CN111848680B - Bidentate phosphine-phosphine oxide ligand and intermediate, preparation method and application thereof - Google Patents

Bidentate phosphine-phosphine oxide ligand and intermediate, preparation method and application thereof Download PDF

Info

Publication number
CN111848680B
CN111848680B CN201910363711.8A CN201910363711A CN111848680B CN 111848680 B CN111848680 B CN 111848680B CN 201910363711 A CN201910363711 A CN 201910363711A CN 111848680 B CN111848680 B CN 111848680B
Authority
CN
China
Prior art keywords
group
alkyl
aryl
substituted
alkoxy
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
Application number
CN201910363711.8A
Other languages
Chinese (zh)
Other versions
CN111848680A (en
Inventor
汤文军
李博文
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Institute of Organic Chemistry of CAS
Original Assignee
Shanghai Institute of Organic Chemistry of CAS
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Shanghai Institute of Organic Chemistry of CAS filed Critical Shanghai Institute of Organic Chemistry of CAS
Priority to CN201910363711.8A priority Critical patent/CN111848680B/en
Publication of CN111848680A publication Critical patent/CN111848680A/en
Application granted granted Critical
Publication of CN111848680B publication Critical patent/CN111848680B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—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
    • B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
    • B01J31/1845—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms the ligands containing phosphorus
    • 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
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/06—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid amides
    • 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
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
    • B01J2231/42—Catalytic cross-coupling, i.e. connection of previously not connected C-atoms or C- and X-atoms without rearrangement
    • B01J2231/4205—C-C cross-coupling, e.g. metal catalyzed or Friedel-Crafts type
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/80—Complexes comprising metals of Group VIII as the central metal
    • B01J2531/82—Metals of the platinum group
    • B01J2531/824—Palladium

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Health & Medical Sciences (AREA)
  • Inorganic Chemistry (AREA)
  • Materials Engineering (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention discloses a bidentate phosphine-phosphine oxide ligand and an intermediate, a preparation method and application thereof. The phosphine oxide compound is shown as a formula I and/or ent-I. The phosphine oxide compound is used as a metal ligand and applied to Suzuki-Miyaura coupling reaction, so that the generation of a self-coupled byproduct is avoided, and the alpha-aryl carbonyl compound is obtained; and ligand and goldThe dosage of the catalyst is less.

Description

Bidentate phosphine-phosphine oxide ligand and intermediate, preparation method and application thereof
Technical Field
The invention relates to a bidentate phosphine-phosphine oxide ligand and an intermediate, a preparation method and application thereof.
Background
The α -arylcarbonyl structure is widely present in molecules with pharmaceutical and biological activities. For example, chiral aryl propionic acid nonsteroidal drugs are published in the sixties of the last century, and the drugs have the effects of high efficiency, high fever reduction, pain alleviation, inflammation resistance and the like, have the characteristics of strong curative effect, small dosage, low toxicity, quick action and the like, are widely accepted by people, most representative of the drugs are ibuprofen, naproxen, flurbiprofen and the like, and the drugs are the first hundred strong drugs sold in the world (J.Nat.chem.biol.2011,7,803; Curr.drug Metab.2001,2,37.J.Am.chem.Soc.2017,139, 2825.). For the construction of such structures, the strategy generally adopted by chemists is the reaction between a halogenated aromatic hydrocarbon and a metal-alpha-carbonyl reagent, but this method is only applicable to halogenated aromatic hydrocarbons with higher activity. Other methods, such as the reaction of a pre-prepared enolate compound with an equivalent amount of a metal reagent, still suffer from a number of drawbacks: some metal reagents are sensitive to air and moisture, poor in functional group compatibility, high in toxicity of used reagents and the like. Under such historical circumstances, transition metal catalyzed α -arylation reactions and cross-coupling reactions of α -halocarbonyl compounds have received widespread attention.
The project group of Buchwald and Hartwig et al made a milestone contribution in the development of asymmetric alpha-arylation reactions (J.Am.Chem.Soc.1997,119, 11108; J.Am.Chem.Soc.1997,119, 12382.). In 1997, they first developed a-arylation reaction between palladium-catalyzed ketones, esters, amides and aryl halides, and began to be the first of the a-arylation reaction. The method can efficiently construct the building blocks which are very important in the synthesis field, but the application range of the reaction is limited due to the need of using strong alkali, limitation to constructing quaternary carbon chiral centers and the like.
Currently, a number of outstanding achievements are also achieved in the cross-coupling reaction of α -halocarbonyl compounds, mostly with the transition metals nickel, iron, cobalt (j.am. chem. soc.2005,127, 4594; angew. chem., int. ed.2009,48,154; j.am. chem. soc.2010,132, 1264; j.am. chem. soc.2014,136, 17662; j.am. chem. soc.2015,137, 7128; chem. eur. j.2018,24,2059). However, the following limitations still exist: 1) reaction systems of nickel catalysis and the like are generally low in catalytic efficiency (for example, the usage amount of the catalyst is generally more than 5 mol%), and the usage amount of the catalyst is large, so that the cost is undoubtedly increased in large-scale production, and much inconvenience is brought to aftertreatment; 2) the preparation of the used Grignard reagent and zinc reagent is complicated and is sensitive to air and moisture; 3) the lack of substrate universality, steric hindrance and functional group compatibility still needs to be improved; 4) the operation is relatively inconvenient, and some reactions need to control the dropwise addition of the Grignard reagent even within one hour.
Figure BDA0002047585180000011
The palladium-catalyzed asymmetric Suzuki coupling reaction of the alpha-halogenated carbonyl compound and the arylboronic acid can well compensate the defects. Through decades of efforts of chemists, palladium-catalyzed chemistry has been developed rapidly, the dosage of many palladium-catalyzed reactions can be reduced to 0.001 mol%, and the palladium-catalyzed coupling reaction has more excellent large steric hindrance and functional group tolerance and wider catalytic reaction types compared with metals such as nickel catalysis. However, the difficulty of realizing the asymmetric coupling reaction is very large, and the method still remains blank so far and has no report.
Among the numerous types of cross-coupling reactions, Suzuki coupling relies on: 1) the reaction condition is mild; 2) the boric acid and the derivative thereof have easily obtained raw materials, are cheaper, and are environment-friendly and safe compared with other organic metal reagents; 3) have broad functional group compatibility; 4) the advantages of simple post-treatment and the like are favored by numerous chemists. However, in the cross-coupling reaction, how to efficiently control the selectivity of the cross-coupling product and the self-coupling byproduct is a problem for chemists. Alpha-arylcarbonyl compounds containing a chiral center of a tertiary carbon still lack efficient synthetic methods.
In view of the above, there is an urgent need in the art to develop a catalyst with higher practicability and higher efficiency, so as to achieve the reaction of the asymmetric α -halocarbonyl compound and the arylboronic acid with higher yield or higher optical selectivity under the premise of low catalyst usage.
Disclosure of Invention
The invention provides a bidentate phosphine-phosphine oxide ligand and an intermediate, a preparation method and application thereof. The bidentate phosphine-phosphine oxide ligand is used as a ligand for the coupling reaction of the alpha-halogenated carbonyl compound and the aryl boric acid, avoids the generation of self coupling byproducts, obtains the alpha-aryl carbonyl compound with higher yield or higher enantioselectivity, and has wide applicable substrate range. In addition, the amount of the ligand and the metal catalyst is less.
The invention provides a phosphine oxide compound which is a compound shown as a formula I and/or a compound shown as an ent-I:
Figure BDA0002047585180000021
wherein R is1Is H,
Figure BDA0002047585180000022
C1-10Alkoxy radical, C6-30Aryl, one or more C1-4Alkoxy-substituted C6-30Aryl, C substituted by one or more phenyl groups2～6Or, C2～6A heterocyclic group of (a);
R1aand R1bIndependently is C1-4Alkyl radical, C6-30Aryl, or one or more R1a-1Substituted C6-30An aryl group;
R1a-1independently is C1-4Alkoxy radical, C1-4Alkyl, halogen substituted C1-4Alkyl, amino or hydroxy;
said C is2～6Heterocyclyl and said one or more phenyl-substituted C2～6The heteroatom in heteroaryl of (a) is selected from N, O and S, the number of heteroatoms is independently 1,2 or 3;
R2is C1-10Alkoxy, C substituted by one or more phenyl groups1-10Alkoxy radical, C6-30Aryl, one or more R2-1Substituted C6-30Aryl, phenoxy,
Figure BDA0002047585180000031
C2～6A heterocyclic group of,
Figure BDA0002047585180000032
C1-10Alkyl or
Figure BDA0002047585180000033
The R is2-1Independently is C1-4Alkoxy radical, C1-4Alkyl, halogen substituted C1-4Alkyl, halogen, amino or hydroxy;
R2aand R2bIndependently H, C1-4Alkyl or C6-30An aryl group;
said C2～6The heteroatom in the heterocyclic group of (a) is selected from N, O and S, the number of heteroatoms is 1,2 or 3;
R2cis C1-4Alkyl or amino;
R2dis C1-4An alkyl group;
R3is C1-10Alkyl, one or more R3-1Substituted C1-10Alkyl, halogen, C3-10Cycloalkyl, one or more R3-2Substituted C3-10Cycloalkyl radical, C6-30Aryl, or one or more R3-3Substituted C6-30An aryl group;
R3-1、R3-2and R3-3Independently is C1-4Alkoxy radical, C1-4Alkyl, halogen substituted C1-4Alkyl, halogen, amino or hydroxy;
R4and R5Independently is C1-10Alkyl, one or more R4-1Substituted C1-10Alkyl radical, C3-12Cycloalkyl, one or more R4-2Substituted C3-12Cycloalkyl radical, C6-30Aryl, one or more R4-3Substituted C6-30Aryl, halogen or
Figure BDA0002047585180000034
R4-1、R4-2And R4-3Independently is C1-4Alkoxy radical, C1-4Alkyl, halogen substituted C1-4Alkyl, halogen, amino or hydroxy;
R4aand R4bIndependently is H or C1-4An alkyl group.
When said C is1-4Alkoxy group, said R1a-1The R is2-1The R is3-1The R is3-2The R is3-3The R is4-1And said R4-2When the number of (2) is plural, C1-4Alkoxy group, said R1a-1The R is2-1The R is3-1The R is3-2The R is3-3The R is4-1And said R4-2Independently can be the same or different.
When R is1Is composed of
Figure BDA0002047585180000035
R1aAnd R1bIndependently is C1-4When alkyl, said C1-4The alkyl group is preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a n-butyl group,
Figure BDA0002047585180000036
Or a tert-butyl group, and a methyl group is also preferable.
When R is1Is C1-10At alkoxy, the C1-10Alkoxy is preferably C1-4An alkoxy group. Said C is1-4The alkoxy group is preferably a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, a,
Figure BDA0002047585180000037
Or tert-butoxy, and methoxy is also preferable.
When R is1Is C6-30Aryl is said to C6-30Aryl is preferably C6-20Aryl, may also be preferably C6-14Aryl, more preferably phenyl or anthracenyl (e.g. phenyl
Figure BDA0002047585180000041
)。
When R is1Is one or more than one C1-4Alkoxy-substituted C6-30Aryl is said to C6-30Aryl is preferably C6-20Aryl, may also be preferably C6-14And (4) an aryl group.
When R is1Is one or more than one C1-4Alkoxy-substituted C6-30Aryl is said to C1-4Alkoxy is independently preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,
Figure BDA0002047585180000042
Or tert-butoxy, and methoxy is also preferable.
When R is1Is one or more than one C1-4Alkoxy-substituted C6-30Aryl is said to C1-4Alkoxy-substituted C6-30Aryl is preferably dimethoxyphenyl
Figure BDA0002047585180000043
When R is1C substituted by one or more phenyl groups2～6When said heteroaryl is said C2～6Is preferably C3～5A heteroaryl group.
When R is1C substituted by one or more phenyl groups2～6When said heteroaryl is said C2～6The heteroatom in the heteroaryl group of (a) is preferably N.
When R is1C substituted by one or more phenyl groups2～6When said heteroaryl is said C2～6The number of hetero atoms of the heteroaryl group in (1) is preferred.
When R is1C substituted by one or more phenyl groups2～6In the case of the heteroaryl group of (2), the number of the phenyl group substitution is preferably 2.
When R is1C substituted by one or more phenyl groups2～6In the case of heteroaryl, said phenyl is substituted by C2～6The heteroaryl group of (A) is preferably 2 phenyl-substituted N-containing C3～5And further preferably 2 phenyl-substituted pyrrolyl (e.g. phenyl)
Figure BDA0002047585180000044
)。
When said R is1a-1Independently is C1-4At alkoxy, the C1-4Alkoxy is independently preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,
Figure BDA0002047585180000045
Or tert-butoxy.
When said R is1a-1Independently halogen substituted C1-4In the case of alkyl, the halogen is independently preferably F, Cl, Br or I.
When said R is1a-1Independently halogen substituted C1-4When alkyl, said C1-4Alkyl is independently preferably methyl, ethyl, n-propyl, isopropyl, n-butyl,
Figure BDA0002047585180000046
Or a tert-butyl group.
When R is2Is C1-10At alkoxy, the C1-10Alkoxy is preferably C1-4Alkoxy, more preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,
Figure BDA0002047585180000051
Or a tert-butoxy group, and also preferably a methoxy group, an isopropoxy group or a tert-butoxy group.
When R is2C substituted by one or more phenyl groups1-10At alkoxy, the C1-10Alkoxy is preferably C1-3An alkoxy group. Said C is1-3The alkoxy group may be methoxy, ethoxy, n-propoxy or isopropoxy, and may also be methoxy.
When R is2C substituted by one or more phenyl groups1-10In the case of an alkoxy group, the number of the phenyl substitution is preferably 1.
When R is2C substituted by one or more phenyl groups1-10When alkoxy, said one or more phenyl groups substituted C1-10The alkoxy group is preferably a benzyloxy group.
When R is2Is C6-30Aryl is said to C6-30Aryl is preferably C6-20Aryl, may also be preferably C6-14Aryl, more preferably anthryl
Figure BDA0002047585180000052
When R is2Is one or more R2-1Substituted C6-30Aryl is said to C6-30Aryl is preferably C6-20Aryl, may also be preferably C6-14Aryl, more preferably phenyl.
When R is2Is one or more R2-1Substituted C6-30Aryl radical, said R2-1Is C1-4At alkoxy, the C1-4Alkoxy is independently preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,
Figure BDA0002047585180000053
Or tert-butoxy, and methoxy is also preferable.
When R is2Is one or more R2-1Substituted C6-30When aryl is said to R2-1The number of (b) is preferably 1,2,3 or 4, and may be preferably 2.
When R is2Is one or more R2-1Substituted C6-30When aryl is said to R2-1Substituted C6-30Aryl is preferably C1-4Alkoxy-substituted C6-20Aryl, more preferably 2 methoxy-substituted C6-14Aryl radicals, e.g.
Figure BDA0002047585180000054
When R is2Is composed of
Figure BDA0002047585180000055
R2aAnd R2bIndependently is C1-4When alkyl, said C1-4Alkyl is independently preferably methyl, ethyl, n-propyl, isopropyl, n-butyl,
Figure BDA0002047585180000056
Or a tert-butyl group, and a methyl group is also preferable.
When R is2Is C2～6When it is a heterocyclic group of (B), said C2～6The heterocyclic group of (A) is preferably C2～4The heterocyclic group of (1).
When R is2Is C2～6When it is a heterocyclic group of (B), said C2～6The hetero atom in the heterocyclic group of (3) is preferably O.
When R is2Is C2～6When it is a heterocyclic group of (B), said C2～6The number of hetero atoms in the heterocyclic group of (3) is preferably 1.
When R is2Is C2～6When it is a heterocyclic group of (B), said C2～6Preferred "C" in the heterocyclic group of (1)2～4The hetero atom of (a) is O, and the hetero atom is 1 ".
When R is2Is composed of
Figure BDA0002047585180000061
R2cIs C1-4When alkyl, said C1-4The alkyl group is preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a n-butyl group,
Figure BDA0002047585180000062
Or a tert-butyl group.
When R is2Is C1-10When alkyl, said C1-10The alkyl group is preferably C1-4An alkyl group. Said C is1-4The alkyl group is preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a n-butyl group,
Figure BDA0002047585180000063
Or a tert-butyl group.
When R is3Is C1-10When alkyl, said C1-10The alkyl group is preferably C1-4An alkyl group. Said C is1-4The alkyl group is preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a n-butyl group,
Figure BDA0002047585180000064
Or a tert-butyl group, and a tert-butyl group is also preferable.
When R is3Is R3-1Substituted C1-10When alkyl, said C1-10The alkyl group is preferably C1-4An alkyl group.
When R is3In the case of halogen, the halogen is preferably F, Cl, Br or I.
When R is3Is C3-10When a cycloalkyl group is present, C is3-10Cycloalkyl is preferably C3-6A cycloalkyl group.
When R is3Is R3-2Substituted C3-10When a cycloalkyl group is present, C is3-10Cycloalkyl is preferably C3-6A cycloalkyl group.
When R is3Is C6-30Aryl is said to C6-30Aryl is preferably C6-20Aryl, may also be preferably C6-14And (4) an aryl group.
When R is3Is R3-3Substituted C6-30Aryl is said to C6-30Aryl is preferably C6-20Aryl, may also be preferably C6-14And (4) an aryl group.
When R is4And R5Independently is C3-12When a cycloalkyl group is present, C is3-12Cycloalkyl is preferably C3-10A cycloalkyl group. Said C is3-10The cycloalkyl group may be a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, or an adamantyl group, and may also be an adamantyl group.
When R is4And R5Independently is C1-10When alkyl, said C1-10The alkyl group is preferably C1-4An alkyl group. Said C is1-4The alkyl group is preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a n-butyl group,
Figure BDA0002047585180000065
Or a tert-butyl group, and a tert-butyl group is also preferable.
When R is4And R5Independently is R4-1Substituted C1-10When alkyl, said C1-10The alkyl group is preferably C1-4An alkyl group.
When R is4And R5Independently is R4-2Substituted C3-12When alkyl, said C3-12Radical is preferably C3-10And (4) a base.
When R is4And R5Independently is C6-30Aryl is said to C6-30Aryl is preferably C6-20Aryl, or C6-14And (4) an aryl group.
When R is4And R5Independently is R4-3Substituted C6-30Aryl is said to C6-30Aryl is preferably C6-20Aryl, may also be preferably C6-14And (4) an aryl group.
When R is4And R5Independently halogen, the halogen is preferably F, Cl, Br or I.
In a preferred embodiment of the present invention, the phosphine oxide compound is
Figure BDA0002047585180000071
In a preferred embodiment of the invention, R1Is H,
Figure BDA0002047585180000072
C1-10Alkoxy radical, C6-30Aryl, one or more C1-4Alkoxy-substituted C6-30Aryl, or C substituted by one or more phenyl groups2～6The heteroaryl group of (a).
In a preferred embodiment of the invention, R1Is composed of
Figure BDA0002047585180000073
C1-10Alkoxy, one or more C1-4Alkoxy-substituted C6-30Aryl, or C substituted by one or more phenyl groups2～6The heteroaryl group of (a).
In a preferred embodiment of the invention, R1Is composed of
Figure BDA0002047585180000074
In a preferred embodiment of the invention, when R is1Is composed of
Figure BDA0002047585180000075
When R is in the above-mentioned range1aAnd said R1bIndependently is C1-4Alkyl or C6-30And (4) an aryl group.
In a preferred embodiment of the invention, when R is1Is composed of
Figure BDA0002047585180000076
When R is in the above-mentioned range1aAnd said R1bIndependently is C6-30And (4) an aryl group.
In a preferred embodiment of the invention, when R is1Is composed of
Figure BDA0002047585180000077
When R is in the above-mentioned range1aAnd said R1bThe same is true.
In a preferred embodiment of the invention, when R is1Is composed of
Figure BDA0002047585180000078
When R is in the above-mentioned range1aAnd said R1bIs C6-30And (4) an aryl group.
In a preferred embodiment of the invention, R2Is C1-10Alkoxy, C substituted by one or more phenyl groups1-10Alkoxy radical, C6-30Aryl, one or more R2-1Substituted C6-30Aryl, or, phenoxy.
In a preferred embodiment of the invention, R2Is C1-10Alkoxy, one or more phenylSubstituted C1-10Alkoxy or phenoxy.
In a preferred embodiment of the invention, R2Is C1-10An alkoxy group.
In a preferred embodiment of the invention, R3Is C1-10Alkyl, or one or more R3-1Substituted C1-10An alkyl group.
In a preferred embodiment of the invention, R3Is C1-10An alkyl group.
In a preferred embodiment of the invention, R4And R5Independently is C1-10Alkyl, one or more R4-1Substituted C1-10Alkyl radical, C3-12Cycloalkyl, one or more R4-2Substituted C3-12Cycloalkyl radical, C6-30Aryl, or one or more R4-3Substituted C6-30And (4) an aryl group.
In a preferred embodiment of the invention, R4And R5Independently is C1-10Alkyl, one or more R4-1Substituted C1-10Alkyl radical, C3-12Cycloalkyl, one or more R4-2Substituted C3-12A cycloalkyl group.
In a preferred embodiment of the invention, R4And R5Independently is C3-12Cycloalkyl or C1-10An alkyl group.
In a preferred embodiment of the invention, R4And R5The same is true.
In a preferred embodiment of the invention, R4And R5Is C3-12Cycloalkyl or C1-10An alkyl group.
In a preferred embodiment of the invention, R1Is composed of
Figure BDA0002047585180000081
C1-10Alkoxy, one or more C1-4Alkoxy-substituted C6-30Aryl, or C substituted by one or more phenyl groups2～6The heteroaryl group of (a); the R is1aAnd said R1bIndependent of each otherGround is C1-4Alkyl or C6-30An aryl group;
R2is C1-10Alkoxy, C substituted by one or more phenyl groups1-10Alkoxy or phenoxy;
R3is C1-10An alkyl group;
and, R4And R5Independently is C1-10Alkyl, one or more R4-1Substituted C1-10Alkyl radical, C3-12Cycloalkyl, one or more R4-2Substituted C3-12A cycloalkyl group.
In a preferred embodiment of the invention, R1Is composed of
Figure BDA0002047585180000082
The R is1aAnd said R1bIndependently is C6-30An aryl group;
R2is C1-10An alkoxy group;
R3is C1-10An alkyl group;
and, R4And R5Independently is C3-12Cycloalkyl or C1-10An alkyl group.
In a preferred embodiment of the invention, R1Is composed of
Figure BDA0002047585180000083
The R is1aAnd said R1bIs C6-30An aryl group;
R2is C1-10An alkoxy group;
R3is C1-10An alkyl group;
and, R4And R5Is C3-12Cycloalkyl or C1-10An alkyl group.
The phosphine oxide compound is optionally any one of the following compounds:
Figure BDA0002047585180000091
the invention also provides a preparation method of the phosphine oxide compound, which comprises the following steps: in an organic solvent, carrying out reduction reaction of a compound II and a reducing agent as shown in the following formula to obtain the phosphine oxide compound;
Figure BDA0002047585180000092
wherein, the product corresponding to the compound II is a compound I; when the compound II is
Figure BDA0002047585180000093
Then, the product corresponding to the compound ent-II is the compound ent-I.
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 amount of the reducing agent can be a conventional amount, and preferably the molar ratio of the reducing agent to the compound II is 1-10, such as 5.
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. The acid-binding agent can be used in a conventional amount, for example, the molar ratio of the acid-binding agent to the compound II is 10.
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 can be the conventional temperature of the reaction in the field, preferably 60-90 ℃, for example 80 ℃.
The method for monitoring the progress of the reduction reaction in the reduction reaction may be a method which is conventionally used in the art (for example, a method for monitoring the progress of the reduction reaction in the prior art)31P-NMR), compound II is generally absent or not at the end of the reaction. The time of the reduction reaction is preferably 6 to 24 hours, for example 8 hours.
After the reduction reaction is finished, the method also comprises the following post-treatment steps: the reaction solution after the completion of the reaction is cooled to room temperature, adjusted to neutral (adjusted with an alkaline reagent, for example, 30% aqueous sodium hydroxide solution), extracted (ethyl acetate is preferable as an extraction solvent), dried, concentrated, and subjected to column chromatography (for example, neutral alumina is used as a packing; and petroleum ether-ethyl acetate (20:1 to 10:1, for example, 15:1) is used as an eluent).
The invention also provides a phosphine oxide compound which is a compound shown as a formula II and/or a compound shown as an ent-II:
Figure BDA0002047585180000101
wherein R is1、R2、R3、R4And R5The definitions of (A) and (B) are as described above.
The phosphine oxide compound intermediate is preferably any one of the following compounds:
Figure BDA0002047585180000111
the invention also provides a preparation method of the phosphine oxide intermediate, which comprises the following steps:
in the presence of an alkaline reagent, carrying out a reaction of a compound III and a compound A in an organic solvent according to the following formula to obtain a compound II;
Figure BDA0002047585180000112
wherein X is halogen.
In formula III, when X is a halogen, the halogen is Cl, Br or I, for example Cl.
In the reaction, the basic agent may be a basic agent conventional in the art, preferably one or more of Lithium Diisopropylamide (LDA), lithium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, and sodium bis (trimethylsilyl) amide and 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 1.5.
In the reaction, the organic solvent may be an organic solvent conventional in the art such a reaction, preferably one or more of an aromatic hydrocarbon solvent (e.g., toluene), an ether solvent (e.g., tetrahydrofuran, dioxane, diethyl ether) and a halogenated hydrocarbon solvent (e.g., dichloromethane), more preferably an ether solvent. The amount of the organic solvent to be used is not particularly limited as long as the reaction is not affected.
In the reaction, the molar ratio of the compound a to the compound III may be a ratio conventional in such reactions in the art, preferably 1 to 5.0, for example 1.5.
In the reaction, the temperature of the reaction may be a temperature conventional in the art. For example, an alkaline reagent is dripped at a low temperature (-78 ℃), heat preservation is carried out for 1 hour after dripping is finished, and the reaction is carried out at a temperature of 70-80 ℃.
The compound III is preferably
Figure BDA0002047585180000121
Figure BDA0002047585180000122
The compound A is preferably bis (1-adamantyl) phosphorus chloride, bis (1-tert-butyl) phosphorus chloride or bis (1-cyclohexyl) phosphorus chloride.
The progress of the reaction can be monitored by monitoring methods conventional in the art (e.g., TIC, HPLC, LC-MS), typically with disappearance or absence of compound III as the end point of the reaction. The time of 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: after the reaction is completed, the reaction solution is cooled, quenched (a quenching reagent such as saturated ammonium chloride), extracted (an extraction solvent such as ethyl acetate), washed with water (washed with saturated saline water), dried, concentrated and subjected to column chromatography (the eluent is preferably petroleum ether-ethyl acetate (in a volume ratio of 1:1 to 5:1, for example, 2: 1)).
The invention also provides an application of the phosphine oxide compound as a metal ligand in the Suzuki-Miyaura coupling reaction as shown in the formula;
Figure BDA0002047585180000131
wherein, formula C
Figure BDA0002047585180000132
To represent
Figure BDA0002047585180000133
X is halogen;
R6is C1-10Alkyl radical, C6-30Aryl, or one or more R6-1Substituted C1-10An alkyl group;
R6-1independently is C6-20Aryl, or, one or more C1-4Alkoxy-substituted C6-20An aryl group;
R7is C1-10Alkyl, or, one or more C6-20Aryl substituted C1-10An alkyl group;
y represents
Figure BDA0002047585180000134
A1Is C-R8aOr N; a. the2Is C-R8bOr N; a. the3Is C-R8cOr N; a. the4Is C-R8dOr N; a. the5Is C-R8eOr N; a. the1、A2、A3、A4And A5Up to 2 nitrogen atoms;
the R is8a、R8b、R8c、R8dAnd R8eIndependently H, C1-4Alkyl, halogen substituted C1-4Alkyl radical, C1-4Alkoxy radical, C6-20Aryl, phenoxy, benzyloxy, methylthio, methyl ethyl methyl phenyl,
Figure BDA0002047585180000135
Or halogen; r9aAnd R9bIndependently is phenyl or C1-4An alkyl group; r10Is C1-4An alkyl group;
or, R8a、R8b、R8c、R8dAnd R8eAny two adjacent groups in (a) together with the atoms to which they are attached form C6-20Aryl radical, C1-4Alkoxy-substituted C6-20Aryl radical, C3-10Heteroaryl or C2-6A heterocyclic group;
said C3-10Heteroaryl and said C3-6The heteroatoms in the heterocycle are independently selected from N and O, and the number of heteroatoms is 1,2 or 3.
The use of, in formula C, the R6-1The C is1-4Alkoxy and said C6-20The number of aryl groups is independently 1 or more; the R is6-1The C is1-4Alkoxy and said C6-20When the number of aryl groups is independently plural, R is6-1The C is1-4Alkoxy and said C6-20The aryl groups may be the same or different.
In the formula C, when R is6Is C1-10When alkyl, said C1-10The alkyl group is preferably C1-4Alkyl groups, such as tert-butyl.
In the formula C, when R is6Is C6-30Aryl is said to C6-30Aryl is preferably C6-14Aryl radicals, for example phenyl.
In the context of the above-mentioned application,in the formula C, when R6Is R6-1Substituted C1-10When it is alkyl, said R6-1Substituted C1-10C in alkyl1-10The alkyl group is preferably C1-3Alkyl groups, such as methyl.
In the formula C, when R is6Is R6-1Substituted C1-10When it is alkyl, said R6-1The number of (b) is preferably 1 or 2, more preferably 2.
In the formula C, when R is6Is R6-1Substituted C1-10Alkyl radical, each R6-1Independently is C6-20Aryl is said to C6-20Aryl is preferably C6-14Aryl radicals, for example phenyl.
In the formula C, when R is6Is R6-1Substituted C1-10Alkyl radical, each R6-1Independently is C1-4Alkoxy-substituted C6-20Aryl is said to C1-4Alkoxy-substituted C6-20C in aryl6-20Aryl is preferably C6-14Aryl radicals, for example phenyl.
In the formula C, when R is6Is R6-1Substituted C1-10Alkyl radical, each R6-1Independently is C1-4Alkoxy-substituted C6-20Aryl is said to C1-4The number of alkoxy substitutions is preferably 1 or 2, for example 2.
In the formula C, when R is6Is R6-1Substituted C1-10Alkyl radical, each R6-1Independently is C1-4Alkoxy-substituted C6-20Aryl is said to C1-4Alkoxy-substituted C6-20Aryl is preferably methoxy-substituted C6-14Aryl, more preferably methoxy-substituted phenyl, e.g.
Figure BDA0002047585180000141
In the formula C, when R is7Is C1-10When alkyl, said C1-10Alkyl is preferably C1-4Alkyl radicals, e.g. methyl, ethyl, isoPropyl or n-propyl.
In the formula C, when R is7Is C6-20Aryl substituted C1-10When alkyl, said C6-20Aryl substituted C1-10C in alkyl1-10Alkyl is preferably C1-3Alkyl groups, such as ethyl.
In the formula C, when R is7Is C6-20Aryl substituted C1-10When alkyl, said C6-20Aryl substituted C1-10C in alkyl6-20Aryl is preferably C6-14Aryl radicals, for example phenyl.
In the formula C, when R is7Is C6-20Aryl substituted C1-10When alkyl, said C6-20Aryl substituted C1-10Alkyl is preferably C6-14Aryl substituted C1-3Alkyl radicals, e.g.
Figure BDA0002047585180000142
The use, formula D, wherein when R is8a、R8b、R8c、R8dAnd R8eIndependently is C1-4When alkyl, said C1-4The alkyl group is preferably a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl group, for example a methyl or isopropyl group.
The use, formula D, wherein when R is8a、R8b、R8c、R8dAnd R8eIndependently halogen substituted C1-4In the case of alkyl, the halogen is preferably F, Cl, Br or I, for example F.
The use, formula D, wherein when R is8a、R8b、R8c、R8dAnd R8eIndependently halogen substituted C1-4When alkyl, said C1-4Alkyl is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, for example methyl.
The use, formula D, wherein when R is8a、R8b、R8c、R8dAnd R8eIndependently is C1-4At alkoxy, the C1-4Alkoxy is preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy, for example methoxy.
The use, formula D, wherein when R is8a、R8b、R8c、R8dAnd R8eIndependently C6-20Aryl is said to C6-20Aryl is preferably C6-14Aryl radicals, for example phenyl.
The use, formula D, wherein when R is8a、R8b、R8c、R8dAnd R8eIndependently is
Figure BDA0002047585180000151
R10Is C1-4When alkyl, said C1-4Alkyl is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, for example ethyl.
The use, formula D, wherein when R is8a、R8b、R8c、R8dAnd R8eIndependently halogen, the halogen is preferably F, Cl, Br or I, for example F or Cl.
In the formula D, when R is8a、R8b、R8c、R8dAnd R8eAny two adjacent groups in (a) together with the atoms to which they are attached form C6-20Aryl is said to C6-20Aryl is preferably C6-14Aryl, for example naphthyl.
In the formula D, when R is8a、R8b、R8c、R8dAnd R8eAny two adjacent groups in (a) together with the atoms to which they are attached form C3-10When it is heteroaryl, said C3-10Heteroaryl is preferably "C3-5Heteroaryl with hetero atoms being O', e.g. furyl
Figure BDA0002047585180000152
In the formula D, when R is8a、R8b、R8c、R8dAnd R8eAny two adjacent groups in (a) together with the atoms to which they are attached form C2-6When it is heterocyclic, said C2-6The heterocyclic group is preferably "C2-4Heterocyclyl, hetero atoms being O', e.g.
Figure BDA0002047585180000153
In a preferred embodiment of the invention, said use, of formula C, wherein R6Is R6-1Substituted C1-10An alkyl group; each R6-1Independently is C1-4Alkoxy-substituted C6-20And (4) an aryl group.
In a preferred embodiment of the invention, said use is where said compound E has an ee value of preferably > 70%, more preferably > 90%, e.g. 81%, 94%.
The application also preferably comprises a preparation method of the compound;
a process for the preparation of said compound E, comprising the steps of: and (2) carrying out Suzuki-Miyaura coupling reaction on the compound C and the compound D in a solvent in the presence of a palladium catalyst, the compound I and an alkaline reagent to obtain a compound E.
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 preferably palladium acetate.
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 0.01.
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 0.012.
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 (e.g. potassium carbonate), an alkali metal fluoride (potassium fluoride) and an alkali metal phosphate.
In the Suzuki-Miyaura coupling reaction, the molar ratio of the basic reagent to the compound C is preferably 1-5, such as 2.
In the Suzuki-Miyaura coupling reaction, the molar ratio of the compound D to the compound C is preferably 1-4, such as 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 an organic solvent. 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.
In the Suzuki-Miyaura coupling reaction, the reaction temperature is preferably 40-80 ℃, and more preferably 60 ℃.
The compound C is preferably any one of the following compounds:
Figure BDA0002047585180000161
the compound D is preferably any one of the following compounds:
Figure BDA0002047585180000171
in the Suzuki-Miyaura coupling reaction, the progress of the reaction can be monitored by monitoring methods conventional in the art (e.g., TIC, HPLC, LC-MS), and the disappearance of compound C or the absence of compound C as the end point of the reaction is generally used. The reaction time is preferably 24 to 60 hours, more preferably 48 hours.
The invention also provides an application of the compound shown in the formula I as a metal ligand in preparing the alpha-aryl alkyl carboxylic acid compound shown in the formula F:
Figure BDA0002047585180000172
wherein, formula C, Y, R6、R7And M are as defined in claim 12.
The invention also provides a compound shown as the formula E:
Figure BDA0002047585180000181
wherein, formula C, Y, R6And R7Are as defined in claim 12.
The compound shown in the formula E is preferably any one of the following compounds:
Figure BDA0002047585180000182
the inventor has found through long-lasting and intensive research that the chiral phosphine ligand of the invention can synthesize a series of alpha-aryl amide compounds with better yield and higher enantioselectivity in asymmetric Suzuki-Miyaura coupling reaction, and has high substrate compatibility (compatibility with halogen, trifluoromethyl, methylthio, ester group and the like) for different functional groups and mild reaction conditions (no need of high temperature or strong alkali). At present, metal nickel, iron and cobalt are adopted to catalyze asymmetric Negishi and Kumada coupling of an alpha-bromocarbonyl compound, and the catalyst has large equivalent, harsh reaction conditions, poor substrate universality, complex operation and the like, and has poor practicability.
The alpha-aryl amide compounds can be hydrolyzed to obtain alpha-aryl carboxylic acid compounds (such as ibuprofen, naproxen or flurbiprofen) with pharmaceutical activity. Under the action of the bidentate phosphine-phosphine oxide ligand, the compound is synthesized with high yield and/or high enantioselectivity, and the catalyst used is low in equivalent weight, mild in reaction condition, excellent in functional group and substrate universality and strong in economical and practical performance. The present invention has been completed based on this finding.
In the present invention, "Ad" is an abbreviation for adamantane.
In the present invention, the term "compound" may exist as a single stereoisomer or as a mixture thereof (e.g., as a racemate, for example, as a mixture of unequal amounts of enantiomers) if a stereoisomer exists. The term "stereoisomer" refers to either a cis-trans isomer or an optical isomer. The stereoisomers can be separated, purified and enriched by an asymmetric synthesis method or a chiral separation method (including but not limited to thin layer chromatography, rotary chromatography, column chromatography, gas chromatography, high pressure liquid chromatography and the like), and can also be obtained by chiral resolution in a mode of forming bonds (chemical bonding and the like) or salifying (physical bonding and the like) with other chiral compounds and the like. The term "single stereoisomer" means that the compound contains no less than 90% by weight of a stereoisomer. Typical single stereoisomers are for example L-glutamic acid with a purity of more than 98.5%.
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 atoms1～10Alkyl 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 "benzyloxy" both refer to an alkyl or benzyl 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), and may be of a fused, spiro and bridged (e.g., adamantyl) structure. 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 herein) 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 parts of 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 bidentate phosphine-phosphine oxide ligand is used as a metal ligand in Suzuki-Miyaura coupling reaction, the generation of a self-coupled byproduct is avoided, and the alpha-aryl carbonyl compound is obtained (the yield can reach 80%); the bidentate phosphine-phosphine oxide ligand with a single configuration is used as a metal ligand in Suzuki-Miyaura coupling reaction, and the alpha-aryl carbonyl compound with a single configuration (ee value is as high as 94 percent) can be obtained at high selectivity; and the dosage of the ligand and the metal catalyst is lower.
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 Synthesis route to chiral ligand I-1
Figure BDA0002047585180000201
S1 preparation of (R) -3-tert-butyl-4-methoxy-2, 3-dihydrobenzo [ d ] [1,3] oxo, phospho-penta-3-oxo-6-trifluoromethanesulfonate (b):
taking a Schlenk tube, adding a stirrer for drying, adding a compound a (1.8g,7mmol,1equiv), adding triethylamine (1.95mL,14mmol,2equiv), adding dichloromethane for dissolving, reducing the reaction system to 0 ℃, taking another single-port bottle, adding N-phenyl bis (trifluoromethanesulfonyl) imide (3g,8.4mmol,1.2equiv), dissolving with dichloromethane, transferring the solution into a Schlenk tube, after the transfer is finished, heating the reaction system to room temperature for reaction for 3 hours, detecting the reaction progress by TLC (thin layer chromatography), and after the reaction is finished, concentrating to be thickAnd (4) performing column chromatography to obtain a white solid compound b (2.4g, 88% yield).1H NMR(500MHz,CDCl3)δ6.49(t,J＝1.9Hz,1H),6.37(dd,J＝3.2,1.8Hz,1H),4.57(dd,J＝14.0,2.8Hz,1H),4.47(dd,J＝14.0,10.6Hz,1H),3.90(s,2H),1.26(d,J＝16.7Hz,7H)；13C NMR(125MHz,CDCl3)δ167.3(d,J＝17.7Hz),162.0(d,J＝2.8Hz),155.2(d,J＝2.1Hz),118.7(q,J＝320.9Hz),103.2(d,J＝90.5Hz),100.2(d,J＝5.5Hz),97.8(d,J＝5.9Hz),67.3(d,J＝58.6Hz),56.4,33.9(d,J＝74.1Hz),26.6,26.6；19F NMR(376MHz,CDCl3)δ-72.7(s)；31P NMR(162MHz,CDCl3)δ62.4(s)；ESI-MS:m/z 389.0[M+H]+(ii) a HRMS (ESI) calculated as [ M + H, C13H17F3O6PS]+389.0432; tested 389.0430.
S2 preparation of (R) -3-tert-butyl-4-hydroxy-2, 3-dihydrobenzo [ d ] [1,3] oxo, phospho-pentan-3-oxo-6-trifluoromethanesulfonate (c):
taking a Schlenk tube, adding a stirrer to dry, adding a compound b (3.06g,7.9mmol,1equiv), dissolving with dichloroethane, cooling a reaction system to 0 ℃, adding boron tribromide (2.3mL,23.7mmol,3equiv), after dropwise addition, heating to 60 ℃, and reacting for 48 hours; TLC tracks the progress of the reaction to the end, the reaction system is cooled to 0 ℃, water is slowly added to quench the reaction, layers are separated, methylene chloride is used for extracting a water phase, an organic phase is combined, anhydrous sodium sulfate is used for drying, filtration, concentration and column chromatography are carried out, and a white solid compound c (2.42g, 82% yield) is obtained.1H NMR(500MHz,CDCl3)δ11.26(s,1H),6.46(dd,J＝3.1,1.9Hz,1H),6.26(t,J＝2.2Hz,1H),4.58(dd,J＝14.1,3.2Hz,1H),4.46(dd,J＝14.1,10.8Hz,1H),1.30(d,J＝17.0Hz,9H)；13C NMR(125MHz,CDCl3)δ167.2(d,J＝18.5Hz),161.6(d,J＝3.1Hz),155.4(d,J＝2.2Hz),118.7(q,J＝320.8Hz),102.8(d,J＝6.4Hz),100.6(d,J＝93.9Hz),97.6(d,J＝5.7Hz),66.8(d,J＝61.1Hz),33.7(d,J＝73.9Hz),24.6(d,J＝0.9Hz)；19F NMR(376MHz,CDCl3)δ-73.0(s)；31P NMR(162MHz,CDCl3)δ67.0(s)；ESI-MS:m/z 375.05[M+H]+,397.05[M+Na]+(ii) a HRMS (ESI) calculated as [ M + H, C12H15F3O6PS]+375.0278; tested 375.0274.
Preparation of (R) -3-tert-butyl-6-diphenylamino-4-hydroxy-2, 3-dihydrobenzo [ d ] [1,3] oxy, phospho-pentan-3-oxy (d):
adding a stirrer into a three-neck flask, drying, and adding compound c (9.9g,26.5mmol,1equiv), diphenylamine (6.73g,39.8mmol,1.5equiv), Pd into the reaction tube2(dba)3(1.94g,2.12mmol,8 mol%), XPhos (2g,4.24mmol,16 mol%), cesium carbonate (13g,39.5mmol,1.5equiv), purging nitrogen three times, redistilled xylene (150mL), reacting at 110 ℃ for 12 hours, monitoring the progress of the reaction by TLC, after the reaction is finished, cooling the reaction system to room temperature, after xylene is drained, adding water and dichloromethane, extracting the aqueous phase with dichloromethane, combining the organic phases, washing with sodium chloride aqueous solution three times, drying with anhydrous sodium sulfate, filtering, and concentrating; column chromatography gave compound d (7.8g, 75% yield) as a pale yellow solid.1H NMR(500MHz,CH3OD)δ7.39～7.30(m,4H),7.20～7.13(m,6H),6.00～5.97(m,1H),5.85～5.80(m,1H),4.66(dd,J＝14.2,3.1Hz,1H),4.23(dd,J＝14.2,10.5Hz,1H),1.28(d,J＝16.5Hz,9H)；13C NMR(151MHz,CH3OD)δ169.6(d,J＝18.1Hz),161.4(d,J＝2.9Hz),157.6,147.7,130.7,127.9,126.3,100.4(d,J＝6.3Hz),95.9(d,J＝5.5Hz),93.1(d,J＝102.2Hz),67.4(d,J＝61.0Hz),34.3(d,J＝76.0Hz),24.9；31P NMR(162MHz,CH3OD)δ67.1(s)；ESI-MS:m/z 394.15[M+H]+(ii) a HRMS (ESI) calculated as [ M + H, C23H25NO3P]+394.1568; tested 394.1567.
S4 preparation of (R) -3-tert-butyl-6- (diphenylamino) -4-isopropoxy-2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-penta-n-yl-3-oxy (III-1):
taking a Schlenk tube, adding a stirrer to dry, adding a compound d (275mg,0.70mmol,1equiv), potassium carbonate (284mg,2.10mmol,3equiv), pumping nitrogen for three times, adding DMF to dissolve, adding iodoisopropane (0.14mL,1.4mmol,2equiv) to the reaction system, reacting at room temperature for 3 hours, removing a large amount of DMF by using a pump, adding water and ethyl acetate to separate liquid, washing the organic phase with water for multiple times, ensuring that the mixture will be driedDMF in the system was removed completely, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography to give compound III-1(298mg, 95% yield) as a white solid.1H NMR(500MHz,CDCl3)δ7.33～7.27(m,4H),7.16～7.07(m,6H),6.04～5.97(m,2H),4.49～4.40(m,1H),4.38～4.30(m,2H),1.33～1.22(m,15H)；13C NMR(125MHz,CDCl3)δ168.1(d,J＝17.4Hz),159.7,155.6,146.5,129.4,126.1,124.6,97.9(dd,J＝138.5,5.3Hz),70.5,66.7(d,J＝59.4Hz),33.6(d,J＝74.5Hz),25.0,21.7,21.7；31P NMR(162MHz,CDCl3)δ62.2(s)；ESI-MS:m/z 436.25[M+H]+(ii) a HRMS (ESI) calculated as [ M + H, C26H31NO3P]+436.2040; tested 436.2036.
Preparation of (2R,3R) -3-tert-butyl-2- (bis ((3R) -1-adamantyl) phosphoryl) -6- (diphenylamino) -4-isopropoxy-2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-penta-yoke-3-oxy (II-1) S5:
taking a Schlenk tube, adding a stirrer for drying, adding the compound III-1(1g,2.3mmol,1equiv), drawing nitrogen for three times, adding a redistilled tetrahydrofuran solution, reducing the temperature of the reaction system to-78 ℃, slowly adding an LDA solution (1.8mL,3.45mmol,1.5equiv), and maintaining the temperature for 1 hour; bis (1-adamantyl) phosphonium chloride (1.2g,3.45mmol,1.5equiv) was added to the reaction and directly warmed to 70 ℃; reacting overnight; detecting the reaction progress by TLC, slowly dropwise adding hydrogen peroxide at 0 ℃ after the reaction is finished, and heating to room temperature for reacting for 1 hour; adding sodium thiosulfate solution at 0 ℃ for quenching redundant hydrogen peroxide, adding ethyl acetate for extraction, combining organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, concentrating, and performing column chromatography separation to obtain a white solid compound II-1(1g, 59% yield).1H NMR(500MHz,CDCl3)δ7.33～7.28(m,4H),7.16～7.09(m,6H),6.09～6.06(m,1H),6.05～6.03(m,1H),4.89(dd,J＝8.6,2.3Hz,1H),4.36～4.29(m,1H),2.29～2.18(m,6H),2.15～2.08(m,6H),2.05～1.94(m,6H),1.79～1.64(m,12H),1.38(d,J＝16.5Hz,9H),1.29(d,J＝6.1Hz,3H),1.22(d,J＝6.0Hz,3H)；13C NMR(125MHz,CDCl3)δ166.3(d,J＝6.2Hz),166.0(d,J＝6.6Hz),159.7(d,J＝2.9Hz),155.2,146.7,129.6,126.1,124.6,99.6(d,J＝5.9Hz),97.3(d,J＝4.9Hz),71.2～70.5(m),70.8,42.1(dd,J＝55.6,2.9Hz),41.6(d,J＝57.6Hz),36.9,36.8,36.7,36.5,34.7(d,J＝78.2Hz),28.1,28.0,28.0,27.9,26.6,22.1,21.6；31P NMR(162MHz,CDCl3)δ61.3(d,J＝7.6Hz),51.1(d,J＝5.1Hz)；ESI-MS:m/z 752.40[M+H]+(ii) a HRMS (ESI) calculated as [ M + H, C46H60NO4P2]+752.3992; tested 752.3992.
S6. preparation of bis ((3S) -1-adamantyl) ((2S,3S) -3-tert-butyl-6-dianilino-4-isopropoxy-2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-pentan-2-) phosphine oxide (I-1):
taking a Schlenk tube, adding a stirrer to dry, adding a compound 3-52(1g,1.33mmol,1equiv), pumping nitrogen for three times, adding a redistilled toluene solution to dissolve, adding a redistilled triethylamine (1.85mL,13.3mmol,10equiv), reducing the temperature of a reaction system to 0 ℃, slowly adding trichlorosilane (0.67mL,6.65mmol,5equiv), raising the temperature to 80 ℃ and reacting for 8 hours;31P-NMR (nuclear magnetic resonance) monitors the reaction to the end, the reaction temperature is reduced to 0 ℃, 30% sodium hydroxide aqueous solution after oxygen removal is slowly added to quench the reaction, a large amount of bubbles are generated in the system, ethyl acetate after oxygen removal is added to extract after the quenching is finished, anhydrous sodium sulfate is dried, the mixture is concentrated by a vacuum pump, and neutral alumina is used for purifying to obtain a white solid I-1(720mg, 74% yield), and all the operations are carried out under the protection of nitrogen. [ alpha ] to]D 25:55.2°(c＝0.80,CHCl3).1H NMR(500MHz,CDCl3)δ7.27～7.22(m,5H),7.12～7.01(m,5H),6.23～6.12(m,2H),5.52(dd,J＝6.7,3.3Hz,1H),4.43～4.34(m,1H),2.27～2.20(m,3H),2.18～.96(m,12H),1.90～1.83(m,3H),1.82～1.72(m,6H),1.70～1.60(m,6H),1.22(d,J＝6.0Hz,3H),1.15(d,J＝6.0Hz,3H),1.06(d,J＝12.3Hz,9H)；13C NMR(125MHz,CDCl3)δ165.8(d,J＝1.6Hz),160.2(d,J＝13.4Hz),152.0,147.6,129.3,124.8,123.3,106.4(d,J＝14.8Hz),102.9(d,J＝1.6Hz),99.8,79.1(dd,J＝61.6,46.5Hz),70.4,41.8,41.4,41.0,37.0,37.0,36.8,36.8,33.3(dd,J＝25.2,7.4Hz),28.1,28.0,28.0,27.3,27.2,22.0,21.6；31P NMR(162MHz,CDCl3)δ49.1(d,J＝38.7Hz),1.5(d,J＝38.1Hz)；ESI-MS:m/z 736.65[M+H]+(ii) a HRMS (ESI) calculated as [ M + Na, C46H59NNaO3P2]+758.3870; tested 758.3862.
According to the results of previous studies by the inventors (J.Am.chem.Soc.2014,136, 570-573; org.Lett.2012,14, 2258-:
Figure BDA0002047585180000231
the middle 'phosphorus oxygen five-membered ring C' is subjected to hydrogen extraction by strong base such as Lithium Diisopropylamide (LDA), and then reacts with an electrophilic reagent to generate the compound
Figure BDA0002047585180000232
The compound of (1). Through detection, in the compounds with the structure, the substituent M on the phosphorus oxygen five-membered ring and the substituent N on the P atom are positioned on two sides of a plane formed by nitrogen, carbon and oxygen, and the reaction is as follows:
Figure BDA0002047585180000233
therefore, the steric configuration of the product can be deduced according to the research result only after the steric configuration of the substituent N on the P atom in the raw material a is determined. The raw materials in the example are
Figure BDA0002047585180000241
As a result of previous studies by the inventors, it is presumed that the configuration of the present embodiment is
Figure BDA0002047585180000242
Example 2 preparation of bis-tert-butyl ((2S,3S) -3-tert-butyl-6-dianilino-4-isopropyl-2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-penta-2-) phosphine oxide (I-2):
Figure BDA0002047585180000243
bis-tert-butyl ((2S,3S) -3-tert-butyl-6-dianilino-4-isopropyl-2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-penta-n-2-) phosphine oxide (I-2) was prepared by the preparation method of reference example 1.
[α]D 25:62.7°(c＝0.82,CHCl3).1H NMR(500MHz,CDCl3)δ7.29～7.23(m,4H),7.13～7.00(m,6H),6.13～6.08(m,2H),5.43(dd,J＝7.3,3.3Hz,1H),4.39～4.29(m,1H),1.37(d,J＝13.1Hz,9H),1.24～1.17(m,15H),1.05(d,J＝12.3Hz,9H)；13C NMR(125MHz,CDCl3)δ165.61(d,J＝2.0Hz),160.12(d,J＝13.3Hz),152.0,147.5,129.3,125.1,123.5,105.33(dd,J＝15.4,1.7Hz),101.74(d,J＝2.0Hz),98.8,80.77(dd,J＝62.1,46.5Hz),70.3,36.93(dd,J＝7.5,1.1Hz),36.50(dd,J＝7.4,1.1Hz),33.18(dd,J＝25.5,7.7Hz),27.4,27.4,27.2,27.1,27.1,21.9,21.9；31P NMR(162MHz,CDCl3)δ56.7(d,J＝38.6Hz),1.6(d,J＝38.9Hz)；ESI-MS:m/z 580.35[M+H]+(ii) a HRMS (ESI) calculated as [ M + H, C34H48NO3P2]+580.3108; tested 580.3104.
Example 3 preparation of bis-tert-butyl ((2S,3S) -3-tert-butyl-6-dimethylamino-4-methoxy-2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-pentan-2-) phosphine oxide (I-3):
Figure BDA0002047585180000244
bis-tert-butyl ((2S,3S) -3-tert-butyl-6-dimethylamino-4-methoxy-2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-penta-n-2-) phosphine oxide (I-3) was prepared by the preparation method of reference example 1.
[α]D 25:101.2°(c＝1.00,CHCl3).1H NMR(500MHz,CDCl3)δ5.95～5.75(m,2H),5.41(dd,J＝8.0,3.5Hz,1H),3.81(s,3H),2.97(s,6H),1.41(d,J＝13.0Hz,9H),1.21(d,J＝13.5Hz,9H),0.99(d,J＝12.3Hz,9H)；13C NMR(125MHz,CDCl3)δ166.1(d,J＝2.0Hz),162.2,162.1,97.1,88.9,88.2,80.8(dd,J＝62.5,46.9Hz),55.2,36.8(d,J＝1.7Hz),36.3(d,J＝1.6Hz),27.4,27.3,27.1,26.8,26.7；31P NMR(162MHz,CDCl3)δ57.1(d,J＝39.3Hz),1.6(d,J＝39.3Hz)；ESI-MS:m/z 428.25[M+H]+(ii) a HRMS (ESI) calculated as [ M + H, C22H40O3P2]+428.2480; tested 428.2478.
Example 4 preparation of ((2S,3S) -4-tert-butoxy-3-tert-butyl-2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-pentan-2-) bis-tert-butylphosphine oxide (I-4):
Figure BDA0002047585180000251
((2S,3S) -4-tert-butoxy-3-tert-butyl-2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-pentan-2-) bis-tert-butylphosphine oxide (I-4) was prepared by the preparation method of reference example 1.
[α]D 19:39.2°(c＝0.46,CHCl3).1H NMR(500MHz,CDCl3)δ7.31(t,J＝7.7Hz,2H),7.17(t,J＝8.1Hz,1H),7.09(t,J＝7.4Hz,1H),6.96(d,J＝8.5Hz,2H),6.60(d,J＝8.1Hz,1H),6.44(dd,J＝8.1,3.6Hz,1H),5.51(dd,J＝7.4,3.3Hz,1H),5.51(dd,J＝7.4,3.3Hz,1H),1.43(d,J＝13.2Hz,9H),1.22(d,J＝13.6Hz,9H),1.08(d,J＝12.6Hz,9H)；13C NMR(125MHz,CDCl3)δ164.4(d,J＝2.0Hz),158.6(d,J＝13.4Hz),131.4,118.0(d,J＝17.4Hz),114.8(d,J＝1.7Hz),105.7,80.6,79.7(dd,J＝63.0,46.8Hz),36.7(dd,J＝10.2,0.6Hz),36.3(dd,J＝10.3,0.6Hz),33.5(dd,J＝24.9,7.6Hz),29.3(d,J＝1.9Hz),27.2,27.1(d,J＝11.0Hz),26.9；31P NMR(162MHz,CDCl3)δ58.4(d,J＝40.3Hz),6.1(d,J＝40.3Hz)；ESI-MS:m/z 427.30[M+H]+,449.30[M+Na]+(ii) a HRMS (ESI) calculated as [ M + H, C23H41O3P2]+427.2527; tested 427.2525.
Example 5 preparation of ((2S,3S) -4- (9-anthracenyl) -3-tert-butyl-2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-pentan-2-) bis-tert-butylphosphine oxide (I-5):
Figure BDA0002047585180000252
((2S,3S) -3-tert-butyl-4- (9-anthryl) -2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-pentan-2-) bis-tert-butylphosphine oxide (I-5) was prepared by the preparation method of reference example 1.
[α]D 20:21.1°(c＝0.47,CHCl3).1H NMR(500MHz,CDCl3)δ8.47(s,1H),8.01(d,J＝8.4Hz,2H),7.81(d,J＝8.7Hz,1H),7.63(d,J＝8.7Hz,1H),7.49～7.41(m,3H),7.41～7.36(m,1H),7.34～7.29(m,1H),7.06(dd,J＝7.2,3.1Hz,1H),7.02(d,J＝8.1Hz,1H),5.46(dd,J＝7.0,2.7Hz,1H),1.46(d,J＝13.1Hz,9H),1.39(d,J＝13.5Hz,9H),0.37(d,J＝12.4Hz,9H)；13C NMR(125MHz,CDCl3)δ164.2(d,J＝2.3Hz),142.4(d,J＝17.2Hz),136.0,131.5,131.4,131.1,131.0,128.9,128.8,128.4,127.4,127.2(d,J＝3.0Hz),126.8,125.8,125.8,125.8,125.7(d,J＝2.4Hz),125.6,125.5(d,J＝2.4Hz),125.0,110.7,79.8(dd,J＝63.2,47.7Hz),37.0(dd,J＝4.5,1.4Hz),36.5(dd,J＝4.5,1.2Hz),32.5(dd,J＝26.7,7.2Hz),27.7,27.6,27.1,26.8,26.6(d,J＝15.5Hz)；31P NMR(162MHz,CDCl3)δ57.2(d,J＝42.5Hz),8.6(d,J＝42.7Hz)；ESI-MS:m/z 531.35[M+H]+,553.25[M+Na]+(ii) a HRMS (ESI) calculated as [ M + H, C33H41O2P2]+531.2577; 531.2576 is detected; [ M + Na, C ]33H40NaO2P2]+553.2400; tested 553.2396.
EXAMPLE 6 preparation of bis-tert-butyl ((2S,3S) -3-tert-butyl-4- (2, 6-dimethoxyphenyl) -2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-pentan-2-) phosphine oxide (I-6):
Figure BDA0002047585180000261
bis-tert-butyl ((2S,3S) -3-tert-butyl-4- (2, 6-dimethoxyphenyl) -2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-penta-n-2-) phosphine oxide (I-6) was prepared by the preparation method of reference example 1.
[α]D 21:63.2°(c＝0.52,CHCl3).1H NMR(500MHz,CDCl3)δ7.31～7.24(m,2H),6.82(dd,J＝7.4,3.3Hz,1H),6.78(d,J＝8.0Hz,1H),6.60(d,J＝8.4Hz,1H),6.56(d,J＝8.3Hz,1H),5.43(dd,J＝8.1,3.2Hz,1H),3.71(s,3H),3.69(s,3H),1.45(d,J＝13.0Hz,9H),1.28(d,J＝13.6Hz,9H),0.74(d,J＝12.2Hz,9H)；13C NMR(125MHz,CDCl3)δ163.4(d,J＝2.2Hz),158.1,157.2,138.7(d,J＝18.1Hz),130.5,129.3,124.8(d,J＝2.1Hz),124.7(d,J＝3.8Hz),119.4,109.6,104.1,103.6,79.8(dd,J＝63.5,47.8Hz),55.8,55.5,36.9(dd,J＝16.9,1.4Hz),36.6(dd,J＝16.8,1.4Hz),32.8(dd,J＝24.9,7.9Hz),27.5(d,J＝5.4Hz),27.1,26.6(d,J＝15.5Hz)；31P NMR(162MHz,CDCl3)δ57.5(d,J＝41.3Hz),8.5(d,J＝41.3Hz)；ESI-MS:m/z 491.6[M+H]+,513.6[M+Na]+(ii) a HRMS (ESI) calculated as [ M + H, C27H41O4P2]+491.2476; tested 491.2475.
Example 7 preparation of bis-tert-butyl ((2S,3S) -3-tert-butyl-4-isopropoxy-2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-penta-2-) phosphine oxide (I-7):
Figure BDA0002047585180000262
bis-tert-butyl ((2S,3S) -3-tert-butyl-4-isopropoxy-2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-pentan-2-) phosphine oxide (I-7) was prepared by the preparation method of reference example 1.
[α]D 19:78.6°(c＝0.88,CHCl3).1H NMR(500MHz,CDCl3)δ7.15(t,J＝8.1Hz,1H),6.47～6.37(m,2H),5.45(dd,J＝7.4,3.3Hz,1H),4.60(dp,J＝12.0,5.9Hz,1H),1.41(d,J＝13.1Hz,9H),1.31(d,J＝6.0Hz,3H),1.28(d,J＝6.0Hz,3H),1.18(d,J＝13.6Hz,9H),1.03(d,J＝12.3Hz,9H)；13C NMR(125MHz,CDCl3)δ164.9,160.2(d,J＝12.7Hz),132.1,112.2(d,J＝17.7Hz),106.0(d,J＝2.0Hz),103.9,80.3(dd,J＝62.3,46.6Hz),70.5,36.9(dd,J＝3.6,1.3Hz),36.5(dd,J＝3.5,1.2Hz),27.4(d,J＝5.2Hz),27.2(d,J＝14.9Hz),27.1,22.2,22.0；31P NMR(162MHz,CDCl3)δ57.8(d,J＝40.1Hz),3.2(d,J＝40.5Hz)；ESI-MS:m/z413.60[M+H]+(ii) a HRMS (ESI) calculated as [ M + H, C22H39O3P2]+413.2374; tested 413.2369.
Example 8 preparation of bis-tert-butyl ((2S,3S) -3-tert-butyl-4- (phenoxy) -2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-penta-2-) phosphine oxide (I-8):
Figure BDA0002047585180000271
bis-tert-butyl ((2S,3S) -3-tert-butyl-4- (phenoxy) -2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-pentan-2-) phosphine oxide (I-8) was prepared by the preparation method of reference example 1.
[α]D 18:-66.9°(c＝0.85,CHCl3).1H NMR(500MHz,CDCl3)δ7.31(t,J＝7.7Hz,2H),7.17(t,J＝8.1Hz,1H),7.09(t,J＝7.4Hz,1H),6.96(d,J＝8.5Hz,2H),6.60(d,J＝8.1Hz,1H),6.44(dd,J＝8.1,3.6Hz,1H),5.51(dd,J＝7.4,3.3Hz,1H),5.51(dd,J＝7.4,3.3Hz,1H),1.43(d,J＝13.2Hz,9H),1.22(d,J＝13.6Hz,9H),1.08(d,J＝12.6Hz,9H)；13C NMR(125MHz,CDCl3)δ165.3(d,J＝2.1Hz),159.34(d,J＝13.2Hz),156.5,132.3,129.8,123.7,119.1,114.4(dd,J＝20.5,2.1Hz),110.8(d,J＝1.7Hz),106.3,80.6(dd,J＝61.6,47.6Hz),37.0(dd,J＝2.8,1.3Hz),36.5(dd,J＝2.6,1.2Hz),27.4(d,J＝5.3Hz),27.1(d,J＝15.1Hz),27.1；31PNMR(162MHz,CDCl3)δ58.0(d,J＝40.3Hz),2.3(d,J＝40.3Hz)；ESI-MS:m/z 447.20[M+H]+(ii) a HRMS (ESI) calculated as [ M + H, C25H37O3P2]+447.2217; tested 447.2212.
Example 9 preparation of bis-tert-butyl ((2S,3S) -3-tert-butyl-4- (benzyloxy) -2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-penta-n-2-) phosphine oxide (I-9):
Figure BDA0002047585180000272
bis-tert-butyl ((2S,3S) -3-tert-butyl-4- (2, 6-dimethoxyphenyl) -2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-penta-n-2-) phosphine oxide (I-9) was prepared by the preparation method of reference example 1.
[α]D 19:-59.2°(c＝0.6,CHCl3).1H NMR(500MHz,CDCl3)δ7.42(d,J＝7.4Hz,2H),7.34(d,J＝7.6Hz,2H),7.29(t,J＝7.3Hz,1H),7.18(t,J＝8.1Hz,1H),6.51(dd,J＝8.1,3.7Hz,1H),6.48(d,J＝8.1Hz,1H),5.50(dd,J＝7.5,3.4Hz,1H),5.12(q,J＝12.1Hz,2H),1.43(d,J＝13.1Hz,9H),1.20(d,J＝13.6Hz,9H),1.03(d,J＝12.4Hz,9H)；13C NMR(125MHz,CDCl3)δ164.8(d,J＝1.9Hz),160.8(d,J＝12.8Hz),136.7,132.4,128.5,127.9,127.2,111.4(d,J＝16.3Hz),105.0(d,J＝1.8Hz),104.6,80.5(dd,J＝62.3,46.8Hz),70.3,36.9(dd,J＝2.7,1.3Hz),36.5(dd,J＝2.5,1.1Hz),27.4(d,J＝5.2Hz),27.2(d,J＝14.9Hz),27.1；31P NMR(162MHz,CDCl3)δ58.7(d,J＝40.1Hz),2.2(d,J＝40.1Hz)；ESI-MS:m/z 461.35[M+H]+,483.35[M+Na]+(ii) a HRMS (ESI) calculated as [ M + H, C26H39O3P2]+461.2375; tested 461.2369.
Example 10 preparation of bis-tert-butyl ((2S,3S) -3-tert-butyl-6- (2, 5-diphenyl-1-pyrrolyl) -4-methoxy-2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-penta-n-2-) phosphine oxide (I-10):
Figure BDA0002047585180000281
bis-tert-butyl ((2S,3S) -3-tert-butyl-6- (2, 5-diphenyl-1-pyrrolyl) -4-methoxy-2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-penta-yoke-2-) phosphine oxide (I-10) was prepared by the preparation method of reference example 1.
1H NMR(500MHz,CDCl3)δ7.20～7.07(m,10H),6.48(s,2H),6.20(s,1H),6.08(d,J＝2.4Hz,1H),5.45(dd,J＝7.6,3.3Hz,1H),3.45(s,3H),1.35(d,J＝13.2Hz,9H),1.16(d,J＝13.6Hz,9H),1.01(d,J＝12.5Hz,9H)；13C NMR(125MHz,CDCl3)δ164.53(d,J＝1.8Hz),161.27(d,J＝13.2Hz),143.0,135.6,133.2,128.6,128.0,126.5,110.0,105.7,105.4(d,J＝1.7Hz),81.2(dd,J＝60.8,47.9Hz),55.7,37.0(dd,J＝6.3,1.2Hz),36.5(dd,J＝6.4,1.1Hz),32.9(dd,J＝25.2,7.6Hz),27.5,27.5,27.1,27.0,26.9；31P NMR(162MHz,CDCl3)δ57.3(d,J＝39.5Hz),-0.37(d,J＝39.5Hz)；ESI-MS:m/z 602.6[M+H]+(ii) a HRMS (ESI) calculated as [ M + H, C36H46NO3P2]+602.2947; tested 602.2947.
EXAMPLE 11 preparation of bis-tert-butyl ((2S,3S) -3-tert-butyl-4-methoxy-6- (2, 6-dimethoxyphenyl) -2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-pentan-2-) phosphine oxide (I-11):
Figure BDA0002047585180000282
bis-tert-butyl ((2S,3S) -3-tert-butyl-4-methoxy-6- (2, 6-dimethoxyphenyl) -2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-pentan-2-) phosphine oxide (I-11) was prepared by the preparation method of reference example 1.
[α]D 25:59.8°(c＝0.24,CHCl3).1H NMR(500MHz,CDCl3)δ7.26(t,J＝8.8Hz,1H),6.63(d,J＝8.4Hz,2H),6.46(s,1H),6.44(d,J＝3.6Hz,1H),5.51(dd,J＝7.7,3.3Hz,1H),3.80(s,3H),3.71(s,6H),1.43(d,J＝13.1Hz,9H),1.24(d,J＝13.6Hz,9H),1.09(d,J＝12.4Hz,9H)；13C NMR(125MHz,CDCl3)δ164.2(d,J＝2.1Hz),160.9(d,J＝12.9Hz),157.8,139.0,129.0,119.7,108.7(d,J＝17.2Hz),107.3,106.4(d,J＝1.7Hz),104.7,80.5(dd,J＝62.9,46.9Hz),56.1,55.5,37.1～37.0(m),36.7～36.6(m),33.2(dd,J＝25.1,7.7Hz),27.6,27.5,27.3,27.2,27.2；31P NMR(162MHz,CDCl3)δ57.8(d,J＝40.9Hz),2.8(d,J＝40.6Hz)；ESI-MS:m/z 521.35[M+H]+(ii) a HRMS (ESI) calculated as [ M + Na, C28H42NaO5P2]+543.2407; tested 543.2400.
EXAMPLE 12 preparation of bis-tert-butyl ((2S,3S) -3-tert-butyl-4, 6-dimethoxy-2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-pentan-2-) phosphine oxide (I-12):
Figure BDA0002047585180000291
bis-tert-butyl ((2S,3S) -3-tert-butyl-4, 6-dimethoxy-2, 3-dihydrobenzo [ d ] [1,3] oxy, phosphine-pentan-2-) phosphine oxide (I-12) was prepared by the preparation method of reference example 1.
1H NMR(500MHz,CDCl3)δ6.08～5.93(m,2H),5.44(dd,J＝7.9,3.3Hz,1H),3.76(d,J＝2.3Hz,6H),1.40(d,J＝13.1Hz,9H),1.19(d,J＝13.6Hz,9H),0.98(d,J＝12.4Hz,9H)；13C NMR(125MHz,CDCl3)δ165.7(d,J＝2.1Hz),164.2,162.1(d,J＝13.6Hz),102.1(d,J＝17.4Hz),91.9(d,J＝2.1Hz).89.4,81.1(dd,J＝62.0,47.5Hz),55.6,55.5,36.9(dd,J＝4.1,1.2Hz),36.5(dd,J＝3.9,1.2Hz),33.0(dd,J＝25.3,7.7Hz),27.5,27.4,27.1,26.9,26.8；31PNMR(162MHz,CDCl3)δ58.5(d,J＝39.5Hz),1.4(d,J＝39.6Hz)；ESI-MS:m/z 415.20[M+H]+,437.25[M+Na]+; HRMS (ESI) calculated as [ M + H, C26H35F5NO3P2]+415.2163; tested 415.2162.
EXAMPLE 13 preparation of chiral ligand ent-I-1
Figure BDA0002047585180000292
To be provided with
Figure BDA0002047585180000293
As a starting material, a chiral ligand ent-I-1 was prepared by reference to the preparation method of example 1.
[α]D 25:-68.4°(c＝0.75,CHCl3).1H NMR(500MHz,CDCl3)δ7.27～7.22(m,5H),7.12～7.01(m,5H),6.23～6.12(m,2H),5.52(dd,J＝6.7,3.3Hz,1H),4.43～4.34(m,1H),2.27～2.20(m,3H),2.18～.96(m,12H),1.90～1.83(m,3H),1.82～1.72(m,6H),1.70～1.60(m,6H),1.22(d,J＝6.0Hz,3H),1.15(d,J＝6.0Hz,3H),1.06(d,J＝12.3Hz,9H)；13C NMR(125MHz,CDCl3)δ165.8(d,J＝1.6Hz),160.2(d,J＝13.4Hz),152.0,147.6,129.3,124.8,123.3,106.4(d,J＝14.8Hz),102.9(d,J＝1.6Hz),99.8,79.1(dd,J＝61.6,46.5Hz),70.4,41.8,41.4,41.0,37.0,37.0,36.8,36.8,33.3(dd,J＝25.2,7.4Hz),28.1,28.0,28.0,27.3,27.2,22.0,21.6；31P NMR(162MHz,CDCl3)δ49.1(d,J＝38.7Hz),1.5(d,J＝38.1Hz)；ESI-MS:m/z 736.65[M+H]+(ii) a HRMS (ESI) calculated as [ M + Na, C46H59NNaO3P2]+758.3870; tested 758.3862.
Example 14
A25 mL Schlenk tube was dried, charged with α -bromoamide racemate C1(0.25mmol,1equiv), arylboron reagent D1(0.5mmol,2equiv), potassium fluoride or potassium carbonate (0.5mmol,2equiv), palladium acetate (1 mol%) and the compound bis ((3S) -1-adamantyl) ((2S,3S) -3-tert-butyl-6-dianilino-4-isopropoxy-2, 3-dihydrobenzo [ D ] [1,3] oxy, phosphine-penta-2-) phosphine oxide (I-1) prepared in example 1 as chiral ligand (1.2 mol%), at a palladium/ligand molar ratio of 1:1.2, nitrogen was pumped three times and sealed. Toluene (2mL) was added. Heating the reaction system to 60 ℃ for reaction for 48 hours, cooling to room temperature, adding water (10mL) and dichloromethane (10mL), separating, combining organic phases, drying by anhydrous sodium sulfate, concentrating, separating by column chromatography to obtain a white solid product, and determining an enantiomeric excess value (ee) by a chiral high-pressure liquid phase.
Figure BDA0002047585180000301
(R) -N- (bis (2-methoxyphenyl) methyl) -2- (4-methoxyphenyl) propionamide (E1) as a white solid, 77% yield, 91% ee.
The enantiomeric excess value (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 0.8mL/min at 25 ℃, n-hexane/isopropanol: 85/15,230nm,17.81min (S),22.86min (R); [ alpha ] to]D 25:3.2°(c＝0.30,CHCl3).IR(cm-1):3416.9,3311.8,2928.7,2836.7,1652.2,1511.4,1246.6,1029.4,837.4,754.3,735.4,570.3；1H NMR(500MHz,CDCl3)δ7.23(d,J＝8.6Hz,2H),7.21～7.12(m,3H),7.08～7.04(m,1H),6.91(d,J＝8.6Hz,2H),6.87～6.82(m,2H),6.80(t,J＝7.5Hz,1H),6.75(dd,J＝13.0,8.2Hz,2H),6.53(d,J＝9.0Hz,1H),3.83(s,3H),3.65(s,3H),3.63(s,3H),3.57(q,J＝7.2Hz,1H),1.50(d,J＝7.3Hz,3H)；13C NMR(125MHz,CDCl3)δ167.3,157.2,157.2,128.7,128.7,128.6,128.6,128.6,120.5,120.4,111.0,110.9,55.5,55.5,53.2,50.7,36.0,29.4,22.1,14.0；ESI-MS:m/z 420.10[M+H]+,442.10[M+Na]+(ii) a HRMS (ESI) calculated as [ M + H, C21H27BrNO3]+420.1174, detected 420.1169.
Example 15
With the compound bis ((3S) -1-adamantyl) ((2S,3S) -3-tert-butyl-6-dianilino-4-isopropoxy-2, 3-dihydrobenzo [ D ] [1,3] oxy, phosphine-pentayoke-2-) phosphine oxide (I-1) prepared in example 1 as a chiral ligand, an α -arylamide compound E2 having a chiral tertiary carbon center was prepared by an asymmetric Suzuki-Miyaura coupling reaction involving α -bromoamide C1 catalyzed by transition metal palladium and arylboronic acid D2, according to the preparation method of example 14 (the reaction route is shown below).
Figure BDA0002047585180000311
(R) -N- (bis (2-methoxyphenyl) methyl) -2- (4- (dianilino) phenyl) propanamide (E2) white solid, 75% yield, 90% ee.
The enantiomeric excess value (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 0.8mL/min, n-hexane/isopropanol: 93/7,230nm,17.61min (S),28.69min (R); [ alpha ] to]D 25:1.8°(c＝0.30,CHCl3).IR(cm-1):3268.2,2962.2,2925.1.1667.2,1638.0,1586.0,1507.9,1492.7,1261.8,1243.0,1102.0,1026.0,866.5,799.1,696.4,621.3,504.2；1H NMR(500MHz,CDCl3)δ7.28～7.23(m,4H),7.22～7.14(m,5H),7.11～6.99(m,9H),6.89～6.75(m,5H),6.55(d,J＝8.9Hz,1H),3.72(s,3H),3.69(s,3H),3.57(q,J＝7.2Hz,1H),1.52(d,J＝7.2Hz,3H)；13C NMR(125MHz,CDCl3)δ172.9,157.2,157.1,147.9,146.9,136.1,129.5,129.4,129.3,128.9,128.8,128.4,128.3,128.2,124.5,124.2,122.9,120.5,120.2,111.0,110.8,55.4,55.4,50.0,46.7,18.2；ESI-MS:m/z 543.30[M+H]+(ii) a HRMS (ESI) calculated as [ M + H, C36H35N2O3]+543.2644, detected 543.2642.
Example 16
With the compound bis ((3S) -1-adamantyl) ((2S,3S) -3-tert-butyl-6-dianilino-4-isopropoxy-2, 3-dihydrobenzo [ D ] [1,3] oxy, phosphine-pentayoke-2-) phosphine oxide (I-1) prepared in example 1 as a chiral ligand, an α -arylamide compound E3 having a chiral tertiary carbon center was prepared by an asymmetric Suzuki-Miyaura coupling reaction involving α -bromoamide C1 catalyzed by transition metal palladium and arylboronic acid D3, according to the preparation method of example 14 (the reaction route is shown below).
Figure BDA0002047585180000312
(R) -N- (bis (2-methoxyphenyl) methyl) -2- (4- (methylthio) phenyl) propanamide (E3) is a white solid, 60% yield, 85% ee.
The enantiomeric excess value (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: 85/15,230nm,18.95min (S),24.27min (R); 85% ee.Chiral HPLC conditions AD-H, nhexane iPrOH 85:15, flow rate 0.8mL/min,230nm, t1＝18.95min,t2＝24.27min.[α]D 25:3.9°(c＝0.32,CHCl3).IR(cm-1):3418.8,3308.8,2929.3,2835.7,1652.1,1490.7,1462.3,1288.8,1246.2,1124.5,1028.4,867.5,754.2,574.5；1HNMR(500MHz,CDCl3)δ7.31～7.11(m,7H),7.05(d,J＝7.1Hz,1H),6.89～6.72(m,5H),6.53(d,J＝8.9Hz,1H),3.66(s,3H),3.62(s,3H),3.57(q,J＝7.3Hz,1H),2.50(s,3H),1.51(d,J＝7.2Hz,3H)；13C NMR(125MHz,CDCl3)δ172.6,157.1,157.0,138.6,137.3,129.3,129.2,128.8,128.7,128.4,128.3,128.3,127.2,120.4,120.3,110.9,110.8,55.3,55.2,50.2,46.9,18.3,16.1；ESI-MS:m/z 422.45[M+H]+(ii) a HRMS (ESI) calculated as [ M + H, C25H28NO3S]+422.1789, detected 422.1784.
Example 17
With the compound bis ((3S) -1-adamantyl) ((2S,3S) -3-tert-butyl-6-dianilino-4-isopropoxy-2, 3-dihydrobenzo [ D ] [1,3] oxy, phosphine-pentayoke-2-) phosphine oxide (I-1) prepared in example 1 as a chiral ligand, an α -arylamide compound E4 having a chiral tertiary carbon center was prepared by an asymmetric Suzuki-Miyaura coupling reaction involving α -bromoamide C1 catalyzed by transition metal palladium and arylboronic acid D4, according to the preparation method of example 14 (the reaction route is shown below).
Figure BDA0002047585180000321
(R) -N- (bis (2-methoxyphenyl) methyl) -2- (4-isobutylphenyl) propionamide (E4) as a white solid, 71% yield, 90% ee.
The enantiomeric excess value (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 0.8mL/min at 25 ℃, n-hexane/isopropanol: 90/10,230nm,14.37min (S),22.12min (R); 90% ee]D 25:-8.7°(c＝0.65,CHCl3).IR(cm-1):3419.9,2960.1,2924.0,1733.2,1653.1,1489.7,1458.0,1260.5,1027.4,862.6,800.0,752.4,705.3；1H NMR(500MHz,CDCl3)δ7.26～7.12(m,7H),7.05～6.99(m,1H),6.91～6.83(m,2H),6.81～6.72(m,3H),6.55(d,J＝9.0Hz,1H),3.65(s,3H),3.64～3.57(m,4H),2.51(d,J＝7.2Hz,2H),1.90(dp,J＝13.5,6.7Hz,1H),1.53(d,J＝7.2Hz,3H),0.95(d,J＝6.6Hz,6H)；13C NMR(125MHz,CDCl3)δ173.0,157.0,156.9,140.6,138.9,129.6,129.3,129.1,128.8,128.3,128.1,127.8,120.3,120.1,110.8,110.6,55.2,55.1,50.0,46.9,45.1,30.4,22.5,22.5,18.2；ESI-MS:m/z 432.50[M+H]+(ii) a HRMS (ESI) calculated as [ M + H, C28H34NO3]+432.2535, detected 432.2533.
Example 18
With the compound bis ((3S) -1-adamantyl) ((2S,3S) -3-tert-butyl-6-dianilino-4-isopropoxy-2, 3-dihydrobenzo [ D ] [1,3] oxy, phosphine-pentayoke-2-) phosphine oxide (I-1) prepared in example 1 as a chiral ligand, an α -arylamide compound E5 having a chiral tertiary carbon center was prepared by an asymmetric Suzuki-Miyaura coupling reaction involving α -bromoamide C1 catalyzed by transition metal palladium and arylboronic acid D5, according to the preparation method of example 14 (the reaction route is shown below).
Figure BDA0002047585180000322
(R) -N- (bis (2-methoxyphenyl) methyl) -2- (4-biphenyl) propanamide (E5) white solid, 80% yield, 90% ee.
The enantiomeric excess value (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 0.8mL/min at 25 ℃, n-hexane/isopropanol: 85/15,230nm,19.01min (S),27.01min (R); IR (cm) in 90% ee.E-1):3274.1,2955.9,2926.7,1670.2,1642.9,1533.3,1489.1,1462.0,1244.4,1122.0,1030.3,848.3,775.1,751.1,695.8,576.2；1H NMR(500MHz,CDCl3)δ7.62(d,J＝8.2Hz,4H),7.47(t,J＝7.7Hz,2H),7.43～7.35(m,3H),7.22(dd,J＝7.5,1.3Hz,1H),7.19～7.12(m,2H),7.09～7.05(m,1H),6.93(d,J＝8.9Hz,1H),6.86(t,J＝7.4Hz,1H),6.80(t,J＝7.5Hz,1H),6.76(d,J＝8.2Hz,1H),6.73(d,J＝8.2Hz,1H),6.56(d,J＝9.0Hz,1H),3.70～3.63(m,4H),3.61(s,3H),1.58(d,J＝7.2Hz,3H)；13C NMR(125MHz,CDCl3)δ172.7,157.1,157.0,140.8,140.8,140.2,129.3,129.2,129.0,128.8,128.6,128.4,128.3,128.3,127.6,127.5,127.1,120.4,120.2,110.9,110.7,55.3,55.2,50.2,47.1,18.3；ESI-MS:m/z 452.25[M+H]+(ii) a HRMS (ESI) calculated as [ M + H, C30H30NO3]452.2223, detected 452.2220.
Example 19
With the compound bis ((3S) -1-adamantyl) ((2S,3S) -3-tert-butyl-6-dianilino-4-isopropoxy-2, 3-dihydrobenzo [ D ] [1,3] oxy, phosphine-pentayoke-2-) phosphine oxide (I-1) prepared in example 1 as a chiral ligand, an α -arylamide compound E6 having a chiral tertiary carbon center was prepared by an asymmetric Suzuki-Miyaura coupling reaction involving α -bromoamide C1 catalyzed by transition metal palladium and arylboronic acid D6, according to the preparation method of example 14 (the reaction route is shown below).
Figure BDA0002047585180000331
(R) -N- (bis (2-methoxyphenyl) methyl) -2- (4-fluorophenyl) propionamide (E6) as a white solid, 52% yield, 77% ee.
The enantiomeric excess value (ee) is determined by chiral high pressure liquid phase, and the ee value is 77 percent; high-pressure liquid phase conditions: chiral S-Chiral B column, 25 ℃, flow rate of 0.8mL/min, n-hexane/isopropanol: 92/8,230nm,17.54min (S),26.01min (R); [ alpha ] to]D 25:1.2°(c＝0.30,CHCl3).IR(cm-1):3260.8,2961.7,2924.3,1654.0,1513.8,1375.6,1280.1,1261.5,1100.4,1030.5,800.2,705.4,682.0,535.8；1H NMR(500MHz,CDCl3)δ7.28(dd,J＝8.5,5.4Hz,2H),7.22～7.13(m,3H),7.09～7.00(m,3H),6.86(t,J＝7.5Hz,1H),6.83～6.73(m,4H),6.54(d,J＝8.8Hz,1H),3.68(s,3H),3.65～3.57(m,4H),1.51(d,J＝7.2Hz,3H)；13C NMR(125MHz,CDCl3)δ172.5,163.1,161.1,157.1,157.0,137.6,137.5,129.7,129.6,129.2,129.1,128.8,128.4,128.3,128.3,120.5,120.3,115.7,115.6,111.0,110.8,55.3,55.2,50.1,46.6,18.6；19F NMR(376MHz,CDCl3)δ-115.8(s)；ESI-MS:m/z 394.10[M+H]+(ii) a HRMS (ESI) calculated as [ M + H, C24H25NO3]+394.1817, detected 394.1813.
Example 20
With the compound bis ((3S) -1-adamantyl) ((2S,3S) -3-tert-butyl-6-dianilino-4-isopropoxy-2, 3-dihydrobenzo [ D ] [1,3] oxy, phosphine-pentayoke-2-) phosphine oxide (I-1) prepared in example 1 as a chiral ligand, an α -arylamide compound E7 having a chiral tertiary carbon center was prepared by an asymmetric Suzuki-Miyaura coupling reaction involving α -bromoamide C1 catalyzed by transition metal palladium and arylboronic acid D7, according to the preparation method of example 14 (the reaction route is shown below).
Figure BDA0002047585180000341
(R) -N- (bis (2-methoxyphenyl) methyl) -2- (4-ethoxycarbonylphenyl) propanamide (E7) was a white solid, 52% yield, 82% ee.
The enantiomeric excess value (ee) is determined by chiral high-pressure liquid phase, and the ee value is 82 percent; high-pressure liquid phase conditions: chiral S-Chiral B column, 25 ℃, flow rate of 0.8mL/min, n-hexane/isopropanol: 94/6,230nm,33.43min (S),47.57min (R); [ alpha ] to]D 20:2.7°(c＝0.85,CHCl3).IR(cm-1):3618.4,3002.5,2943.8,2293.0,2253.2,1635.4,1444.0,1375.5,1039.3,918.6,750.3；1H NMR(500MHz,CDCl3)δ8.04(d,J＝8.3Hz,2H),7.39(d,J＝8.3Hz,2H),7.20～7.12(m,3H),7.01(dd,J＝7.6,1.4Hz,1H),6.88～6.84(m,1H),6.81～6.73(m,4H),6.54(d,J＝8.8Hz,1H),4.40(q,J＝7.1Hz,2H),3.69～3.63(m,4H),3.61(s,3H),1.53(d,J＝7.2Hz,3H),1.41(t,J＝7.1Hz,3H)；13C NMR(125MHz,CDCl3)δ171.8,166.5,157.1,157.0,146.9,130.1,129.5,129.1,129.0,128.8,128.5,128.4,128.2,128.1,120.5,120.3,111.0,110.8,61.2,55.4,55.2,50.2,47.4,18.4,14.5；ESI-MS:m/z 470.20[M+Na]+(ii) a HRMS (ESI) calculated as [ M + H, C27H30NO5]+448.2120, detected 448.2118.
Example 21
With the compound bis ((3S) -1-adamantyl) ((2S,3S) -3-tert-butyl-6-dianilino-4-isopropoxy-2, 3-dihydrobenzo [ D ] [1,3] oxy, phosphine-pentayoke-2-) phosphine oxide (I-1) prepared in example 1 as a chiral ligand, an α -arylamide compound E8 having a chiral tertiary carbon center was prepared by an asymmetric Suzuki-Miyaura coupling reaction involving α -bromoamide C1 catalyzed by transition metal palladium and arylboronic acid D8, according to the preparation method of example 14 (the reaction route is shown below).
Figure BDA0002047585180000342
(R) -N- (bis (2-methoxyphenyl) methyl) -2- (3-methoxyphenyl) propionamide (E8) as a white solid, 62% yield, 91% ee.
The enantiomeric excess value (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: 96/4,230nm,51.98min (S),72.01min (R); [ alpha ] to]D 25:4.0°(c＝0.37,CHCl3).IR(cm-1):3308.8,2962.4,2926.1,1652.4,1598.6,1457.0,1261.6,1104.0,1030.2,864.5,799.6,703.1；1H NMR(500MHz,CDCl3)δ7.29(t,J＝7.9Hz,1H),7.21～7.11(m,3H),7.04(dd,J＝7.6,1.6Hz,1H),6.91(d,J＝7.5Hz,2H),6.88～6.82(m,3H),6.81～6.72(m,3H),6.53(d,J＝9.0Hz,1H),3.77(s,3H),3.65(s,3H),3.64～3.58(m,4H),1.52(d,J＝7.2Hz,3H)；13C NMR(125MHz,CDCl3)δ172.6,160.1,157.1,157.0,143.4,129.9,129.3,129.2,128.9,128.4,128.3,128.2,120.5 120.4,120.2,113.3,113.2,110.9,110.7,55.3,55.2,55.2,50.2,47.4,18.2；ESI-MS:m/z 406.20[M+H]+(ii) a HRMS (ESI) calculated as [ M + H, C25H28NO4]+406.2016, detected 406.2013.
Example 22
With the compound bis ((3S) -1-adamantyl) ((2S,3S) -3-tert-butyl-6-dianilino-4-isopropoxy-2, 3-dihydrobenzo [ D ] [1,3] oxy, phosphine-pentayoke-2-) phosphine oxide (I-1) prepared in example 1 as a chiral ligand, an α -arylamide compound E9 having a chiral tertiary carbon center was prepared by an asymmetric Suzuki-Miyaura coupling reaction involving α -bromoamide C1 catalyzed by transition metal palladium and arylboronic acid D9, according to the preparation method of example 14 (the reaction route is shown below).
Figure BDA0002047585180000351
(R) -N- (bis (2-methoxyphenyl) methyl) -2- (3-phenoxyphenyl) propanamide (E9) was a white solid, 63% yield, 84% ee.
The enantiomeric excess value (ee) is determined by chiral high-pressure liquid phase, and the ee value is 84 percent; high-pressure liquid phase conditions: chiral S-Chiral B column, 25 ℃, flow rate of 0.8mL/min, n-hexane/isopropanol: 90/10,230nm,29.89min (S),49.58min (R); [ alpha ] to]D 25:-4.7°(c＝0.25,CHCl3).IR(cm-1):3284.2,2961.4,2925.3,1670.6,1488.8,1463.2,1259.8,1103.1,1029.3,800.2,758.9,745.2,692.3,517.9,484.8；1H NMR(500MHz,CDCl3)δ7.36～7.28(m,3H),7.22～7.14(m,3H),7.13～7.05(m,3H),7.01～6.93(m,4H),6.90～6.74(m,5H),6.53(d,J＝8.9Hz,1H),3.69(s,3H),3.66(s,3H),3.59(q,J＝7.3Hz,1H),1.51(d,J＝7.2Hz,3H)；13C NMR(125MHz,CDCl3)δ172.3,157.8,157.1,157.0,157.0,143.7,130.2,129.9,129.3,129.2,128.8,128.4,128.3,128.3,123.5,122.9,120.4,120.3,119.0,118.5,117.5,111.0,110.8,55.3,55.2,50.2,47.2,18.1；ESI-MS:m/z 468.25[M+H]+(ii) a HRMS (ESI) calculated as [ M + H, C26H26NO4]+468.2173, detected 468.2169.
Example 23
With the compound bis ((3S) -1-adamantyl) ((2S,3S) -3-tert-butyl-6-dianilino-4-isopropoxy-2, 3-dihydrobenzo [ D ] [1,3] oxy, phosphine-pentayoke-2-) phosphine oxide (I-1) prepared in example 1 as a chiral ligand, an α -arylamide compound E10 having a chiral tertiary carbon center was prepared by an asymmetric Suzuki-Miyaura coupling reaction involving α -bromoamide C1 catalyzed by transition metal palladium and arylboronic acid D10, according to the preparation method of example 14 (the reaction route is shown below).
Figure BDA0002047585180000352
(R) -N- (bis (2-methoxyphenyl) methyl) -2- (2-methylphenyl) propanamide (E10) was a white solid, 62% yield, 35% ee.
The enantiomeric excess value (ee) is determined from a chiral high pressure liquid phase,an ee value of 35% was measured; high-pressure liquid phase conditions: chiral AD-H column, flow rate 0.8mL/min at 25 ℃, n-hexane/isopropanol: 90/10,230nm,50.99min (S),56.55min (R);1H NMR(500MHz,CDCl3)δ7.34～7.31(m,1H),7.28～7.25(m,1H),7.24～7.22(m,2H),7.17～7.08(m,4H),6.87(d,J＝9.2Hz,1H),6.86～6.77(m,2H),6.73(dd,J＝7.9,3.6Hz,2H),6.53(d,J＝9.2Hz,1H),3.82(q,J＝7.3Hz,1H),3.62(s,3H),3.60(s,3H),2.24(s,3H),1.55(d,J＝7.3Hz,3H)；13C NMR(125MHz,CDCl3)δ173.0,157.0,157.0,139.6,137.1,130.8,129.3,129.2,128.6,128.6,128.3,128.2,127.3,127.2,126.7,120.3,120.3,110.8,110.7,55.2,55.1,50.2,44.0,19.8,17.5；ESI-MS:m/z 390.20[M+H]+,412.15[M+Na]+(ii) a HRMS (ESI) calculated as [ M + H, C25H28NO3]+390.2068, detected 390.2064.
Example 24
With the compound bis ((3S) -1-adamantyl) ((2S,3S) -3-tert-butyl-6-dianilino-4-isopropoxy-2, 3-dihydrobenzo [ D ] [1,3] oxy, phosphine-pentayoke-2-) phosphine oxide (I-1) prepared in example 1 as a chiral ligand, an α -arylamide compound E11 having a chiral tertiary carbon center was prepared by an asymmetric Suzuki-Miyaura coupling reaction involving α -bromoamide C1 catalyzed by transition metal palladium and arylboronic acid D11, according to the preparation method of example 14 (the reaction route is shown below).
Figure BDA0002047585180000361
(R) -N- (bis (2-methoxyphenyl) methyl) -2- (2- [1,1' -biphenyl ]) -4-propionamide (E11) as a white solid, 60% yield, 89% ee.
The enantiomeric excess value (ee) is determined by chiral high-pressure liquid phase, and the ee value is 89%; high-pressure liquid phase conditions: chiral S-Chiral B column, 25 ℃, flow rate of 0.8mL/min, n-hexane/isopropanol: 92/8,230nm,22.44min (S),37.01min (R); [ alpha ] to]D 25:-2.3°(c＝0.32,CHCl3).IR(cm-1):3258.2,3064.5,2926.5,1675.7,1644.9,1556.6,1490.8,1462.6,1245.8,1124.6,1029.9,879.7,766.9,754.0,718.9,698.1,574.7；1HNMR(500MHz,CDCl3)δ7.60～7.53(m,2H),7.50～7.37(m,4H),7.25～7.14(m,5H),7.09(d,J＝7.3Hz,1H),6.93(d,J＝8.8Hz,1H),6.88(t,J＝7.5Hz,1H),6.85～6.74(m,3H),6.57(d,J＝8.8Hz,1H),3.70(s,3H),3.68～3.61(m,4H),1.56(d,J＝7.2Hz,3H)；13C NMR(125MHz,CDCl3)δ172.0,160.9,158.9,157.1,157.0,143.2,143.2,135.5,135.5,131.0,131.0,129.0,129.0,128.9,128.8,128.7,128.5,128.4,128.3,127.9,127.9,127.7,124.2,124.2,120.5,120.3,115.8,115.6,110.9,110.7,55.3,55.2,50.2,46.9,18.3；19F NMR(376MHz,CDCl3)δ-115.8(s)；ESI-MS:m/z 492.50[M+Na]+(ii) a HRMS (ESI) calculated as [ M + H, C30H29FNO3]+470.2131, detected 470.2126.
Example 25
With the compound bis ((3S) -1-adamantyl) ((2S,3S) -3-tert-butyl-6-dianilino-4-isopropoxy-2, 3-dihydrobenzo [ D ] [1,3] oxy, phosphine-pentayoke-2-) phosphine oxide (I-1) prepared in example 1 as a chiral ligand, an α -arylamide compound E12 having a chiral tertiary carbon center was prepared by an asymmetric Suzuki-Miyaura coupling reaction involving α -bromoamide C1 catalyzed by transition metal palladium and arylboronic acid D12, according to the preparation method of example 14 (the reaction route is shown below).
Figure BDA0002047585180000371
(R) -N- (bis (2-methoxyphenyl) methyl) -2- (2- (3, 4-dimethylphenyl)) propionamide (E12) as a white solid, 71% yield, 90% ee.
The enantiomeric excess value (ee) is determined by chiral high-pressure liquid phase, and the ee value is 89%; high-pressure liquid phase conditions: chiral OD-H column, 25 ℃, flow rate 0.8mL/min, n-hexane/isopropanol: 96/4,230nm,21.71min (S),30.47min (R); [ alpha ] to]D 25:1.6°(c＝0.34,CHCl3).IR(cm-1):3415.4,3311.9,2925.7,1652.5,1490.3,1462.2,1374.4,1246.4,1125.6,1051.8,1028.0,828.3,753.1,701.5,586.3；1H NMR(500MHz,CDCl3)δ7.21～7.12(m,4H),7.08～7.03(m,3H),6.89～6.82(m,2H),6.81～6.72(m,3H),6.53(d,J＝9.0Hz,1H),3.63(s,3H),3.62(s,3H),3.56(q,J＝7.3Hz,1H),2.28(s,3H),2.27(s,3H),1.51(d,J＝7.2Hz,3H)；13C NMR(125MHz,CDCl3)δ173.2,157.1,157.0,139.2,137.0,135.4,130.1,129.4,129.3,128.9,128.3,128.2,125.5,120.4,120.2,110.9,110.7,55.2,55.1,50.1,46.9,19.9,19.5,18.3；ESI-MS:m/z 404.20[M+Na]+(ii) a HRMS (ESI) calculated as [ M + H, C26H30NO3]+404.2221, detected 404.2220.
Example 26
With the compound bis ((3S) -1-adamantyl) ((2S,3S) -3-tert-butyl-6-dianilino-4-isopropoxy-2, 3-dihydrobenzo [ D ] [1,3] oxy, phosphine-pentayoke-2-) phosphine oxide (I-1) prepared in example 1 as a chiral ligand, an α -arylamide compound E13 having a chiral tertiary carbon center was prepared by an asymmetric Suzuki-Miyaura coupling reaction involving α -bromoamide C1 catalyzed by transition metal palladium and arylboronic acid D13, according to the preparation method of example 14 (the reaction route is shown below).
Figure BDA0002047585180000372
(R) -N- (bis (2-methoxyphenyl) methyl) -2- (2- (4-chloro-3-methoxyphenyl)) propionamide (E13) as a white solid, 64% yield, 92% ee.
The enantiomeric excess value (ee) is determined by chiral high-pressure liquid phase, and the ee value is 92 percent; high-pressure liquid phase conditions: chiral S-Chiral B column, 25 ℃, flow rate of 0.8mL/min, n-hexane/isopropanol: 92/8,230nm,25.67min (S),34.34min (R); [ alpha ] to]D 25:5.3°(c＝0.43,CHCl3).1H NMR(500MHz,CDCl3)δ7.36(d,J＝8.0Hz,1H),7.21～7.13(m,3H),7.05(dd,J＝7.6,1.4Hz,1H),6.91～6.83(m,3H),6.83～6.73(m,4H),6.54(d,J＝9.0Hz,1H),3.79(s,3H),3.67(s,3H),3.64～3.55(m,4H),1.51(d,J＝7.2Hz,3H)；13CNMR(125MHz,CDCl3)δ172.2,157.1,157.0,155.3,141.9,130.3,129.2,129.0,128.8,128.5,128.4,128.3,121.3,120.8,120.4,120.3,111.7,111.0,110.8,56.2,55.3,55.2,50.2,47.1,18.3；ESI-MS:m/z 440.10[M+H]+,462.10[M+Na]+(ii) a HRMS (ESI) calculated as [ M + H, C25H27ClNO4]+440.1627, detected 440.1623.
Example 27
With the compound bis ((3S) -1-adamantyl) ((2S,3S) -3-tert-butyl-6-dianilino-4-isopropoxy-2, 3-dihydrobenzo [ D ] [1,3] oxy, phosphine-pentayoke-2-) phosphine oxide (I-1) prepared in example 1 as a chiral ligand, an α -arylamide compound E14 having a chiral tertiary carbon center was prepared by an asymmetric Suzuki-Miyaura coupling reaction involving α -bromoamide C1 catalyzed by transition metal palladium and arylboronic acid D14, according to the preparation method of example 14 (the reaction route is shown below).
Figure BDA0002047585180000381
(R) -N- (bis (2-methoxyphenyl) methyl) -2- (2- (4-fluoro-3-methoxyphenyl)) propionamide (E14) as a white solid, 70% yield, 94% ee.
The enantiomeric excess value (ee) is determined by chiral high-pressure liquid phase, and the ee value is 94 percent; high-pressure liquid phase conditions: chiral S-Chiral B column, 25 ℃, flow rate of 0.8mL/min, n-hexane/isopropanol: 90/10,230nm,18.71min (S),26.45min (R); [ alpha ] to]D 25:9.9°(c＝0.43,CHCl3).IR(cm-1):3330.7,2961.9,2925.9,1645.2,1536.8,1463.6,1260.6,1246.5,1097.4,1029.6,799.7,762.1,753.8,706.1；1H NMR(500MHz,CDCl3)δ7.21～7.13(m,3H),7.10～7.02(m,2H),6.88～6.73(m,7H),6.54(d,J＝9.0Hz,1H),3.79(s,3H),3.68(s,3H),3.64(s,3H),3.58(q,J＝7.1Hz,1H),1.51(d,J＝7.2Hz,3H)；13C NMR(125MHz,CDCl3)δ172.5,157.1,157.0,151.7(d,J＝245.2Hz),147.9(d,J＝10.9Hz),138.2(d,J＝3.8Hz),129.2,129.1,128.8,128.5,128.3,128.3,120.4,120.2,120.13(d,J＝6.7Hz),116.0(d,J＝18.2Hz),112.9(d,J＝1.7Hz),111.0,110.8,56.3,55.3,55.2,50.2,47.0,18.5；19F NMR(376MHz,CDCl3)δ-140.4(s)；ESI-MS:m/z 446.25[M+Na]+(ii) a HRMS (ESI) calculated as [ M + Na,C25H26FNNaO4]+446.1736, detected 446.1738.
Example 28
With the compound bis ((3S) -1-adamantyl) ((2S,3S) -3-tert-butyl-6-dianilino-4-isopropoxy-2, 3-dihydrobenzo [ D ] [1,3] oxy, phosphine-pentayoke-2-) phosphine oxide (I-1) prepared in example 1 as a chiral ligand, an α -arylamide compound E15 having a chiral tertiary carbon center was prepared by an asymmetric Suzuki-Miyaura coupling reaction involving α -bromoamide C1 catalyzed by transition metal palladium and arylboronic acid D15, according to the preparation method of example 14 (the reaction route is shown below).
Figure BDA0002047585180000391
(R) -N- (bis (2-methoxyphenyl) methyl) -2- (2- (4-methoxy-3-trifluoromethylphenyl)) propionamide (E15) as a white solid, 71% yield, 81% ee.
The enantiomeric excess value (ee) is determined by chiral high-pressure liquid phase, and the ee value is 81 percent; high-pressure liquid phase conditions: chiral IC column, 25 ℃, flow rate of 0.8mL/min, n-hexane/isopropanol: 92/8,230nm,39.40min (S),57.08min (R); [ alpha ] to]D 20:4.0°(c＝0.7,CHCl3).1H NMR(500MHz,CDCl3)δ7.55～7.50(m,1H),7.46(dd,J＝8.5,1.8Hz,1H),7.24～7.13(m,3H),7.05(d,J＝6.7Hz,1H),7.00(d,J＝8.6Hz,1H),6.90～6.74(m,5H),6.55(d,J＝8.9Hz,1H),3.92(s,3H),3.69(s,3H),3.65(s,3H),3.59(q,J＝7.2Hz,1H),1.51(d,J＝7.2Hz,3H)；13C NMR(125MHz,CDCl3)δ172.2,157.0,157.0,156.6(d,J＝1.5Hz),133.5,132.8,129.1,128.9,128.7,128.5,128.4,128.2,126.6(q,J＝5.1Hz),123.7(q,J＝272.5Hz),120.4,120.3,118.9(q,J＝30.9Hz),112.4,110.9,110.8,56.2,55.3,55.2,50.1,46.3,18.5；19F NMR(376MHz,CDCl3)δ-62.3(s)；ESI-MS:m/z 474.20[M+H]+,496.15[M+Na]+(ii) a HRMS (ESI) calculated as [ M + H, C26H27F3NO4]+474.1888, detected 474.1887.
Example 29
With the compound bis ((3S) -1-adamantyl) ((2S,3S) -3-tert-butyl-6-dianilino-4-isopropoxy-2, 3-dihydrobenzo [ D ] [1,3] oxy, phosphine-pentayoke-2-) phosphine oxide (I-1) prepared in example 1 as a chiral ligand, an α -arylamide compound E16 having a chiral tertiary carbon center was prepared by an asymmetric Suzuki-Miyaura coupling reaction involving α -bromoamide C1 catalyzed by transition metal palladium and arylboronic acid D16, according to the preparation method of example 14 (the reaction route is shown below).
Figure BDA0002047585180000392
(R) -N- (bis (2-methoxyphenyl) methyl) -2- (2- (4-benzyloxy-3-chlorophenyl)) propionamide (E16) as a white solid, 70% yield, 87% ee.
The enantiomeric excess value (ee) is measured by chiral high-pressure liquid phase, and the ee value is 87%; high-pressure liquid phase conditions: chiral S-Chiral B column, 25 ℃, flow rate of 0.8mL/min, n-hexane/isopropanol: 85/15,230nm,22.08min (S),35.46min (R); [ alpha ] to]D 20:3.6°(c＝1.00,CHCl3).1H NMR(500MHz,CDCl3)δ7.52～7.45(m,2H),7.44～7.32(m,4H),7.22～7.10(m,4H),7.06～7.02(m,1H),6.95(d,J＝8.5Hz,1H),6.89～6.72(m,5H),6.54(d,J＝8.9Hz,1H),5.19(s,2H),3.66(s,3H),3.62(s,3H),3.53(q,J＝7.2Hz,1H),1.49(d,J＝7.2Hz,3H)；13C NMR(125MHz,CDCl3)δ172.3,157.1,157.0,153.3,136.6,135.3,129.9,129.1,129.0,128.8,128.4,128.3,128.3,128.2,127.2,127.2,123.5,120.4,120.3,114.4,110.9,110.8,71.0,55.3,55.2,50.1,46.3,18.4；ESI-MS:m/z 516.25[M+H]+(ii) a HRMS (ESI) calculated as [ M + Na, C31H30ClNNaO4]+538.1762, detected 538.1756.
Example 30
With the compound bis ((3S) -1-adamantyl) ((2S,3S) -3-tert-butyl-6-dianilino-4-isopropoxy-2, 3-dihydrobenzo [ D ] [1,3] oxy, phosphine-pentayoke-2-) phosphine oxide (I-1) prepared in example 1 as a chiral ligand, an α -arylamide compound E17 having a chiral tertiary carbon center was prepared by an asymmetric Suzuki-Miyaura coupling reaction involving α -bromoamide C1 catalyzed by transition metal palladium and arylboronic acid D17, according to the preparation method of example 14 (the reaction route is shown below).
Figure BDA0002047585180000401
(R) -N- (bis (2-methoxyphenyl) methyl) -2- (2- (2-fluoro-4-methoxyphenyl)) propionamide (E17) as a white solid, 62% yield, 75% ee.
The enantiomeric excess value (ee) is determined by chiral high-pressure liquid phase, and the ee value is 75 percent; high-pressure liquid phase conditions: chiral AD-H column, flow rate 0.8mL/min at 25 ℃, n-hexane/isopropanol: 85/15,230nm,18.88min (S),30.02min (R); [ alpha ] to]D 20:0.7°(c＝0.50,CHCl3).1H NMR(500MHz,CDCl3)δ7.28～7.23(m,2H),7.21～7.16(m,1H),7.16～7.11(m,1H),7.07(d,J＝7.5Hz,1H),6.95(d,J＝8.5Hz,1H),6.87(t,J＝7.5Hz,1H),6.83～6.71(m,3H),6.71～6.63(m,2H),6.54(d,J＝8.8Hz,1H),3.86(q,J＝7.1Hz,1H),3.80(s,3H),3.73(s,3H),3.66(s,3H),1.48(d,J＝7.2Hz,3H)；13C NMR(125MHz,CDCl3)δ172.0,162.0,160.1～159.9(m),157.1(d,J＝14.7Hz),129.5(d,J＝5.9Hz),129.3,129.2,128.9,128.4,128.2,128.2,120.6(d,J＝15.3Hz),120.5,120.2,111.0,110.7,110.3(d,J＝3.0Hz),101.7(d,J＝26.3Hz),55.8,55.3,55.2,50.1,38.9,17.2；19F NMR(376MHz,CDCl3)δ-116.1(s)；ESI-MS:m/z 424.20[M+H]+,446.15[M+Na]+(ii) a HRMS (ESI) calculated as [ M + Na, C25H26FNNaO4]+446.1737, detected 446.1738.
Example 31
With the compound bis ((3S) -1-adamantyl) ((2S,3S) -3-tert-butyl-6-dianilino-4-isopropoxy-2, 3-dihydrobenzo [ D ] [1,3] oxy, phosphine-pentayoke-2-) phosphine oxide (I-1) prepared in example 1 as a chiral ligand, an α -arylamide compound E18 having a chiral tertiary carbon center was prepared by an asymmetric Suzuki-Miyaura coupling reaction involving α -bromoamide C1 catalyzed by transition metal palladium and arylboronic acid D18, according to the preparation method of example 14 (the reaction route is shown below).
Figure BDA0002047585180000411
(R) -N- (bis (2-methoxyphenyl) methyl) -2- (6-methoxynaphthalen-2-yl) propanamide (E18) egg yolk solid, 72% yield, 94% ee.
The enantiomeric excess value (ee) is determined by chiral high-pressure liquid phase, and the ee value is 94 percent; high-pressure liquid phase conditions: chiral AD-H column, flow rate 0.8mL/min at 25 ℃, n-hexane/isopropanol: 85/15,230nm,26.31min (S),39.18min (R); [ alpha ] to]D 25:1.33°(c＝1.00,CHCl3).IR(cm-1):3269.0,2934.2,2837.9,1670.1,1632.4,1516.4,1489.7,1463.5,1265.3,1243.0,1122.9,1029.5,860.7,758.5,745.2,651.8,575.0；1H NMR(500MHz,CDCl3)δ7.78(d,J＝8.5Hz,1H),7.74～7.69(m,2H),7.41(dd,J＝8.4,1.7Hz,1H),7.22～7.10(m,5H),7.04(dd,J＝7.6,1.4Hz,1H),6.96(d,J＝9.0Hz,1H),6.84(t,J＝7.5Hz,1H),6.76(t,J＝7.5Hz,1H),6.71(d,J＝8.1Hz,1H),6.68(d,J＝8.1Hz,1H),6.56(d,J＝9.0Hz,1H),3.95(s,3H),3.77(q,J＝7.2Hz,1H),3.47(s,3H),3.44(s,3H),1.62(d,J＝7.2Hz,3H)；13C NMR(125MHz,CDCl3)δ172.9,157.8,157.0,156.9,136.8,133.9,129.3,129.2,129.1,129.1,128.8,128.3,128.3,128.1,127.4,127.0,126.5,120.3,120.1,119.2,110.8,110.6,105.7,55.4,55.0,55.0,50.2,47.2,18.2；ESI-MS:m/z 456.20[M+H]+(ii) a HRMS (ESI) calculated as [ M + H, C29H30NO4]+456.2171, detected 456.2169.
Confirmation of the stereoconfiguration of compound E18: derivatization methods conventional in the art are employed:
carrying out derivatization reaction on commercial naproxen with R configuration, bis (2-methoxyphenyl) methylamine, dicyclohexylcarbodiimide and N-hydroxysuccinimide according to the following formula to obtain a compound E18;
Figure BDA0002047585180000412
the compound E18 was subjected to chiral high pressure liquid chromatography (high pressure liquid phase condition: chiral AD-H column, 25 ℃, flow rate: 0.8mL/min, n-hexane/isopropanol), and detected to have a retention time of 42.05min for E18(R type).
And (3) derivatizing a mixture of naproxen with R configuration and S configuration, and under the same conditions, by chiral high pressure liquid chromatography, wherein the peak emergence time of the derivative is 26.31min and 39.18 min. The retention time of E18(R type) was 42.05min, and it was found that E18 in the S configuration had a retention time of 26.31 min.
Further, it is presumed that the compound E18 having a retention time of 26.31min is S-form in this example
Figure BDA0002047585180000413
Compound E18 with a retention time of 39.18min is of the R form
Figure BDA0002047585180000421
Example 32
With the compound bis ((3S) -1-adamantyl) ((2S,3S) -3-tert-butyl-6-dianilino-4-isopropoxy-2, 3-dihydrobenzo [ D ] [1,3] oxy, phosphine-pentayoke-2-) phosphine oxide (I-1) prepared in example 1 as a chiral ligand, an α -arylamide compound E19 having a chiral tertiary carbon center was prepared by an asymmetric Suzuki-Miyaura coupling reaction involving α -bromoamide C1 catalyzed by transition metal palladium and arylboronic acid D19, according to the preparation method of example 14 (the reaction route is shown below).
Figure BDA0002047585180000422
(R) -N- (bis (2-methoxyphenyl) methyl) -2- (anthracen-2-yl) propanamide (E19) is an egg white solid, 65% yield, 91% ee.
The enantiomeric excess value (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: 88/12,230nm,29.95min (S),34.94min (R); [ alpha ] to]D 25:1.61°(c＝0.42,CHCl3).IR(cm-1):3316.6,2956.3,2925.3,1733.5,1672.0,1599.7,1490.1,1462.1,1292.5,1246.2,1124.6,1028.0,865.6,754.2,713.2,617.2,418.8；1H NMR(500MHz,CDCl3)δ8.45(s,1H),8.40(s,1H),8.06～8.00(m,3H),7.91(s,1H),7.53～7.46(m,2H),7.42(d,J＝8.8Hz,1H),7.19(d,J＝7.5Hz,1H),7.16～7.07(m,2H),7.07～6.98(m,2H),6.82(t,J＝7.5Hz,1H),6.74(t,J＝7.5Hz,1H),6.69(d,J＝8.2Hz,1H),6.64(d,J＝8.2Hz,1H),6.56(d,J＝9.0Hz,1H),3.83(q,J＝7.1Hz,1H),3.42(s,3H),3.38(s,3H),1.66(d,J＝7.2Hz,3H)；13C NMR(125MHz,CDCl3)δ172.6,157.0,157.0,138.7,132.1,131.9,131.8,131.1,129.3,129.2,128.9,128.8,128.3,128.3,128.2,126.5,126.3,126.2,126.2,125.7,125.6,120.4,120.2,110.9,110.7,55.1,55.0,50.3,47.6,17.9；ESI-MS:m/z 476.25[M+H]+(ii) a HRMS (ESI) calculated as [ M + H, C32H30NO3]+476.2223, detected 476.2220.
Example 33
With the compound bis ((3S) -1-adamantyl) ((2S,3S) -3-tert-butyl-6-dianilino-4-isopropoxy-2, 3-dihydrobenzo [ D ] [1,3] oxy, phosphine-pentayoke-2-) phosphine oxide (I-1) prepared in example 1 as a chiral ligand, an α -arylamide compound E20 having a chiral tertiary carbon center was prepared by an asymmetric Suzuki-Miyaura coupling reaction involving α -bromoamide C1 catalyzed by transition metal palladium and arylboronic acid D20, according to the preparation method of example 14 (the reaction route is shown below).
Figure BDA0002047585180000431
(R) -N- (bis (2-methoxyphenyl) methyl) -2- (benzofuran-5-yl) propanamide (E20) was a white solid, 61% yield, 91% ee.
The enantiomeric excess value (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,21.69min (S),30.99min (R); [ alpha ] to]D 25:2.33°(c＝0.35,CHCl3).1H NMR(500MHz,CDCl3)δ7.66(d,J＝2.1Hz,1H),7.55(d,J＝1.5Hz,1H),7.51(d,J＝8.5Hz,1H),7.25(dd,J＝8.7,1.8Hz,1H),7.18～7.10(m,3H),7.01(dd,J＝7.6,1.4Hz,1H),6.89(d,J＝8.9Hz,1H),6.85～6.81(m,1H),6.78～6.72(m,3H),6.70(d,J＝8.0Hz,1H),6.52(d,J＝9.0Hz,1H),3.74(q,J＝7.2Hz,1H),3.55(s,3H),3.51(s,3H),1.58(d,J＝7.2Hz,3H)；13C NMR(125MHz,CDCl3)δ173.2,157.0,156.9,154.3,145.7,136.3,129.2,129.1,128.8,128.3,128.3,128.2,128.0,124.6,120.5,120.4,120.2,111.6,110.8,110.6,106.7,55.1,55.0,50.2,18.7；ESI-MS:m/z 416.20[M+H]+(ii) a HRMS (ESI) calculated as [ M + H, C26H26NO4]+416.1858, detected 416.1856.
Example 34
With the compound bis ((3S) -1-adamantyl) ((2S,3S) -3-tert-butyl-6-dianilino-4-isopropoxy-2, 3-dihydrobenzo [ D ] [1,3] oxy, phosphine-pentayoke-2-) phosphine oxide (I-1) prepared in example 1 as a chiral ligand, an α -arylamide compound E21 having a chiral tertiary carbon center was prepared by an asymmetric Suzuki-Miyaura coupling reaction involving α -bromoamide C1 catalyzed by transition metal palladium and arylboronic acid D21, according to the preparation method of example 14 (the reaction route is shown below).
Figure BDA0002047585180000432
(R) -N- (bis (2-methoxyphenyl) methyl) -2- (benzofuran-2-yl) propanamide (E21) was a white solid, 72% yield, 87% ee.
The enantiomeric excess value (ee) is measured by chiral high-pressure liquid phase, and the ee value is 87%; high-pressure liquid phase conditions: chiral S-Chiral B column, 25 ℃, flow rate of 0.8mL/min, n-hexane/isopropanol: 90/10,230nm,29.00min (S),50.05min (R); [ alpha ] to]D 25:4.1°(c＝0.35,CHCl3).IR(cm-1):3419.2,2927.2,1652.6,1490.0,1463.9,1246.1,1162.0,1028.9,881.6,753.9,418.8；1H NMR(500MHz,CDCl3)δ7.57(d,J＝7.6Hz,1H),7.48(d,J＝8.1Hz,1H),7.33～7.26(m,3H),7.28～7.23(m,1H),7.20～7.12(m,3H),6.87(t,J＝7.5Hz,1H),6.81(t,J＝7.5Hz,1H),6.73(t,J＝8.9Hz,2H),6.64(s,1H),6.56～6.52(m,1H),3.86(q,J＝7.3Hz,1H),3.53(s,3H),3.51(s,3H),1.64(d,J＝7.3Hz,3H)；13C NMR(125MHz,CDCl3)δ170.0,157.7,157.0,157.0,155.0,128.9,128.9,128.8,128.5,128.4,128.4,128.3,124.2,123.0,121.0,120.4,120.2,111.1,110.8,110.7,103.8,55.1,55.0,50.5,41.7,15.8；ESI-MS:m/z 416.10[M+H]+(ii) a HRMS (ESI) calculated as [ M + Na, C26H25NNaO4]+438.1681, detected 438.1676.
Example 35
With the compound bis ((3S) -1-adamantyl) ((2S,3S) -3-tert-butyl-6-dianilino-4-isopropoxy-2, 3-dihydrobenzo [ D ] [1,3] oxy, phosphine-pentayoke-2-) phosphine oxide (I-1) prepared in example 1 as a chiral ligand, an α -arylamide compound E22 having a chiral tertiary carbon center was prepared by an asymmetric Suzuki-Miyaura coupling reaction involving α -bromoamide C1 catalyzed by transition metal palladium and arylboronic acid D22, according to the preparation method of example 14 (the reaction route is shown below).
Figure BDA0002047585180000441
(R) -N- (bis (2-methoxyphenyl) methyl) -2- (benzo [ d ] [1,3] dioxin-5-yl) propanamide (E22) is a white solid, 70% yield, 91% ee.
The enantiomeric excess value (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 0.8mL/min at 25 ℃, n-hexane/isopropanol: 85/15,230nm,25.01min (S),32.87min (R); [ alpha ] to]D 25:21.1°(c＝0.83,CHCl3).IR(cm-1):3648.6,3418.4,3308.0,2925.7,2853.2,1733.4,1652.1,1600.4,1489.0,1288.4,1245.8,1032.2,935.6,811.2,793.2,754.1,701.6,616.1；1HNMR(500MHz,CDCl3)δ7.21～7.13(m,3H),7.07(dd,J＝7.6,1.5Hz,1H),6.89～6.73(m,8H),6.53(d,J＝8.9Hz,1H),5.96(s,2H),3.70(s,3H),3.67(s,3H),3.53(q,J＝7.2Hz,1H),1.48(d,J＝7.2Hz,3H)；13C NMR(125MHz,CDCl3)δ172.7,157.1,157.0,148.1,146.7,135.7,129.3,129.2,128.8,128.4,128.3,128.3,121.3,120.4,120.3,110.9,110.8,108.5,108.5,101.2,55.3,55.2,50.1,47.0,18.5；ESI-MS:m/z 420.20[M+H]+(ii) a HRMS (ESI) calculated as [ M + H, C25H26NO5]+420.1810, detected 420.1805.
Example 36
With the compound bis ((3S) -1-adamantyl) ((2S,3S) -3-tert-butyl-6-dianilino-4-isopropoxy-2, 3-dihydrobenzo [ D ] [1,3] oxy, phosphine-pentayoke-2-) phosphine oxide (I-1) prepared in example 1 as a chiral ligand, an α -arylamide compound E23 having a chiral tertiary carbon center was prepared by an asymmetric Suzuki-Miyaura coupling reaction involving α -bromoamide C1 catalyzed by transition metal palladium and arylboronic acid D23, according to the preparation method of example 14 (the reaction route is shown below).
Figure BDA0002047585180000451
(R) -N- (bis (2-methoxyphenyl) methyl) -2- (1-methyl-1-indol-5-yl) propionamide (E23) as a white solid, 66% yield, 87% ee.
The enantiomeric excess value (ee) is measured by chiral high-pressure liquid phase, and the ee value is 87%; high-pressure liquid phase conditions: chiral OD-H column, 25 ℃, flow rate 0.8mL/min, n-hexane/isopropanol: 90/10,230nm,29.68min (S),51.30min (R); [ alpha ] to]D 25:8.6°(c＝0.35,CHCl3).IR(cm-1):3414.8,2924.5,1662.7,1490.9,1088.1,793.1,752.9,467.3；1H NMR(500MHz,CDCl3)δ7.57(d,J＝1.4Hz,1H),7.33(d,J＝8.4Hz,1H),7.18～7.07(m,5H),7.02(dd,J＝7.6,1.5Hz,1H),6.94(d,J＝9.1Hz,1H),6.81(td,J＝7.5,0.9Hz,1H),6.75(td,J＝7.5,0.9Hz,1H),6.72～6.65(m,2H),6.52(d,J＝9.1Hz,1H),6.48～6.46(m,1H),3.82(s,3H),3.73(q,J＝7.2Hz,1H),3.49(s,3H),3.48(s,3H),1.59(d,J＝7.3Hz,3H)；13C NMR(125MHz,CDCl3)δ173.9,157.1,157.0,136.2,132.6,129.5,129.4,129.4,129.0,128.9,128.4,128.2,128.1,122.1,120.3,120.2,120.1,110.8,110.6,109.6,101.1,55.1,55.0,50.1,47.4,33.1,18.6；ESI-MS:m/z 429.15[M+H]+(ii) a HRMS (ESI) calculated as [ M + H, C27H29N2O3]+429.2177, detected 429.2173.
Example 37
With the compound bis ((3S) -1-adamantyl) ((2S,3S) -3-tert-butyl-6-dianilino-4-isopropoxy-2, 3-dihydrobenzo [ D ] [1,3] oxy, phosphine-pentayoke-2-) phosphine oxide (I-1) prepared in example 1 as a chiral ligand, an α -arylamide compound E24 having a chiral tertiary carbon center was prepared by an asymmetric Suzuki-Miyaura coupling reaction involving α -bromoamide C1 catalyzed by transition metal palladium and arylboronic acid D24, according to the preparation method of example 14 (the reaction route is shown below).
Figure BDA0002047585180000452
(R) -N- (bis (2-methoxyphenyl) methyl) -2- (6-methoxypyridin-3-yl) propanamide (E24) white solid, 70% yield, 84% ee.
The enantiomeric excess value (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 0.8mL/min at 25 ℃, n-hexane/isopropanol: 85/15,230nm,16.59min (S),26.37min (R); [ alpha ] to]D 25:-3.2°(c＝0.30,CHCl3).1H NMR(500MHz,CDCl3)δ8.09(d,J＝2.4Hz,1H),7.56(dd,J＝8.6,2.5Hz,1H),7.23～7.14(m,3H),7.06(dd,J＝7.6,1.4Hz,1H),6.91～6.72(m,6H),6.54(d,J＝8.8Hz,1H),3.94(s,3H),3.71(s,3H),3.66(s,3H),3.54(q,J＝7.2Hz,1H),1.49(d,J＝7.2Hz,3H)；13C NMR(125MHz,CDCl3)δ172.2,163.6,157.1,157.0,146.0,138.3,130.0,129.1,129.1,128.7,128.5,128.4,128.3,120.5,120.3,111.1,111.0,110.8,55.4,55.3,53.6,50.1,44.0,18.5；ESI-MS:m/z 407.55[M+H]+(ii) a HRMS (ESI) calculated as [ M + H, C24H27N2O4]+407.1970, detected 407.1965.
Example 38
With the compound bis ((3S) -1-adamantyl) ((2S,3S) -3-tert-butyl-6-dianilino-4-isopropoxy-2, 3-dihydrobenzo [ D ] [1,3] oxy, phosphine-pentayoke-2-) phosphine oxide (I-1) prepared in example 1 as a chiral ligand, an α -arylamide compound E25 having a chiral tertiary carbon center was prepared by an asymmetric Suzuki-Miyaura coupling reaction involving α -bromoamide C2 catalyzed by transition metal palladium and arylboronic acid D1, according to the preparation method of example 14 (the reaction route is shown below).
Figure BDA0002047585180000461
(R) -N- (bis (2-methoxyphenyl) methyl) -2- (4-methoxyphenyl) butanamide (E25) is a white solid, 50% yield, 90% ee.
The enantiomeric excess value (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 0.8mL/min at 25 ℃, n-hexane/isopropanol: 90/10,230nm,12.15min (S),18.45min (R); [ alpha ] to]D 25:1.8°(c＝0.30,CHCl3).IR(cm-1):3269.6,2955.7,2929.2,2834.2,1668.2,1643.8,1552.7,1509.2,1490.2,1239.9,1174.6,1025.6,824.0,752.7,609.7,538.3,520.3；1H NMR(500MHz,CDCl3)δ7.25～7.20(m,2H),7.20～7.12(m,3H),7.03(dd,J＝7.6,1.6Hz,1H),6.92～6.88(m,2H),6.85(td,J＝7.5,1.0Hz,1H),6.82～6.72(m,4H),6.54(d,J＝8.8Hz,1H),3.82(s,3H),3.68(s,3H),3.63(s,3H),3.25(dd,J＝8.5,6.7Hz,1H),2.25～2.16(m,1H),1.82～1.70(m,1H),0.86(t,J＝7.4Hz,3H)；13C NMR(125MHz,CDCl3)δ172.5,158.8,157.1,157.0,132.3,129.5,129.3,129.2,128.7,128.3,128.3,128.2,120.3,120.2,114.1,110.8,110.7,55.4,55.3,55.2,54.5,49.9,26.1,12.5；ESI-MS:m/z 420.20[M+H]+,442.20[M+Na]+(ii) a HRMS (ESI) calculated as [ M + H, C26H30NO4]+420.2174, detected 420.2169.
Example 39
With the compound bis ((3S) -1-adamantyl) ((2S,3S) -3-tert-butyl-6-dianilino-4-isopropoxy-2, 3-dihydrobenzo [ D ] [1,3] oxy, phosphine-pentayoke-2-) phosphine oxide (I-1) prepared in example 1 as a chiral ligand, an α -arylamide compound E26 having a chiral tertiary carbon center was prepared by an asymmetric Suzuki-Miyaura coupling reaction involving α -bromoamide C3 catalyzed by transition metal palladium and arylboronic acid D1, according to the preparation method of example 14 (the reaction route is shown below).
Figure BDA0002047585180000462
(R) -N- (bis (2-methoxyphenyl) methyl) -2- (4-methoxyphenyl) hexanamide (E26) was a white solid, 54% yield, 92% ee.
The enantiomeric excess value (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 0.8mL/min at 25 ℃, n-hexane/isopropanol: 90/10,230nm,34.22min (S),43.76min (R); [ alpha ] to]D 25:-0.38°(c＝0.30,CHCl3).IR(cm-1):3419.2,3315.4,2999.7,2954.4,2926.7,1652.3,1509.9,1463.1,1288.6,1246.5,1178.2,1030.3,869.4,753.4,570.4,531.7；1H NMR(500MHz,CDCl3)δ7.23～7.20(m,2H),7.19～7.11(m,3H),7.02(dd,J＝7.6,1.5Hz,1H),6.92～6.87(m,2H),6.84(t,J＝7.5Hz,1H),6.80～6.76(m,3H),6.74(d,J＝8.1Hz,1H),6.53(d,J＝8.8Hz,1H),3.82(s,3H),3.68(s,3H),3.62(s,3H),3.33(dd,J＝8.5,6.8Hz,1H),2.21～2.13(m,1H),1.77～1.67(m,1H),1.32～1.25(m,2H),1.23～1.13(m,2H),0.84(t,J＝7.1Hz,3H)；13C NMR(125MHz,CDCl3)δ172.6,158.8,157.1,157.1,132.6,129.4,129.4,129.3,128.8,128.3,128.3,128.2,120.4,120.2,114.2,110.9,110.7,55.5,55.3,55.2,52.8,49.9,32.7,30.1,22.7,14.1；ESI-MS:m/z 448.20[M+H]+,470.20[M+Na]+(ii) a HRMS (ESI) calculated as [ M + Na, C28H33NNaO4]+470.2312, detected 470.2302.
Example 40
With the compound bis ((3S) -1-adamantyl) ((2S,3S) -3-tert-butyl-6-dianilino-4-isopropoxy-2, 3-dihydrobenzo [ D ] [1,3] oxy, phosphine-pentayoke-2-) phosphine oxide (I-1) prepared in example 1 as a chiral ligand, an α -arylamide compound E27 having a chiral tertiary carbon center was prepared by an asymmetric Suzuki-Miyaura coupling reaction involving α -bromoamide C4 catalyzed by transition metal palladium and arylboronic acid D1, according to the preparation method of example 14 (the reaction route is shown below).
Figure BDA0002047585180000471
(R) -N- (bis (2-methoxyphenyl) methyl) -2- (4-methoxyphenyl) -4-methylpentanamide (E27) white solid, 42% yield, 91% ee.
The enantiomeric excess value (ee) is determined by chiral high-pressure liquid phase, and the ee value is 91 percent; high-pressure liquid phase conditions: chiral S-Chiral B column, 25 ℃, flow rate of 0.8mL/min, n-hexane/isopropanol: 94/6,230nm,16.82min (S),39.07min (R); [ alpha ] to]D 25:-4.3°(c＝0.40,CHCl3).1H NMR(500MHz,CDCl3)δ7.25～7.11(m,5H),7.01(d,J＝7.0Hz,1H),6.93～6.70(m,7H),6.52(d,J＝7.9Hz,1H),3.82(s,3H),3.67(s,3H),3.62(s,3H),3.50～3.43(m,1H),2.04～1.96(m,1H),1.73～1.61(m,1H),1.47～1.41(m,1H),0.88(d,J＝6.4Hz,3H),0.85(d,J＝6.4Hz,3H)；13C NMR(125MHz,CDCl3)δ172.8,158.8,157.1,157.0,132.5,129.5,129.2,129.2,128.8,128.4,128.3,128.2,120.4,120.2,114.2,110.9,110.7,55.5,55.4,55.3,50.5,50.0,41.7,25.7,23.2,22.0；ESI-MS:m/z 448.20[M+H]+,470.20[M+Na]+(ii) a HRMS (ESI) calculated as [ M + H, C28H34NO4]+448.2486, detected 448.2482.
EXAMPLE 41
With the compound bis ((3S) -1-adamantyl) ((2S,3S) -3-tert-butyl-6-dianilino-4-isopropoxy-2, 3-dihydrobenzo [ D ] [1,3] oxy, phosphine-pentayoke-2-) phosphine oxide (I-1) prepared in example 1 as a chiral ligand, an α -arylamide compound E28 having a chiral tertiary carbon center was prepared by an asymmetric Suzuki-Miyaura coupling reaction involving α -bromoamide C5 catalyzed by transition metal palladium and arylboronic acid D1, according to the preparation method of example 14 (the reaction route is shown below).
Figure BDA0002047585180000481
(R) -N- (bis (2-methoxyphenyl) methyl) -2- (4-methoxyphenyl) -4-phenylbutanamide (E28) white solid, 50% yield, 90% ee.
The enantiomeric excess value (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 0.8mL/min, n-hexane/isopropanol: 15,230nm,12.92min (S),21.95min (R); [ alpha ] to]D 25:-13.0°(c＝0.45,CHCl3).IR(cm-1):3269.6,2951.9,2931.8,1643.1,1537.7,1511.4,1489.4,1461.2,1290.1,1243.7,1176.2,1051.5,1028.6,824.9,751.2,699.2,606.5,585.9；1HNMR(500MHz,CDCl3)δ7.29～7.11(m,10H),7.00(dd,J＝7.6,1.3Hz,1H),6.92(d,J＝8.6Hz,2H),6.86(t,J＝7.3Hz,1H),6.83～6.72(m,4H),6.56(d,J＝8.8Hz,1H),3.84(s,3H),3.68(s,3H),3.62(s,3H),3.37～3.32(m,1H),2.61～2.50(m,3H),2.09～2.01(m,1H)；13C NMR(125MHz,CDCl3)δ172.2,158.8,157.0,156.9,141.8,132.1,129.5,129.2,129.1,128.8,128.6,128.4,128.4,128.2,128.1,125.9,120.4,120.1,114.2,110.8,110.6,55.5,55.3,55.2,51.6,49.9,34.3,33.7；ESI-MS:m/z 496.30[M+H]+,518.25[M+Na]+(ii) a HRMS (ESI) calculated as [ M + H, C32H34NO4]+496.2483, detected 496.2482.
EXAMPLE 42 catalysis of the asymmetric coupling reaction of alpha-bromoamides with aryl boronic acids by different ligands
α -arylamide-based compound E having a chiral tertiary carbon center was prepared by an asymmetric Suzuki-Miyaura coupling reaction in which α -bromoamide C and arylboronic acid D1 were participated, with the yield and ee value shown in table 1 below, using the preparation method of reference example 14.
Figure BDA0002047585180000482
TABLE 1
Figure BDA0002047585180000491
Remarking: in the table, "-" indicates that the ee value was not detected; "-91" indicates that the ee value of compound ent-E is 91%.
As can be seen from the above table, the phosphine ligand I-1 of the present invention, applied to asymmetric Suzuki-Miyaura coupling reaction as a metal ligand, gives good yield and excellent selectivity (77% yield, 91% enantioselectivity). This result is fully shown: the ligand of the invention is applied to asymmetric Suzuki-Miyaura coupling reaction, and chiral alpha-aryl amide compounds can be efficiently prepared.
EXAMPLE 43 study of ligand I-1 catalysis of different substrates
The alpha-aryl amide compounds prepared in examples 7-35, and the yields and ee values thereof are summarized as follows:
Figure BDA0002047585180000501
therefore, the catalytic synthesis of various alpha-aryl carbonyl compounds (such as halogen, trifluoromethyl, methylthio, ester group, heterocyclic group or heteroaryl as substituent) by using the ligand of the invention has wide substrate application range. Moreover, the ligand of the invention is applied to the coupling reaction of large steric hindrance aryl halide and aryl boric acid, and the reaction can also obtain good yield, excellent enantioselectivity and substrate universality.
Example 44
A25 mL Schlenk tube was dried, and E1(76mg,0.18mmol,1equiv) was added to the tube, followed by 2mL (2M) of aqueous hydrochloric acid. And heating the reaction system to reflux reaction for 2-3 hours, cooling to room temperature, adding dichloromethane, separating, extracting, combining organic phases, drying with anhydrous sodium sulfate, concentrating, and performing column chromatography separation to obtain a white solid product 30mg, wherein the yield is 80%.
Figure BDA0002047585180000511
[α]D 25:-58.6°(c＝0.90,CHCl3).1H NMR(500MHz,CD3OD)δ7.20(d,J＝8.1Hz,2H),7.09(d,J＝8.1Hz,2H),4.88(s,1H),3.66(q,J＝7.1Hz,1H),2.44(d,J＝7.2Hz,2H),1.83(dp,J＝13.6,6.8Hz,1H),1.42(d,J＝7.2Hz,3H),0.89(d,J＝6.6Hz,6H)；13C NMR(125MHz,CD3OD)δ178.5,141.5,139.8,130.3,128.2,46.3,46.0,31.4,22.7,19.1；ESI-MS:m/z229.0[M+Na]+(ii) a HRMS (ESI) calculated as [ M +2Na-H, C13H17Na2O2]+251.1021, detected 251.1018.
Example 45
Referring to the preparation method of example 44, α -aryl carboxylic acid compound F18 (R-naproxen) having a chiral tertiary carbon center was prepared by hydrolysis (the reaction scheme is shown below).
Figure BDA0002047585180000512
[α]D 25:-43.9°(c＝0.90,CHCl3).1H NMR(500MHz,CDCl3)δ7.75～7.66(m,3H),7.42(dd,J＝8.5,1.7Hz,1H),7.17～7.09(m,2H),3.91(s,3H),3.88(q,J＝7.2Hz,1H),1.60(d,J＝7.2Hz,3H)；13C NMR(125MHz,CDCl3)δ180.9,157.8,135.0,133.9,129.4,129.0,127.4,126.3,126.3,119.2,105.7,55.4,45.4,18.3；ESI-MS:m/z 231.0[M+H]+HRMS (ESI) calculated as [ M +2Na-H, C14H13Na2O3]+275.658, detected 275.0655.
Example 46
Referring to the preparation method of example 44, α -arylcarboxylic acid-based compound F11 (R-flurbiprofen) having a chiral tertiary carbon center was prepared by hydrolysis (the reaction scheme is shown below).
Figure BDA0002047585180000513
[α]D 25:-46.0°(c＝0.90,CHCl3).1H NMR(500MHz,CDCl3)δ7.57～7.51(m,2H),7.48～7.35(m,4H),7.21～7.14(m,2H),3.80(q,J＝7.2Hz,1H),1.57(d,J＝7.2Hz,3H)；13CNMR(125MHz,CDCl3)δ180.3,160.8,158.8,141.0(d,J＝7.7Hz),135.5,131.0(d,J＝3.9Hz),129.1(d,J＝2.9Hz),128.6,128.3(d,J＝13.6Hz),127.8,123.8(d,J＝3.3Hz),115.5(d,J＝23.8Hz),45.0,18.1；19F NMR(376MHz,CDCl3)δ-112.9(s)；ESI-MS:m/z 267.0[M+Na]+(ii) a HRMS (ESI) calculated as [ M +2Na-H, C15H12FNa2O2]+289.0612, detected 289.0611.

Claims (14)

1. A phosphine oxide compound is a compound shown in a formula I and/or a compound shown in a formula ent-I:
Figure 635976DEST_PATH_IMAGE001
wherein R is1Is composed of
Figure 848783DEST_PATH_IMAGE002
、C1-10Alkoxy radical, C6-30Aryl, one or more C1-4Alkoxy-substituted C6-30Aryl or C substituted by one or more phenyl groups2~6The heteroaryl group of (a);
R1aand R1bIndependently is C1-4Alkyl or C6-30An aryl group;
c substituted by said one or more phenyl groups2~6The heteroatoms in the heteroaryl group of (a) are independently selected from N, O and S, the number of heteroatoms is independently 1,2 or 3;
R2is C1-10An alkoxy group;
R3is C1-10An alkyl group;
R4and R5Independently is C1-10Alkyl or C3-12A cycloalkyl group.
2. The phosphine oxide compound of claim 1, wherein when R is1Is composed of
Figure 288991DEST_PATH_IMAGE002
，R1aAnd R1bIndependently is C1-4When alkyl, said C1-4The alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl,
Figure 545529DEST_PATH_IMAGE003
、
Figure 946554DEST_PATH_IMAGE004
Or a tert-butyl group;
and/or when R1Is C1-10At alkoxy, the C1-10Alkoxy is C1-4An alkoxy group;
and/or when R1Is C6-30Aryl is said to C6-30Aryl is C6-20An aryl group;
and/or when R1Is one or more than one C1-4Alkoxy-substituted C6-30When aryl, said C6-30Aryl is C6-20An aryl group;
and/or when R1Is one or more than one C1-4Alkoxy-substituted C6-30When aryl, said C1-4The alkoxy is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,
Figure 556527DEST_PATH_IMAGE005
、
Figure 975876DEST_PATH_IMAGE006
Or tert-butoxy;
and/or when R1C substituted by one or more phenyl groups2~6When said heteroaryl is said to be C2~6Heteroaryl is C3~5A heteroaryl group;
and/or when R1C substituted by one or more phenyl groups2~6When said heteroaryl is said C2~6The heteroatom in the heteroaryl group of (a) is N;
and/or when R1C substituted by one or more phenyl groups2~6When said heteroaryl is said C2~6The number of heteroatoms in the heteroaryl group of (a) is 1;
and/or when R1C substituted by one or more phenyl groups2~6In the case of the heteroaryl group of (1), the number of the phenyl group substitution is 2;
and/or when R2Is C1-10At alkoxy, the C1-10Alkoxy is C1-4An alkoxy group;
and/or when R3Is C1-10When alkyl, said C1-10Alkyl is C1-4An alkyl group;
and/or when R4And R5Independently is C3-12When a cycloalkyl group is present, C is3-12Cycloalkyl being C3-10A cycloalkyl group;
and/or when R4And R5Independently is C1-10When alkyl, said C1-10Alkyl is C1-4An alkyl group;
and/or the phosphine oxide compound is
Figure 154048DEST_PATH_IMAGE007
Or
Figure 291637DEST_PATH_IMAGE008
。
3. The phosphine oxide compound of claim 2, wherein when R is1Is composed of
Figure 970880DEST_PATH_IMAGE002
，R1aAnd R1bIndependently is C1-4When alkyl, said C1-4Alkyl is methyl;
when R is1Is C1-10Alkoxy radical, said C1-10Alkoxy isC1-4At alkoxy, the C1-4The alkoxy is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,
Figure 995468DEST_PATH_IMAGE005
、
Figure 593808DEST_PATH_IMAGE006
Or tert-butoxy;
and/or when R1Is C6-30Aryl is said to C6-30Aryl is C6-14An aryl group;
and/or when R1Is one or more than one C1-4Alkoxy-substituted C6-30Aryl is said to C6-30Aryl is C6-14An aryl group;
and/or when R1Is one or more than one C1-4Alkoxy-substituted C6-30Aryl is said to C1-4Alkoxy is independently methoxy;
and/or when R1C substituted by one or more phenyl groups2~6When said heteroaryl is substituted by one or more phenyl groups2~6The heteroaryl group of (A) is C substituted by 2 phenyl groups3~5The heteroaryl group of (a);
and/or when R2Is C1-10At alkoxy, the C1-10Alkoxy is methoxy, isopropoxy or tert-butoxy;
and/or when R3Is C1-10Alkyl radical, said C1-10Alkyl is C1-4When alkyl, said C1-4The alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl,
Figure 828481DEST_PATH_IMAGE003
、
Figure 921201DEST_PATH_IMAGE004
Or a tert-butyl group;
and/or when R4And R5Independently is C3-12Cycloalkyl radicalsWhen C is in contact with3-12Cycloalkyl being C3-10When a cycloalkyl group is present, C is3-10Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or adamantyl;
and/or when R4And R5Independently is C1-10Alkyl radical, said C1-10Alkyl is C1-4When alkyl, said C1-4The alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl,
Figure 315143DEST_PATH_IMAGE003
、
Figure 694171DEST_PATH_IMAGE004
Or a tert-butyl group.
4. A phosphine oxide compound as claimed in claim 3 wherein when R is1Is C1-10Alkoxy radical, said C1-10Alkoxy is C1-4At alkoxy, the C1-4Alkoxy is methoxy;
and/or when R1Is C6-30Aryl is said to C6-30Aryl is phenyl or anthracenyl;
and/or when R1C substituted by one or more phenyl groups2~6In the case of heteroaryl, said phenyl is substituted by C2~6The heteroaryl of (a) is 2 phenyl-substituted pyrrolyl;
and/or when R3Is C1-10Alkyl radical, said C1-10Alkyl is C1-4When alkyl, said C1-4Alkyl is tert-butyl;
and/or when R4And R5Independently is C3-12When a cycloalkyl group is present, C is3-12Cycloalkyl being C3-10When a cycloalkyl group is present, C is3-10Cycloalkyl is adamantyl;
and/or when R4And R5Independently is C1-10Alkyl radical, said C1-10Alkyl is C1-4When alkyl, said C1-4The alkyl group is a tert-butyl group.
5. The phosphine oxide compound according to any one of claims 1 to 4,
when R is1Is C1-4Alkoxy-substituted C6-30Aryl is said to C1-4Alkoxy-substituted C6-30Aryl is dimethoxyphenyl;
and/or when R1C substituted by one or more phenyl groups2~6When said heteroaryl is substituted by one or more phenyl groups2~6The heteroaryl of (A) is 2 phenyl-substituted N-containing C3~5The heteroaryl group of (a).
6. The phosphine oxide compound as defined in claim 5,
when R is1Is composed of
Figure 557085DEST_PATH_IMAGE002
When R is in the above-mentioned range1aAnd said R1bIndependently is C6-30An aryl group;
and/or when R1C substituted by one or more phenyl groups2~6When said heteroaryl is substituted by one or more phenyl groups2~6The heteroaryl group of (a) is a pyrrolyl group substituted with 2 phenyl groups.
7. The phosphine oxide compound as defined in claim 6,
R1is composed of
Figure 702765DEST_PATH_IMAGE002
；
And/or when R1Is composed of
Figure 436365DEST_PATH_IMAGE002
When R is in the above-mentioned range1aAnd said R1bThe same;
and/or, said R4And said R5The same is true.
8. As claimed in claim1 to 4, wherein R is a phosphine oxide compound1Is composed of
Figure 517454DEST_PATH_IMAGE002
Said R is1aAnd said R1bIs C6-30An aryl group;
R2is C1-10An alkoxy group;
R3is C1-10An alkyl group;
and, R4And R5Is C3-12Cycloalkyl or C1-10An alkyl group.
9. The phosphine oxide compound of claim 1, wherein the phosphine oxide compound is optionally any of:
Figure 857211DEST_PATH_IMAGE009
。
10. the method for producing a phosphine oxide compound according to any one of claims 1 to 9, which comprises the steps of: in an organic solvent, carrying out reduction reaction of a compound II and a reducing agent as shown in the following formula to obtain the phosphine oxide compound;
Figure 291735DEST_PATH_IMAGE010
wherein, the product corresponding to the compound II is a compound I; the product corresponding to the compound ent-II is the compound ent-I.
11. A phosphine oxide compound is a compound shown as a formula II and/or a compound shown as an ent-II:
Figure 4476DEST_PATH_IMAGE011
wherein R is1、R2、R3、R4And R5The definitions of (a) and (b) are as defined in any one of claims 1 to 9.
12. A phosphine oxide compound as claimed in claim 11, wherein said phosphine oxide compound is optionally any one of:
Figure 381100DEST_PATH_IMAGE012
。
13. use of a phosphine oxide compound as defined in any one of claims 1 to 9 as a metal ligand in a Suzuki-Miyaura coupling reaction as follows;
Figure 953026DEST_PATH_IMAGE013
wherein, formula C'
Figure 440508DEST_PATH_IMAGE014
"means"
Figure 273335DEST_PATH_IMAGE015
And/or
Figure 571592DEST_PATH_IMAGE016
”；
Figure 880083DEST_PATH_IMAGE017
Is composed of
Figure 515464DEST_PATH_IMAGE018
X is halogen;
R6is C1-10Alkyl radical, C6-30Aryl or one or more R6-1Substituted C1-10An alkyl group;
R6-1independently is C6-20Aryl radicals or one or more C1-4Alkoxy-substituted C6-20An aryl group;
R7is C1-10Alkyl or one or more C6-20Aryl substituted C1-10An alkyl group.
14. The phosphine oxide compound as defined in any one of claims 1 to 9, as a metal ligand, for use in the preparation of α -arylalkyl carboxylic acids represented by formula F:
Figure 343742DEST_PATH_IMAGE019
wherein, the formula C,
Figure 62168DEST_PATH_IMAGE020
、R6And R7Are as defined in claim 13.
CN201910363711.8A 2019-04-30 2019-04-30 Bidentate phosphine-phosphine oxide ligand and intermediate, preparation method and application thereof Active CN111848680B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201910363711.8A CN111848680B (en) 2019-04-30 2019-04-30 Bidentate phosphine-phosphine oxide ligand and intermediate, preparation method and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201910363711.8A CN111848680B (en) 2019-04-30 2019-04-30 Bidentate phosphine-phosphine oxide ligand and intermediate, preparation method and application thereof

Publications (2)

Publication Number Publication Date
CN111848680A CN111848680A (en) 2020-10-30
CN111848680B true CN111848680B (en) 2021-12-14

Family

ID=72965791

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201910363711.8A Active CN111848680B (en) 2019-04-30 2019-04-30 Bidentate phosphine-phosphine oxide ligand and intermediate, preparation method and application thereof

Country Status (1)

Country Link
CN (1) CN111848680B (en)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011056737A1 (en) * 2009-11-05 2011-05-12 Boehringer Ingelheim International Gmbh Novel chiral phosphorus ligands
CN104650145A (en) * 2015-02-06 2015-05-27 中国科学院上海有机化学研究所 Chiral phosphorous ligand as well as metal catalyst containing ligand and application of chiral phosphorous ligand and catalyst

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011056737A1 (en) * 2009-11-05 2011-05-12 Boehringer Ingelheim International Gmbh Novel chiral phosphorus ligands
CN104650145A (en) * 2015-02-06 2015-05-27 中国科学院上海有机化学研究所 Chiral phosphorous ligand as well as metal catalyst containing ligand and application of chiral phosphorous ligand and catalyst

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Efficient cross-coupling of aryl/alkenyl triflates with acyclic secondary alkylboronic acids;Tengda Si et al.;《Organic & Biomolecular Chemistry》;20171113;第17卷;9903-9909 *
Efficient Synthesis of Sterically Hindered Arenes Bearing Acyclic Secondary Alkyl Groups by Suzuki–Miyaura Cross-Couplings;Chengxi Li et al.;《Angewandte Communication》;20150204;第54卷;3792-3796 *
Novel and Efficient Chiral Bisphosphorus Ligands for Rhodium-Catalyzed Asymmetric Hydrogenation;Wenjun Tang et al.;《Organic Letters》;20100211;第12卷(第5期);1104-1107 *

Also Published As

Publication number Publication date
CN111848680A (en) 2020-10-30

Similar Documents

Publication Publication Date Title
CN107235995B (en) Chiral dihydrosilane compound and synthesis method and application thereof
Metallinos et al. (−)‐Sparteine‐Mediated Directed ortho‐Metalation of N‐Cumyl‐N‐ethylferrocenecarboxamide. Versatile Routes to Functionalized Planar Chiral Ferrocenecarboxamides, Amines, Esters and Phosphines
CN106365949B (en) Chiral spiroindane skeleton compound and preparation method thereof
CN1318412C (en) Process for the manufacture of HMG-CoA reductase inhibitory mevalonic acid derivatives
CN108516992A (en) Photocatalytic synthesis at 1- aryl cyclopropyl phosphonate esters method
CN109718851B (en) Chiral quaternary phosphonium salt phase transfer catalyst and preparation method and application thereof
KR20140112528A (en) Chiral imidodiphosphates and derivatives thereof
CN111662331B (en) Phosphine ligand, preparation method thereof and application of phosphine ligand in catalytic synthesis of ortho-tetra-substituted biaryl
TWI298067B (en) New optically active compound, method for kinetic resolution of carbonic acid derivatives and catalyst thereof
WO2006136695A2 (en) Novel p-chiral functionalised arylphosphines and derivatives, the preparation and use thereof for asymmetrical catalysis
CN111848680B (en) Bidentate phosphine-phosphine oxide ligand and intermediate, preparation method and application thereof
CN109293700B (en) Chiral diphosphine ligand, preparation method, intermediate and application thereof
CN111440205B (en) Biboric acid diol ester, preparation method thereof, intermediate thereof and application thereof
Oga et al. Asymmetric Synthesis of Cyclopentene Compounds Containing All-Carbon Quaternary Stereocenters by (3+ 2) Cycloaddition and Its Application in the Formal Synthesis of (R)-(−)-Puraquinonic Acid
CN110437230B (en) Tertiary amine compound, diphosphine ligand, intermediate and preparation method thereof
CN115850304A (en) Method for stereoselectively preparing 2-alkyl-4-boron-based heterocyclic compound
WO2014051077A1 (en) Method for producing nitrogen-containing heterocyclic compound of high purity
CN104804041B (en) NCP ligands, its iridium complex, synthetic method, intermediate and application
CN114907404A (en) 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazolylphosphine ligand and preparation method and application thereof
CN112430228A (en) Chiral 2, 3-dihydrobenzo [ b ] thiophene 1, 1-dioxide, derivative and preparation method
JPH09263583A (en) Production of n-benzylindole
Kündig et al. Synthesis of [6, n] cis-fused ring compounds via Cr-mediated dearomatisation–ring-closing metathesis
WO2011111762A1 (en) Method for producing diaryl derivative, novel binaphthyl derivative, method for producing arene derivative and novel arene derivative
Weißenbacher et al. Synthesis and characterization of novel aminophosphine ligands based on ferrocenodecaline backbones
CN118724934A (en) Mechanochemical synthesis of alpha-haloalkylboron esters

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant