladium-catalyzed aryl halide 13p and a potassium arylfluoroborate 14a, in accordance with the preparation method of example 8.
(S) -2- (2, 6-dimethoxynaphthyl-1-) -3-methoxybenzaldehyde (E-15 p) as a white solid (79% yield); 91% ee.
The enantiomeric excess (ee) is determined by chiral high-pressure liquid phase, and the ee value is 91 percent; high-pressure liquid phase conditions: chiral OD-H column, 25 ℃, flow rate 0.8mL/min, n-hexane/isopropanol: 90/10,230nm,10.11min (S), 13.32min (R); 1 H NMR(600MHz,CDCl 3 )δ9.47(s,1H),7.84(d,J＝9.0Hz,1H),7.71(dd,J＝7.8,1.0Hz,1H),7.55(dd,J＝14.3,6.1Hz,1H),7.35(d,J＝9.0Hz,1H),7.29(d,J＝8.2Hz,1H),7.15(d,J＝2.6Hz,1H),7.10(d,J＝9.2Hz,1H),7.01(dd,J＝9.2,2.6Hz,1H),3.91(s,3H),3.79(s,3H),3.69(s,3H)； 13 C NMR(151MHz,CDCl 3 )δ192.9,157.9,156.1,153.3,135.9,129.7,129.6,129.3,129.1,128.8,126.4,119.7,119.0,116.4,116.4,113.7,105.9,56.6,56.1,55.3；HRMS(ESI)Calcd.for C 20 H 19 O 4 [M+H] + :323.1283；Found:323.1278.
example 24
Ortho-tetra-substituted biaryl compounds E-15q with axial chirality (the reaction scheme is shown below) were prepared by asymmetric Suzuki-Miyaura coupling reaction involving transition metal palladium catalyzed aryl halide 13q and aryl potassium fluoroborate 14a using the compound 2- ((2S, 3S) -3-tert-butyl-4- (2, 6-dimethoxy-3, 5-dicyclopentylphenyl) -2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-pentylene-propanol (6, baryPhos) prepared in example 1 as chiral ligand, with reference to the preparation method of example 8.
(S) -3-methoxy-2- (6-methoxyquinolin-5-yl) benzaldehyde (E-15 q) as a white solid (80% yield); 89% ee.
Enantiomeric excess (ee) ofThe ee value is 89% by chiral high-pressure liquid phase measurement; high-pressure liquid phase conditions: chiral AD-H column, 25 ℃, flow rate of 0.8mL/min, n-hexane/isopropanol: 85/15,230nm,16.60min (S), 21.61min (R); 1 H NMR(500MHz,CDCl 3 )δ9.50(s,1H),8.79(s,1H),8.23(d,J＝9.2Hz,1H),7.72(d,J＝7.8Hz,1H),7.62–7.53(m,4H),7.29(d,J＝8.2Hz,1H),7.25(dd,J＝7.6,2.6Hz,2H),3.85(s,3H),3.68(s,3H)； 13 C NMR(126MHz,CDCl 3 )δ192.3,157.7,154.7,148.2,143.7,136.0,133.1,131.5,129.5,129.0,127.8,121.6,119.3,116.4,116.2,115.8,56.5,56.0；HRMS(ESI)Calcd.for C 18 H 16 NO 3 [M+H] + :294.1130；Found:294.1125.
example 25
With the compound 2- ((2S, 3S) -3-tert-butyl-4- (2, 6-dimethoxy-3, 5-dicyclopentylphenyl) -2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-penta-nyl) -propanol (6, baryPhos) prepared in example 1 as a chiral ligand, an ortho-tetra-substituted biaryl compound E-15r having axial chirality (the reaction scheme is shown below) was prepared by an asymmetric Suzuki-Miyaura coupling reaction involving a transition metal palladium-catalyzed aryl halide 13r and a potassium arylfluoroborate 14b, in accordance with the preparation method of example 8.
(2S) -2- (6- (1-hydroxyisopropyl-2-yl) -2-methoxynaphthalen-1-yl) -3, 4-dimethoxybenzaldehyde (E-15 r) white solid (92% yield); 91% de.
The stereoisomer excess value (de) is determined by chiral high-pressure liquid phase, and the de value is 89 percent; high-pressure liquid phase conditions: chiral AD-H column, 25 ℃, flow rate of 1mL/min, n-hexane/isopropanol: 70/30,250nm,5.76min,6.41min; 1 H NMR(600MHz,CDCl 3 )δ9.29(s,1H),7.93(d,J＝8.7Hz,2H),7.68(s,1H),7.38(d,J＝9.1Hz,1H),7.23(dd,J＝8.8,1.7Hz,1H),7.19(d,J＝8.7Hz,1H),7.14(d,J＝8.7Hz,1H),4.02(s,3H),3.85(s,3H),3.79–3.74(m,2H),3.47(s,3H),3.08(dq,J＝13.8,6.9Hz,1H),1.34(d,J＝7.0Hz,3H)； 13 C NMR(151MHz,CDCl 3 )δ191.4,158.0,154.3,147.0,138.7,135.0,133.0,130.0,128.8,128.6,127.0,126.2,125.3,124.5,115.7,112.9,111.6,68.5,60.6,56.3,55.9,42.2,17.5；HRMS(ESI)Calcd.for C 23 H 25 O 5 [M+H] + :381.1702；Found:381.1699.
example 26
Ortho-tetra-substituted biaryls E-15s (the reaction scheme is shown below) with axial chirality were prepared by asymmetric Suzuki-Miyaura coupling involving palladium transition metal catalyzed aryl halide 13E and arylboronic acid 14d using the compound 2- ((2S, 3S) -3-tert-butyl-4- (2, 6-dimethoxy-3, 5-dicyclopentylphenyl) -2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-penta-yoke) -propanol prepared in example 1 as chiral ligand.
The reaction steps are as follows: n- (3-bromo-2-formyl-4, 5-dimethoxyphenyl) pivaloamide (13e, 82mg, 0.24mmol), 2-methoxy-1-naphthaleneboronic acid (14d, 97mg, 0.48mmol) and potassium phosphate (156mg, 0.72mmol) were charged into a 10mL Schlenk tube, and the air in the Schlenk tube was replaced with nitrogen gas three times by purging. Degassed toluene (4 mL), tris (dibenzylideneacetone) dipalladium (2.2mg, 0.0024mmol) and chiral phosphine ligand 6 (2.6mg, 0.0049mmol) were added in this order under nitrogen protection. The reaction was stirred at 60 ℃ for 15 hours and then cooled to room temperature. Saturated brine was added to the reaction system, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product is purified by silica gel column chromatography, and the eluent is a mixed solvent of petroleum ether and ethyl acetate with the volume ratio of 3. The eluent containing the product (15S) was concentrated and dried to give (S) -N- (2-formyl-4, 5-dimethoxy-3- (2-methoxy-1-naphthyl) phenyl) pivaloamide (E-15S) as a white solid in 83mg yield 82%.
The enantiomeric excess (ee) is determined by a chiral high-pressure liquid phase, and the ee value is 91 percent; high-pressure liquid phase conditions: chiral AD-H column, flow rate 1mL/min at 25 ℃, n-hexane/isopropanol: 80/20,250nm,4.72min (S), 5.84min (R); 1 H NMR(400MHz,CDCl 3 )δ12.13(s,1H),9.21(s,1H),8.74(s,1H),7.97(d,J＝9.0Hz,1H),7.86–7.82(m,1H),7.41–7.32(m,3H),7.26–7.22(m,1H),4.05(s,3H),3.87(s,3H),3.39(s,3H),1.37(s,9H)； 13 C NMR(126MHz,CDCl 3 )δ194.6,179.1,159.3,154.4,142.2,140.8,136.3,133.9,130.4,128.7,128.0,127.1,124.7,123.8,115.9,113.9,112.6,103.0,60.5,56.3,56.1,40.6,27.6；HRMS(ESI)Calcd.for C 25 H 28 NO 5 [M+H] + :422.1967；Found:422.1962.
example 27
With the compound 2- ((2S, 3S) -3-tert-butyl-4- (2, 6-dimethoxy-3, 5-dicyclopentylphenyl) -2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-penta-nyl) -propanol (6, baryPhos) prepared in example 1 as a chiral ligand, an ortho-tetra-substituted biaryl compound E-15t having axial chirality (the reaction scheme is shown below) was prepared by an asymmetric Suzuki-Miyaura coupling reaction involving a transition metal palladium-catalyzed aryl halide 13s and an arylboronic acid 14E, in accordance with the preparation method of example 26.
(S) -3-benzyloxy-2- (2, 3-dimethoxy-1-naphthyl) -4-methoxybenzaldehyde (E-15 t) as a white solid (87% yield); 96% ee.
The enantiomeric excess (ee) is determined by a chiral high-pressure liquid phase, and the ee value is 96 percent; high-pressure liquid phase conditions: chiral AD-H column, flow rate 1mL/min at 25 ℃, n-hexane/isopropanol: 80/20,250nm,7.82min,11.81min; 1 H NMR(400MHz,CDCl 3 )δ9.40(s,1H),7.96(d,J＝8.7Hz,1H),7.76(d,J＝8.1Hz,1H),7.36(t,J＝7.3Hz,1H),7.28(s,1H),7.23–7.14(m,3H),7.06(dt,J＝14.1,6.9Hz,3H),6.70(d,J＝6.6Hz,2H),4.83(d,J＝10.7Hz,1H),4.57(d,J＝10.6Hz,1H),4.02(s,6H),3.69(s,3H)； 13 C NMR(126MHz,CDCl 3 )δ190.9,158.2,152.0,147.4,146.0,137.2,135.1,131.0,129.0,128.7,127.8,127.5,127.4,126.7,125.4,125.3,124.7,124.57,123.17,111.77,107.9,74.6,60.6,56.0,55.7；HRMS(ESI)Calcd.for C 27 H 25 O 5 [M+H] + :429.1702；Found:429.1695.
example 28
With the compound 2- ((2S, 3S) -3-tert-butyl-4- (2, 6-dimethoxy-3, 5-dicyclopentylphenyl) -2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-penta-nyl) -propanol (6, baryPhos) prepared in example 1 as a chiral ligand, an ortho-tetra-substituted biaryl compound E-15u having axial chirality (the reaction scheme is shown below) was prepared by an asymmetric Suzuki-Miyaura coupling reaction involving a transition metal palladium-catalyzed aryl halide 13h and an arylboronic acid 14E, in accordance with the preparation method of example 26.
(S) -2- (2, 3-dimethoxy-1-naphthyl) -3,4, 5-trimethoxybenzaldehyde (E-15 u) white solid (91% yield); 93% ee.
The enantiomeric excess (ee) is determined by chiral high-pressure liquid phase, and the ee value is 93 percent; high-pressure liquid phase conditions: chiral AD-H column, flow rate 1mL/min at 25 ℃, n-hexane/isopropanol: 70/30,250nm,5.37min and 6.16min; 1 H NMR(400MHz,CDCl 3 )δ9.38(s,1H),7.77(d,J＝8.1Hz,1H),7.46(s,1H),7.41–7.36(m,1H),7.29(s,1H),7.27–7.21(m,1H),7.17(d,J＝8.3Hz,1H),4.04(s,3H),4.02(s,3H),4.01(s,3H),3.71(s,3H),3.56(s,3H)； 13 C NMR(126MHz,CDCl 3 )δ191.0,153.5,151.89,151.9,147.8,147.6,130.9,130.0,129.4,128.3,126.8,125.4,125.2,124.5,122.9,107.8,105.0,61.0,61.0,60.6,56.1,55.6；HRMS(ESI)Calcd.for C 22 H 23 O 6 [M+H] + :383.1495；Found:383.1494.
example 29
With the compound 2- ((2S, 3S) -3-tert-butyl-4- (2, 6-dimethoxy-3, 5-dicyclopentylphenyl) -2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-penta-nyl) -propanol (6, baryPhos) prepared in example 1 as a chiral ligand, an ortho-tetra-substituted biaryl compound E-15v having axial chirality (the reaction scheme is shown below) was prepared by an asymmetric Suzuki-Miyaura coupling reaction involving a transition metal palladium-catalyzed aryl halide 13b and an arylboronic acid 14E, in accordance with the preparation method of example 26.
(S) -2- (2, 3-dimethoxy-1-naphthyl) -6-fluoro-3-methoxybenzaldehyde (E-15 v) as a white solid (89% yield); 92% ee.
The enantiomeric excess (ee) is determined by chiral high-pressure liquid phase, and the ee value is 92 percent; high-pressure liquid phase conditions: chiral AD-H column, flow rate 1mL/min at 25 ℃, n-hexane/isopropanol: 80/20,230nm,7.13min,8.38min; 1 H NMR(600MHz,CDCl 3 )δ9.64(s,1H),7.76(d,J＝8.1Hz,1H),7.38(t,J＝7.5Hz,1H),7.27(d,J＝7.4Hz,2H),7.24–7.21(m,2H),7.10(d,J＝8.4Hz,1H),4.03(s,2H),3.68(s,3H),3.66(s,3H)； 13 C NMR(151MHz,CDCl 3 )δ189.3,157.4,155.7,153.8(d,J＝2.2Hz),151.9,147.0,131.0,129.1,128.4,126.9,125.4,124.6,124.5,124.0(d,J＝8.2Hz),123.0,117.1(d,J＝9.4Hz),116.7(d,J＝22.8Hz),107.9,60.5,56.4,55.6； 19 F NMR(376MHz,cdcl 3 )δ-127.0(dd,J＝9.4,4.6Hz)；HRMS(ESI)Calcd.for C 20 H 18 FO 4 [M+H] + :341.1189；Found:341.1185.
example 30
With the compound 2- ((2S, 3S) -3-tert-butyl-4- (2, 6-dimethoxy-3, 5-dicyclopentylphenyl) -2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-pentylene-propanol (6, baryPhos) prepared in example 1 as a chiral ligand, an ortho-tetra-substituted biaryl compound E-15w having axial chirality (the reaction scheme is shown below) was prepared by asymmetric Suzuki-Miyaura coupling reaction involving a transition metal palladium-catalyzed aryl halide 13t and an arylboronic acid 14d, with reference to the preparation method of example 26.
(S) -2, 6-dimethoxy-4-formyl-3- (2-methoxy-1-naphthyl) pyridine (E-15 w) white solid (83% yield); 90% ee.
The enantiomeric excess (ee) is determined by chiral high-pressure liquid phase, and the ee value is 90 percent; high-pressure liquid phase conditions: chiral AD-H column, flow rate 0.3mL/min at 25 ℃, n-hexane/isopropanol: 98/2,230nm,32.19min and 36.93min; 1 H NMR(500MHz,CDCl 3 )δ9.48(s,1H),7.96(d,J＝9.0Hz,1H),7.85(dd,J＝11.5,5.4Hz,1H),7.40–7.34(m,3H),7.29–7.26(m,1H),6.92(s,1H),4.04(s,3H),3.85(s,3H),3.83(s,3H)； 13 C NMR(126MHz,CDCl 3 )δ191.9,163.2,161.9,155.1,145.5,134.0,130.5,128.9,128.2,126.9,124.6,123.8,114.5,112.9,96.6,56.4,54.1(d,J＝2.0Hz)；HRMS(ESI)Calcd.for C 19 H 17 NNaO 4 [M+Na] + :346.1055；Found:346.1051.
example 31
With the compound 2- ((2S, 3S) -3-tert-butyl-4- (2, 6-dimethoxy-3, 5-dicyclopentylphenyl) -2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-penta-nyl) -propanol (6, baryPhos) prepared in example 1 as a chiral ligand, an ortho-tetra-substituted biaryl compound E-15x having axial chirality (the reaction scheme is shown below) was prepared by an asymmetric Suzuki-Miyaura coupling reaction involving a transition metal palladium-catalyzed aryl halide 13u and an arylboronic acid 14d, in accordance with the preparation method of example 26.
(S) -2, 6-dimethoxy-4-formyl-3- (2-methoxy-1-naphthyl) pyridine (E-15X) white solid (92% yield); 81% ee.
The enantiomeric excess (ee) is determined by chiral high-pressure liquid phase, and the ee value is 81 percent; high-pressure liquid phase conditions: chiral AD-H column, flow rate 0.3mL/min at 25 ℃, n-hexane/isopropanol: 99/1,230nm,11.15min,12.31min; 1 H NMR(500MHz,CDCl 3 )δ9.46(s,1H),7.98–7.94(m,2H),7.86(d,J＝7.6Hz,1H),7.61(d,J＝7.3Hz,1H),7.49(t,J＝7.7Hz,1H),7.39(d,J＝9.1Hz,1H),7.34(pd,J＝6.8,1.4Hz,2H),7.08(d,J＝8.3Hz,1H),3.83(s,3H),1.95(s,3H)； 13 C NMR(126MHz,cdcl 3 )δ193.1,154.1,140.2,138.8,135.6,135.0,133.6,130.2,128.8,128.2,127.9,127.2,124.6,124.4,123.8,118.5,112.7,56.3,19.4；HRMS(ESI)Calcd.for C 19 H 17 O 2 [M+H] + :277.1229；Found:277.1225.
example 32
With the compound 2- ((2S, 3S) -3-tert-butyl-4- (2, 6-dimethoxy-3, 5-dicyclopentylphenyl) -2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-penta-nyl) -propanol (6, baryPhos) prepared in example 1 as a chiral ligand, an ortho-tetra-substituted biaryl compound E-15y having axial chirality (the reaction scheme is shown below) was prepared by an asymmetric Suzuki-Miyaura coupling reaction involving a transition metal palladium-catalyzed aryl halide 13o and an arylboronic acid 14d, in accordance with the preparation method of example 26.
(S) -2,2 '-dimethoxy-1, 1' -binaphthyl-6-carbaldehyde (E-15 y) as a white solid (81% yield); 90% ee.
The enantiomeric excess (ee) is determined by chiral high-pressure liquid phase, and the ee value is 90 percent; high-pressure liquid phase conditions: chiral AD-H column, flow rate 1mL/min at 25 ℃, n-hexane/isopropanol: 80/20,230nm,6.63min,7.21min; 1 H NMR(500MHz,CDCl 3 )δ10.11(s,1H),8.37(d,J＝1.2Hz,1H),8.15(d,J＝9.0Hz,1H),8.01(d,J＝9.0Hz,1H),7.89(d,J＝8.2Hz,1H),7.69(dd,J＝8.8,1.5Hz,1H),7.55(d,J＝9.1Hz,1H),7.47(d,J＝9.1Hz,1H),7.34(t,J＝7.4Hz,1H),7.26–7.20(m,2H),7.07(d,J＝8.5Hz,1H),3.82(s,3H),3.78(s,3H)； 13 C NMR(126MHz,CDCl 3 )δ192.0,157.7,154.9,137.4,135.0,133.7,132.2,131.4,129.8,129.2,128.1,128.1,126.5,126.3,124.8,123.6,123.3,120.0,118.5,114.6,114.0,56.8,56.6；HRMS(ESI)Calcd.for C 23 H 19 O 3 [M+H] + :343.1334；Found:343.1322.
example 33
With the compound 2- ((2S, 3S) -3-tert-butyl-4- (2, 6-dimethoxy-3, 5-dicyclopentylphenyl) -2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-pentylene-propanol (6, baryPhos) prepared in example 1 as a chiral ligand, an ortho-tetra-substituted biaryl compound E-15z having axial chirality (the reaction scheme is shown below) was prepared by asymmetric Suzuki-Miyaura coupling reaction involving a transition metal palladium-catalyzed aryl halide 13v and an arylboronic acid 14d, with reference to the preparation method of example 26.
(S) -2 '-methoxy-1, 1' -binaphthyl-2-sulfonyl fluoride (E-15 z) as a white solid (65% yield); 93% ee.
The enantiomeric excess (ee) is determined by chiral high-pressure liquid phase, and the ee value is 93 percent; high-pressure liquid phase conditions: chiral AD-H column, flow rate 0.6mL/min at 25 ℃, n-hexane/isopropanol: 96/4,250nm,12.22min,13.00min; 1 H NMR(600MHz,CDCl 3 )δ8.06(d,J＝8.5Hz,1H),8.05(d,J＝8.2Hz,1H),7.98(d,J＝8.3Hz,1H),7.89(d,J＝8.2Hz,1H),7.65(d,J＝8.4Hz,1H),7.54(ddd,J＝8.1,6.8,1.1Hz,1H),7.46(d,J＝9.1Hz,1H),7.35(td,J＝8.3,1.1Hz,2H),7.29(d,J＝8.5Hz,1H),7.25–7.23(m,1H),6.99(d,J＝8.4Hz,1H),3.81(s,3H)； 13 C NMR(151MHz,CDCl 3 )δ155.0,146.2,133.5,133.4,132.6,131.0,130.3,128.8,128.2,128.1,127.5,127.0,126.9,126.8,126.5,124.6,123.7,119.0,114.9,112.9,56.3；HRMS(EI)Calcd.for C 21 H 15 FO 4 S[M] + :382.0675；Found:382.0677.
example 34
With the compound 2- ((2S, 3S) -3-tert-butyl-4- (2, 6-dimethoxy-3, 5-dicyclopentylphenyl) -2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-penta-nyl) -propanol (6, baryPhos) prepared in example 1 as a chiral ligand, an ortho-tetra-substituted biaryl compound E-15aa having axial chirality (the reaction scheme is shown below) was prepared by an asymmetric Suzuki-Miyaura coupling reaction involving a transition metal palladium-catalyzed aryl halide 13w and an arylboronic acid 14d, in accordance with the preparation method of example 26.
(S) -6-methoxy-5- (2-methoxy-1-naphthyl) quinoline (E-15 aa) white solid (92% yield); 91% ee.
The enantiomeric excess (ee) is determined by chiral high-pressure liquid phase, and the ee value is 91 percent; high-pressure liquid phase conditions: chiral OD-H column, 25 ℃, flow rate of 0.8mL/min, n-hexane/isopropanol: 90/10,250nm,11.51min,14.97min; 1 H NMR(500MHz,CDCl 3 )δ8.77(d,J＝3.8Hz,1H),8.25(d,J＝9.2Hz,1H),8.00(d,J＝9.1Hz,1H),7.88(d,J＝8.2Hz,1H),7.69(d,J＝9.3Hz,1H),7.46(dd,J＝8.8,3.7Hz,2H),7.34(t,J＝7.4Hz,1H),7.26–7.22(m,1H),7.14(dd,J＝8.5,4.0Hz,1H),7.08(d,J＝8.5Hz,1H),3.81(s,3H),3.78(s,3H)； 13 C NMR(126MHz,CDCl 3 )δ155.0(d,J＝6.1Hz),148.1,144.2,133.9,133.6,130.6,129.9,129.1(d,J＝12.4Hz),128.0,126.6,124.9,123.6,121.2,119.3,118.1,117.3,113.9,56.8(d,J＝9.2Hz)；HRMS(EI)Calcd.for C 21 H 17 NO 2 [M] + :315.1259；Found:315.1252.
example 35
With the compound 2- ((2S, 3S) -3-tert-butyl-4- (2, 6-dimethoxy-3, 5-dicyclopentylphenyl) -2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-penta-nyl) -propanol (6, baryPhos) prepared in example 1 as a chiral ligand, an ortho-tetra-substituted biaryl compound E-15ab (the reaction scheme is shown below) having axial chirality was prepared by an asymmetric Suzuki-Miyaura coupling reaction involving a transition metal palladium-catalyzed aryl halide 13n and an arylboronic acid 14d, in accordance with the preparation method of example 26.
(S) -2,2 '-dimethoxy-1, 1' -binaphthyl (E-15 ab) white solid (89% yield); 90% ee.
The enantiomeric excess (ee) is determined by chiral high-pressure liquid phase, and the ee value is 90 percent; high-pressure liquid phase conditions: chiral OD-H column, 25 ℃, flow rate of 0.7mL/min, n-hexane/isopropanol: 99/1,250nm,10.79min,11.93min; 1 H NMR(500MHz,CDCl 3 )δ7.99(d,J＝9.0Hz,2H),7.88(d,J＝8.2Hz,2H),7.47(d,J＝9.0Hz,2H),7.32(t,J＝7.4Hz,2H),7.22(t,J＝7.6Hz,2H),7.12(d,J＝8.4Hz,2H),3.78(s,6H)； 13 C NMR(126MHz,CDCl 3 )δ155.0,134.0,129.4,129.2,127.9,126.3,125.2,123.5,119.6,114.3,56.9；HRMS(EI)Calcd.for C 22 H 18 O 2 [M] + :314.1307；Found:314.1303.
example 36
With the compound 2- ((2S, 3S) -3-tert-butyl-4- (2, 6-dimethoxy-3, 5-dicyclopentylphenyl) -2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-penta-nyl) -propanol (6, baryPhos) prepared in example 1 as a chiral ligand, an ortho-tetra-substituted biaryl compound E-15ac having axial chirality (the reaction scheme is shown below) was prepared by asymmetric Suzuki-Miyaura coupling reaction involving a transition metal palladium-catalyzed aryl halide 13p and an arylboronic acid 14E, with reference to the preparation method of example 26.
(S) -2,2 '-dimethoxy-1, 1' -binaphthyl (E-15 ac) white solid (89% yield); 90% ee.
The enantiomeric excess (ee) is determined by chiral high-pressure liquid phase, and the ee value is 90 percent; high pressure liquid phase conditions: chiral AD-H column, 25 ℃, flow rate of 0.8mL/min, n-hexane/isopropanol: 95/5,230nm,8.18min,9.97min; 1 H NMR(600MHz,CDCl 3 )δ7.84(d,J＝9.0Hz,2H),7.40(d,J＝9.0Hz,2H),7.16(d,J＝2.6Hz,2H),7.02(d,J＝9.2Hz,2H),6.90(dd,J＝9.2,2.6Hz,2H),3.88(s,6H),3.72(s,6H)； 13 C NMR(151MHz,CDCl 3 )δ156.1,153.6,130.1,129.4,128.0,126.9,120.2,119.2,115.1,106.1,105.9,57.2,55.3,30.2,29.8,14.2；
HRMS(EI)Calcd.for C 24 H 22 O 4 [M] + :374.1518；Found:374.1509.
example 37
With the compound 2- ((2S, 3S) -3-tert-butyl-4- (2, 6-dimethoxy-3, 5-dicyclopentylphenyl) -2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-penta-nyl) -propanol (6, baryPhos) prepared in example 1 as a chiral ligand, the ortho-tetra-substituted biaryl compound E-15ad having axial chirality (the reaction scheme is shown below) was prepared by an asymmetric Suzuki-Miyaura coupling reaction involving a transition metal palladium-catalyzed aryl halide 13x and an arylboronic acid 14f, in accordance with the preparation method of example 26.
(S) -2,2 '-dimethoxy-1, 1' -binaphthyl (E-15 ad) white solid (87% yield); 85% ee.
The enantiomeric excess (ee) is determined by chiral high-pressure liquid phase, and the ee value is 85 percent; high-pressure liquid phase conditions: chiral AD-H column, flow rate 0.8mL/min at 25 ℃, n-hexane/isopropanol: 95/5,250nm,5.39min,6.38min; 1 H NMR(400MHz,CDCl 3 )δ7.82–7.75(m,5H),7.61(d,J＝8.1Hz,4H),7.45(t,J＝7.4Hz,5H),7.37(dd,J＝13.8,7.1Hz,4H),7.23(s,2H),3.94(s,6H)； 13 C NMR(126MHz,CDCl 3 )δ155.3,138.4,134.0,132.4,130.0,129.7,128.8,128.0,127.7,127.2,126.3,126.3,123.9,105.7,55.5；HRMS(EI)Calcd.for C 34 H 26 O 2 [M] + :466.1933；Found:466.1936.
example 38
With the compound 2- ((2S, 3S) -3-tert-butyl-4- (2, 6-dimethoxy-3, 5-dicyclopentylphenyl) -2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-penta-nyl) -propanol (6, baryPhos) prepared in example 1 as chiral ligand, the ortho-tetra-substituted biaryl compound E-15ae having axial chirality (the reaction scheme is shown below) was prepared by an asymmetric Suzuki-Miyaura coupling reaction involving 13y of a transition metal palladium-catalyzed aryl halide and 14g of an arylboronic acid, with reference to the preparation method of example 26.
(S) -2,2', 3' -tetramethoxy-1, 1' -binaphthyl (E-15 ae): white solid (90% yield); 95% ee.
The enantiomeric excess (ee) is determined by chiral high-pressure liquid phase, and the ee value is 95 percent; high-pressure liquid phase conditions: chiral AD-H column, flow rate 0.8mL/min at 25 ℃, n-hexane/isopropanol: 95/5,230nm,12.79min,18.81min; 1 H NMR(500MHz,CDCl 3 )δ7.81(d,J＝8.2Hz,2H),7.40–7.32(m,4H),7.12(q,J＝8.8Hz,4H),4.08(s,6H),3.66(s,6H)； 13 C NMR(126MHz,CDCl 3 )δ152.4,147.4,131.2,129.0,126.6,126.0,125.7,125.2,124.0,107.3,60.7,55.6；HRMS(EI)Calcd.for C 24 H 22 O 4 [M] + :374.1518；Found:374.1494.
example 39
With the compound 2- ((2S, 3S) -3-tert-butyl-4- (2, 6-dimethoxy-3, 5-dicyclopentylphenyl) -2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-penta-nyl) -propanol (6, baryPhos) prepared in example 1 as a chiral ligand, an ortho-tetra-substituted biaryl compound E-15af having axial chirality (the reaction scheme is shown below) was prepared by an asymmetric Suzuki-Miyaura coupling reaction involving a transition metal palladium-catalyzed aryl halide 13z and an arylboronic acid 14d, in accordance with the preparation method of example 26.
(S) -2- (2, 2 '-dimethoxy-1, 1' -binaphthyl-6-yl) -4H-chroman-4-one (E-15 af) white solid (75% yield); 92% ee.
The enantiomeric excess (ee) is determined by a chiral high-pressure liquid phase, and the ee value is 92 percent; high-pressure liquid phase conditions: chiral AD-H column, flow rate 1mL/min at 25 ℃, n-hexane/isopropanol: 75/25,230nm,17.48min,23.31min; 1 H NMR(600MHz,CDCl 3 )δ8.54(s,1H),8.25(d,J＝7.9Hz,1H),8.13(d,J＝9.0Hz,1H),7.90(d,J＝9.1Hz,1H),7.71(dd,J＝11.3,4.2Hz,1H),7.66(dd,J＝9.0,1.8Hz,1H),7.62(d,J＝8.3Hz,1H),7.55(d,J＝9.0Hz,1H),7.45(d,J＝15.9Hz,2H),7.43(d,J＝14.2Hz,1H),7.23(d,J＝9.0Hz,1H),7.20(d,J＝2.5Hz,1H),7.00(d,J＝9.2Hz,1H),6.95–6.90(m,2H),3.91(s,3H),3.83(s,3H),3.76(s,3H)； 13 C NMR(151MHz,CDCl 3 )δ178.5,163.8,156.7,156.4,156.1,153.5,135.6,133.7,130.8,130.1,129.2,128.5,128.4,127.3,126.5,126.4,126.3,125.7,125.2,124.0,123.0,119.8,119.4,119.1,118.1,114.8,107.2,106.0,57.1,56.7,55.3；HRMS(EI)Calcd.for C 32 H 24 O 5 [M] + :488.1624；Found:488.1616.
example 40
With the compound 2- ((2S, 3S) -3-tert-butyl-4- (2, 6-dimethoxy-3, 5-dicyclopentylphenyl) -2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-penta-nyl) -propanol (6, baryPhos) prepared in example 1 as a chiral ligand, an ortho-tetra-substituted biaryl compound E-15ag having axial chirality (the reaction scheme is shown below) was prepared by an asymmetric Suzuki-Miyaura coupling reaction involving an aryl halide 13aa catalyzed by transition metal palladium and an arylboronic acid 14d, with reference to the preparation method of example 26.
(S) - (2, 2 '-dimethoxy-1, 1' -binaphthyl-3-yl) trimethylsilane (E-15 ag) as a white solid (79% yield); 94% ee.
The enantiomeric excess (ee) is determined by chiral high-pressure liquid phase, and the ee value is 94%; high-pressure liquid phase conditions: chiral IC column, 25 ℃, flow rate 0.7mL/min, n-hexane/isopropanol: 100/0,250nm,6.91min,8.01min; 1 H NMR(600MHz,CDCl 3 )δ8.03(s,1H),8.01(d,J＝9.0Hz,1H),7.87(dd,J＝8.1,3.6Hz,2H),7.46(d,J＝9.1Hz,1H),7.34(td,J＝7.8,0.9Hz,2H),7.27–7.24(m,1H),7.21(ddd,J＝8.0,6.8,1.0Hz,1H),7.18(d,J＝8.5Hz,1H),7.13(d,J＝8.5Hz,1H),3.82(s,3H),3.24(s,3H),0.42–0.35(m,9H)； 13 C NMR(151MHz,CDCl 3 )δ161.2,155.1,136.3,135.3,134.1,133.8,130.4,130.0,129.3,128.3,128.0,126.8,126.5,125.5,125.2,124.3,123.8,121.7,120.0,113.8,60.4,56.7,-0.3；HRMS(EI)Calcd.for C 25 H 26 O 2 Si[M] + :386.1702；Found:386.1699.
example 41
With the compound 2- ((2S, 3S) -3-tert-butyl-4- (2, 6-dimethoxy-3, 5-dicyclopentylphenyl) -2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-penta-nyl) -propanol (6, baryPhos) prepared in example 1 as a chiral ligand, an ortho-tetra-substituted biaryl compound E-15ah having axial chirality was prepared by an asymmetric Suzuki-Miyaura coupling reaction involving a transition metal palladium-catalyzed aryl halide 13ab and an arylboronic acid 14d, according to the preparation method of example 26 (the reaction scheme is shown below).
(S) -5- (3, 5-bistrifluoromethylphenyl) -2,2 '-dimethoxy-1, 1' -binaphthyl (E-15 ah): white solid (88% yield); 90% ee.
The enantiomeric excess (ee) is determined by chiral high-pressure liquid phase, and the ee value is 90 percent; high-pressure liquid phase conditions: chiral PC column, 25 ℃, flow rate of 0.7mL/min, acetonitrile/water: 80/20,214nm,6.53min and 7.22min; 1 H NMR(500MHz,CDCl 3 )δ8.12–7.97(m,4H),7.90(d,J＝8.0Hz,1H),7.84(d,J＝9.2Hz,1H),7.48(dd,J＝14.0,9.3Hz,2H),7.35(t,J＝7.2Hz,1H),7.31–7.20(m,4H),7.13(d,J＝8.2Hz,1H),3.82(s,3H),3.78(s,3H)； 13 C NMR(126MHz,CDCl 3 )δ155.2,155.0,143.4,137.0,134.5,133.9,131.7(q,J＝33.4Hz),130.3(d,J＝4.1Hz),129.7(d,J＝0.6Hz),129.2,128.0(d,J＝0.7Hz),126.7,126.5,126.4,126.4,125.8,125.1,125.1,123.6,121.6–120.6(m),120.2,119.2,114.7,114.1,56.9,56.7； 19 F NMR(376MHz,cdcl 3 )δ-62.7；HRMS(EI)Calcd.for C 30 H 20 F 6 O 2 [M] + :526.1367；Found:526.1363.
example 42
With the compound 2- ((2S, 3S) -3-tert-butyl-4- (2, 6-dimethoxy-3, 5-diisopropyl) -2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-penta-nyl) -propanol (I-3) prepared in example 2 as a chiral ligand, an ortho-tetra-substituted biaryl compound E-15a having axial chirality (the reaction scheme is shown below) was prepared by an asymmetric Suzuki-Miyaura coupling reaction involving a transition metal palladium-catalyzed aryl halide 13a and a potassium arylfluoroborate 14a, in accordance with the preparation method of example 8.
The yield was 87%. The enantiomeric excess (ee) is measured by a chiral high-pressure liquid phase, and the ee value is 86 percent; high pressure liquid phase conditions: chiral AD-H column, flow rate 1mL/min at 25 ℃, n-hexane/isopropanol: 70/30,210nm,6.70min (S), 9.67min (R);
example 43
With the compound 3- ((2S, 3S) -3-tert-butyl-4- (2, 6-dimethoxy-3, 5-bis (3, 4-tetramethylcyclopentyl) phenyl) -2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-penta-nyl) -pentanol (I-7) prepared in example 3 as a chiral ligand, an ortho-tetra-substituted biaryl compound E-15a having axial chirality was prepared by an asymmetric Suzuki-Miyaura coupling reaction involving an aryl halide 13a catalyzed by transition metal palladium and a potassium arylfluoroborate 14a, according to the preparation method of example 8 (the reaction scheme is shown below).
The yield was 83%. The enantiomeric excess (ee) is measured by a chiral high-pressure liquid phase, and the ee value is 90 percent; high-pressure liquid phase conditions: chiral AD-H column, flow rate 1mL/min at 25 ℃, n-hexane/isopropanol: 70/30,210nm,6.70min (S), 9.67min (R);
example 44
With the compound (2S, 3S) -3-tert-butyl-4- (2, 6-dimethoxy-3, 5-diphenylphenyl) -2-isopropyl-2, 3-dihydrobenzo [ d ] [1,3] oxy prepared in example 4 as a chiral ligand, the ortho-tetra-substituted biaryl compound E-15a having axial chirality was prepared by asymmetric Suzuki-Miyaura coupling reaction involving an aryl halide 13a catalyzed by transition metal palladium and potassium arylfluoroborate 14a, according to the preparation method of example 8 (the reaction scheme is shown below).
The yield was 83%. The enantiomeric excess (ee) is determined by chiral high-pressure liquid phase, and the ee value is 64 percent; high-pressure liquid phase conditions: chiral AD-H column, flow rate 1mL/min at 25 ℃, n-hexane/isopropanol: 70/30,210nm,6.70min (S), 9.67min (R).
Example 45
With the compound (2S, 3S) -3-tert-butyl-4- (2, 6-dimethoxy-3, 5-dicyclopentylphenyl) -2-isopropyl-2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-pentayoke (I-5) prepared in example 5 as a chiral ligand, an ortho-tetra-substituted biaryl compound E-15a having axial chirality (the reaction scheme is shown below) was prepared by asymmetric Suzuki-Miyaura coupling reaction involving an aryl halide 13a catalyzed by transition metal palladium and a potassium arylfluoroborate 14a, referring to the preparation method of example 8.
The yield was 75%. The enantiomeric excess (ee) is determined by chiral high pressure liquid phase, and the ee value is 84 percent; high-pressure liquid phase conditions: chiral AD-H column, flow rate 1mL/min at 25 ℃, n-hexane/isopropanol: 70/30,210nm,6.70min (S), 9.67min (R).
Example 46
Following the procedure of example 1, the racemate of the compound 2- ((2S, 3S) -3-tert-butyl-4- (2, 6-dimethoxy-3, 5-dicyclopentylphenyl) -2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-penta-nyl) -propanol (6, baryPhos) was prepared. Using this racemate as a ligand, a racemic biaryl compound was prepared in 80 to 92% yield by an asymmetric Suzuki-Miyaura coupling reaction of a transition metal palladium-catalyzed aryl halide with an aryl boronic acid or a potassium aryl fluoroborate, according to the preparation method of example 8 or example 26.
This example was used primarily to prepare the racemate from the examples as a control for determining the enantiomeric excess (ee) of chiral samples. The yield was similar to that of the chiral product in the above example.
Example 47
An ortho-tetra-substituted biaryl compound E-15a having axial chirality (the reaction scheme is shown below) was prepared by asymmetric Suzuki-Miyaura coupling reaction involving an aryl halide 13a and aryl potassium fluoroborate 14a using the chiral ligand-containing palladium metal complex Y-1 prepared in example 7 as a chiral catalyst.
The reaction steps are as follows: 2-bromo-3, 4-dimethoxybenzaldehyde (13a, 60mg, 0.24mmol), potassium 2-formyl-6-methoxyphenyltrifluoroborate (14a, 68mg, 0.28mmol) and potassium phosphate (156mg, 0.72mmol) were charged into a 10mL Schlenk tube, and the air in the Schlenk tube was replaced with nitrogen by purging three times. Degassed toluene (4 mL), deionized water (0.8 mL), and metal complex Y (2.0 mg, 0.0012mmol) were added sequentially under nitrogen. The reaction was stirred at 60 ℃ for 15 hours and then cooled to room temperature. Saturated brine was added to the reaction system, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product is purified by silica gel column chromatography, and the eluent is a mixed solvent of petroleum ether and ethyl acetate with the volume ratio of 4. The eluent containing the product (15 a) was concentrated and spin-dried to give (R) -5,6 '-trimethoxybiphenyl-2, 2' -dialdehyde (E-15 a) as a colorless waxy solid in a yield of 60mg and 82%.
The enantiomeric excess (ee) is determined by chiral high-pressure liquid phase, and the ee value is 92 percent; high-pressure liquid phase conditions: chiral AD-H column, flow rate 1mL/min at 25 ℃, n-hexane/isopropanol: 70/30,210nm,6.70min (S), 9.67min (R). The ee value of the biaryl product obtained in example 8 was identical using the metal complex Y as chiral catalyst.
Comparative examples 1 to 3
Referring to the preparation method of example 8, biaryl 15a having optical activity was prepared using different phosphine ligands as ligands.
The reaction results are shown in table 1:
TABLE 1
| Numbering | Ligands | Yield of | ee％ |
| Comparative example 1 | L8 | 62％ | 32％ |
| Comparative example 2 | L9 | 66％ | 36％ |
| Comparative example 3 | L11 | 60％ | 45％ |
| Example 5 | I-6 | 86％ | 92％ |
From the above table, it can be seen that, when phosphine ligands with different substituents are used as metal ligands in asymmetric Suzuki-Miyaura coupling reaction, the yield and selectivity of the obtained product are significantly improved, especially in enantioselectivity (the difference in ee value can reach 60% at most, and 47% at least). This result is fully shown: the ligand of the invention is applied to asymmetric Suzuki-Miyaura coupling reaction, and chiral ortho-position tetra-substituted biaryl compounds can be efficiently prepared.
Claims (19)
1. A phosphine ligand which is a compound represented by formula I or a racemate thereof:
wherein "-" indicates that the atom herein is a chiral atom; r 1 And R 5 Independently methyl, ethyl, n-propyl or isopropyl; r is 3 Is hydrogen;
R 2 and R 4 Independently of a branch C 3～5 Alkyl radical, C 3～6 Cycloalkyl radical, R 2-1a Substituted C 3～6 Cycloalkyl or C 6～14 An aryl group;
each R 2-1a Independently methyl, ethyl, n-propyl or isopropyl; r is 2-1a The number is 1 or more; when R is 2-1a A plurality of R 2-1a The same or different;
R 6 and R 7 Independently is C 1～3 Alkyl or hydroxy substituted C 1～3 An alkyl group;
R 8 is a hydroxyl group;
R 9 is C 1～10 An alkyl group.
2. A compound of formula I or its racemate according to claim 1, wherein R is as defined in claim 1 2 And R 4 Independently is R 2-1a Substituted C 3～6 When cycloalkyl is present, said R 2-1a Substituted C 3～6 R in cycloalkyl 2-1a The number is 1,2, 3 or 4;
and/or when R 9 Is C 1～10 When alkyl, said C 1～10 Alkyl being straight-chain C 1～10 Alkyl or branched C 3～10 An alkyl group;
and/or the compound shown as the formula I is
3. A compound of formula I or its racemate according to claim 2, wherein R is as defined in claim 2 2 And R 4 Independently is R 2-1a Substituted C 3～6 When cycloalkyl is present, said R 2-1a Substituted C 3～6 R in cycloalkyl 2-1a The number is 4;
and/or when R 9 Is C 1～10 When alkyl, said C 1～10 Alkyl being branched C 3～10 An alkyl group.
4. A compound of formula I or its racemate according to claim 3, wherein R is as defined in claim 3 2 And R 4 Independently of a branch C 3～5 When alkyl, the branch C 3～5 The alkyl is isopropyl,
And/or, when said R is 2 And R 4 Independently is R 2-1a Substituted C 3～6 When a cycloalkyl group is present, C is 3～6 Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
and/or, when said R is 2-1a When the number of the substitution is plural, R is 2-1a Are the same;
and/or, when said R is 2 And R 4 Independently is C 6～14 Aryl is said to C 6～14 Aryl is phenyl;
and/or, when said R is 6 And R 7 Independently is C 1～3 When alkyl, said C 1～3 Alkyl is methyl, ethyl, n-propyl or isopropyl;
and/or, when said R is 6 And R 7 Independently is hydroxy-substituted C 1～3 When alkyl, said C 1～3 Alkyl is methyl, ethyl, n-propyl or isopropyl;
and/or when R 9 Is a branched chain C 3～10 When alkyl, the branch C 3～10 Alkyl being branched C 3～6 An alkyl group.
5. A compound of formula I or its racemate according to claim 4, wherein R is as defined in claim 4 1 And R 5 Independently methyl or isopropyl;
and/or, when said R is 2 And R 4 Independently of a branch C 3～5 When alkyl, the branch C 3～5 Alkyl is isopropyl or
And/or, when said R is 2 And R 4 Independently is R 2-1a Substituted C 3～6 When a cycloalkyl group is present, C is 3～6 Cycloalkyl is cyclopentyl;
and/or, said R 2-1a Is methyl;
and/or, when said R is 6 And R 7 Independently is hydroxy-substituted C 1～3 When alkyl, said C 1～3 Alkyl is methyl;
and/or when R 9 Is a branched chain C 3～10 When alkyl, the branch C 3～10 Alkyl being branched C 3～4 An alkyl group.
6. A compound of formula I or a racemate thereof according to claim 5, wherein R is 9 Is an isopropyl group,
Or a tert-butyl group.
7. A compound of formula I or its racemate according to claim 6, wherein R is 9 Is a tert-butyl group.
8. A compound of formula I or a racemate thereof according to claim 1, wherein R is 1 And R 5 The same;
and/or, R 2 And R 4 The same;
and/or the presence of a gas in the gas,
is composed of
And/or the presence of a gas in the gas,
is composed of
9. A compound of formula I or a racemate thereof according to claim 1, wherein R is 1 And R 5 The same;
and/or, R 2 And R 4 The same;
and/or the presence of a gas in the gas,
is composed of
And/or the presence of a gas in the gas,
is composed of
10. A compound or racemate thereof, wherein the compound is optionally any one of the following compounds:
11. a process for the preparation of a compound of formula I, as claimed in any one of claims 1 to 9, or a racemate thereof, comprising the steps of: in the presence of a reducing agent, carrying out a reduction reaction of the compound II in an organic solvent as shown in the following formula to obtain a compound I;
wherein, ", R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 And R 9 Are as defined in any one of claims 1 to 9.
12. The method for preparing a compound represented by the formula I or a racemate thereof according to claim 11, wherein in the reduction reaction, the reducing agent is a halosilane reducing agent and/or a polysilane reducing agent;
and/or the molar ratio of the reducing agent to the compound II is 1-10;
and/or in the reduction reaction, the organic solvent is an aromatic hydrocarbon solvent and/or an ether solvent;
and/or in the reduction reaction, the temperature of the reduction reaction is 60-80 ℃.
13. A compound of formula II or a racemate thereof:
wherein, ", R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 And R 9 Is as defined in any one of claims 1 to 9.
14. A compound or racemate thereof, which is characterized in that the compound is any one of the following compounds:
15. a process for the preparation of a compound according to claim 13 or 14, comprising the steps of: under the action of an alkaline reagent, carrying out the following reaction of a compound III and a compound A in an organic solvent to obtain a compound;
when A is
When R is 12a And R 12b Independently is C 1～3 Alkyl or hydroxy substituted C 1～3 Alkyl, ", R 1 、R 2 、R 3 、R 4 、R 5 And R 9 Are all as defined in claim 19 or as claimed in claim 14, R 8 Is hydroxy, R 6 、R 7 Independently is C 1～3 Alkyl or hydroxy substituted C 1～3 An alkyl group;
when A is X-R 14 When is, X-R 14 Is 2-iodopropane, the compound III is
The compound is
16. Use of a compound of formula I as defined in any one of claims 1 to 9, or a racemate thereof, as a metal ligand in a Suzuki-Miyaura coupling reaction:
the Suzuki-Miyaura coupling reaction, which comprises the following steps: in the presence of a palladium catalyst, the compound I and an alkaline reagent, carrying out Suzuki-Miyaura coupling reaction on the compound C and the compound D in a solvent to obtain a compound E or a compound ent-E;
alternatively, the Suzuki-Miyaura coupling reaction comprising the steps of: carrying out Suzuki-Miyaura coupling reaction on a compound C and a compound D in a solvent in the presence of a palladium catalyst, the compound I racemate and a basic reagent to obtain a compound E and a compound ent-E;
wherein "
And
"and"
And
", both indicate that the group has axial chirality; q is C or N; when Q is N, R 18 Is absent; m is
or-BF 3 K；
R 15 、R 19 、R 20 And R 24 Independently of one another are F, C 1～10 Alkyl radical, C 1～10 Alkoxy radical, C 6～30 Aryl radical, R 15-1 Substituted C 6～30 Aryl, phenoxy, R 15-2 Substituted phenoxy, -CHO or-OSO 2 F；
R 16 、R 17 、R 18 、R 21 、R 22 And R 23 Independently H, F, C 1～10 Alkyl radical, C 1～10 Alkoxy radical, C 6～30 Aryl, R 16-1 Substituted C 6～30 Aryl, phenoxy, R 16-2 Substituted phenoxy, C 1～10 Silyl, NHPiv, -CHO or-OSO 2 F；
Or, R 16 、R 17 And R 18 Any two adjacent groups together with the carbon atom to which they are attached form
Or, R 21 、R 22 And R 23 Any two adjacent groups together with the carbon atom to which they are attached form
Or, R 15 And R 16 Together with the carbon atom to which they are attached form C 6-10 Aryl, R 15-3 Substituted C 6-10 Aryl radical, C 5-10 Cycloalkyl radical, C 3-10 Heteroaryl or C 5-10 A heterocycloalkyl group; said C is 3-10 Heteroaryl and said C 5-10 The heteroatoms in the heterocycloalkyl group are independently selected from one or more of N, S and O, and the number is 1,2, 3 or 4;
or, R 18 And R 19 Together with the carbon atom to which they are attached form C 6-10 Aryl, R 18-1 Substituted C 6-10 Aryl radical, C 5-10 Cycloalkyl radical, C 3-10 Heteroaryl or C 5-10 A heterocycloalkyl group; said C is 3-10 Heteroaryl and said C 5-10 The heteroatoms in the heterocycloalkyl group are independently selected from one or more of N, S and O, and the number is 1,2, 3 or 4;
or, R 20 And R 21 Together with the carbon atom to which they are attached form C 6-10 Aryl radical, R 20-1 Substituted C 6-10 Aryl radical, C 5-10 Cycloalkyl radical, C 3-10 Heteroaryl or C 5-10 A heterocycloalkyl group; said C is 3-10 Heteroaryl and said C 5-10 The heteroatoms in the heterocycloalkyl group are independently selected from one or more of N, S and O, and the number is 1,2, 3 or 4;
or, R 23 And R 24 Together with the carbon atom to which they are attached form C 6-10 Aryl radical, R 23-1 Substituted C 6-10 Aryl radical, C 5-10 Cycloalkyl radical, C 3-10 Heteroaryl or C 5-10 A heterocycloalkyl group; said C is 3-10 Heteroaryl and said C 5-10 The heteroatoms in the heterocycloalkyl group are independently selected from one or more of N, S and O, and the number is 1,2, 3 or 4;
R 15-1 、R 15-2 、R 16-1 、R 16-2 independently is C 1～10 Alkyl radical, C 1～10 Alkoxy radicalPhenyl, nitro, -CHO or-OSO 2 F；
The R is 15-3 、R 18-1 、R 20-1 And R 23-1 Independently is phenyl, R 15-3-1 Substituted phenyl or
R 15-3-1 Independently is C 1～10 Alkyl or halogen substituted C 1～10 An alkyl group;
the R is 15-1 、R 15-2 、R 16-1 、R 16-2 、R 15-3 、R 18-1 、R 20-1 And R 23-1 And R 15-3-1 The number of (A) is independently one or more, and when a plurality of (B) is provided, the same or different.
17. A compound of formula Y:
wherein, ", R 1 、R 2 、R 4 、R 5 、R 6 、R 7 And R 9 Is as defined in any one of claims 1 to 9.
18. Use of a compound of formula Y according to claim 17 as a catalyst in a Suzuki-Miyaura coupling reaction:
the Suzuki-Miyaura coupling reaction, which comprises the following steps: under the catalysis of the compound Y and in the presence of an alkaline reagent, carrying out Suzuki-Miyaura coupling reaction on the compound C and the compound D in a solvent to obtain a compound E or a compound ent-E;
wherein "
And
"and"
And with
", both indicate that the group has axial chirality; m, Q, R 15 、R 16 、R 17 、R 18 、R 19 、R 20 、R 21 、R 22 、R 23 And R 24 Are as claimed in claim 16.
19. A single crystal of a compound represented by the formula Y-1, wherein the crystal system belongs to the monoclinic system, C 2 Space group, cell parameter of
α＝γ＝90°，β＝113.055(2)°；
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910165339.XA CN111662331B (en) | 2019-03-05 | 2019-03-05 | Phosphine ligand, preparation method thereof and application of phosphine ligand in catalytic synthesis of ortho-tetra-substituted biaryl |
| PCT/CN2020/077397 WO2020177654A1 (en) | 2019-03-05 | 2020-03-02 | Phosphine ligand and preparation method thereof, and application in catalytic synthesis of ortho-tetra-substituted biaromatics |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910165339.XA CN111662331B (en) | 2019-03-05 | 2019-03-05 | Phosphine ligand, preparation method thereof and application of phosphine ligand in catalytic synthesis of ortho-tetra-substituted biaryl |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111662331A CN111662331A (en) | 2020-09-15 |
| CN111662331B true CN111662331B (en) | 2023-03-21 |
Family
ID=72337639
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910165339.XA Active CN111662331B (en) | 2019-03-05 | 2019-03-05 | Phosphine ligand, preparation method thereof and application of phosphine ligand in catalytic synthesis of ortho-tetra-substituted biaryl |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN111662331B (en) |
| WO (1) | WO2020177654A1 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114751937A (en) * | 2022-04-27 | 2022-07-15 | 宁波赜军医药科技有限公司 | Preparation method and application of phosphine ligand Baryphos intermediate |
| CN114805017B (en) * | 2022-04-29 | 2023-10-10 | 上海毕得医药科技股份有限公司 | Preparation method of 2-fluoro-1, 5-hexadiene compound |
| CN115490730B (en) * | 2022-09-30 | 2023-04-21 | 安徽泽升科技有限公司 | Method for synthesizing selenium/sulfur ligand based on chiral BIDIME |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018106746A2 (en) * | 2016-12-06 | 2018-06-14 | Boehringer Ingelheim International Gmbh | Novel chiral dihydrobenzooxaphosphole ligands and synthesis thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016094489A1 (en) * | 2014-12-10 | 2016-06-16 | The Regents Of The University Of California | Phosphorus ligands and methods of use |
| CN109293700B (en) * | 2018-11-07 | 2021-02-09 | 中国科学院上海有机化学研究所 | Chiral diphosphine ligand, preparation method, intermediate and application thereof |
-
2019
- 2019-03-05 CN CN201910165339.XA patent/CN111662331B/en active Active
-
2020
- 2020-03-02 WO PCT/CN2020/077397 patent/WO2020177654A1/en active Application Filing
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018106746A2 (en) * | 2016-12-06 | 2018-06-14 | Boehringer Ingelheim International Gmbh | Novel chiral dihydrobenzooxaphosphole ligands and synthesis thereof |
Non-Patent Citations (2)
| Title |
|---|
| Computationally Assisted Mechanistic Investigation and Development of Pd-Catalyzed Asymmetric Suzuki–Miyaura and Negishi Cross-Coupling Reactions for Tetra-ortho-Substituted Biaryl Synthesis;Nitinchandra D. Patel等;《ACS Catal.》;20180920;第9卷(第2期);第10190-10209页、支持信息第1-29页 * |
| Nitinchandra D. Patel等.Computationally Assisted Mechanistic Investigation and Development of Pd-Catalyzed Asymmetric Suzuki–Miyaura and Negishi Cross-Coupling Reactions for Tetra-ortho-Substituted Biaryl Synthesis.《ACS Catal.》.2018,第9卷(第2期),第10190-10209页、支持信息第1-29页. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN111662331A (en) | 2020-09-15 |
| WO2020177654A1 (en) | 2020-09-10 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN111662331B (en) | Phosphine ligand, preparation method thereof and application of phosphine ligand in catalytic synthesis of ortho-tetra-substituted biaryl | |
| CN106365949B (en) | Chiral spiroindane skeleton compound and preparation method thereof | |
| JPH11500144A (en) | Novel polycyclic aminopyridine compounds that are inhibitors of acetylcholine elastase, methods for their preparation and their use | |
| CN114478337B (en) | Axial chiral sulfur-containing diaryl derivative and synthesis method thereof | |
| CN109734747A (en) | Chiral imino-diacetic phosphate/ester and its derivative | |
| CN107922449A (en) | Chiral phosphoramidimidic acid ester and its derivative | |
| CN112920221B (en) | Chiral phosphoric acid with spiro-bis-dihydrobenzothiole skeleton and preparation method and application thereof | |
| WO2005070875A1 (en) | Process for production of amines | |
| US10072028B2 (en) | Cross-coupling of unactivated secondary boronic acids | |
| Pallikonda et al. | Triflic acid mediated functionalization of α-hydroxyphosphonates: route for sulfonamide phosphonates | |
| EP1423365A1 (en) | Process for the preparation of indole derivatives | |
| CN109293700B (en) | Chiral diphosphine ligand, preparation method, intermediate and application thereof | |
| JP2010500367A (en) | Process for producing substituted-1,2,3,4-tetrahydroisoquinoline derivatives | |
| CN104884450B (en) | The method for preparing voriconazole and the like | |
| CN111171068B (en) | Preparation method of silicon spiro-compound | |
| CN111217809B (en) | Chiral nitrogen-containing diene ligand and preparation method and application thereof | |
| US10196413B2 (en) | Chiral dihydrobenzoazaphosphole ligands and synthesis thereof | |
| US10544177B2 (en) | Chiral dihydrobenzooxaphosphole ligands and synthesis thereof | |
| CN113620931A (en) | Androgen receptor inhibitor and application thereof | |
| WO2015160688A1 (en) | Functionalized azaborine compounds and azaborine-containing biarylcarboxamides, and compositions and methods thereof | |
| CN111848680B (en) | Bidentate phosphine-phosphine oxide ligand and intermediate, preparation method and application thereof | |
| CN111747978B (en) | Silicon-center chiral tetra-substituted silane and preparation method thereof | |
| KR102050066B1 (en) | New 1,1-diboryl-1-metalic alkyl compounds, preparation method thereof and preparation method of 1,1,-diboronate ester compounds using the same | |
| CN112266386B (en) | 2-chloroadenine derivative, preparation method and application | |
| CN111233932B (en) | Chiral phosphoric acid with spiro indane skeleton and preparation method and application thereof |
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 | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20220420 Address after: 315336 room 104-21, No. 262, Binhai Fourth Road, Hangzhou Bay New Area, Ningbo, Zhejiang Applicant after: NINGBO ZEJUN PHARMACEUTICAL CO.,LTD. Address before: 200032 No. 345, Lingling Road, Shanghai, Xuhui District Applicant before: SHANGHAI INSTITUTE OF ORGANIC CHEMISTRY, CHINESE ACADEMY OF SCIENCES |
|
| TA01 | Transfer of patent application right | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |