CN110590841A - Nitrogen-phosphorus ligand and preparation method and application thereof - Google Patents

Nitrogen-phosphorus ligand and preparation method and application thereof Download PDF

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CN110590841A
CN110590841A CN201910808324.0A CN201910808324A CN110590841A CN 110590841 A CN110590841 A CN 110590841A CN 201910808324 A CN201910808324 A CN 201910808324A CN 110590841 A CN110590841 A CN 110590841A
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nitrogen
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CN110590841B (en
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刘心元
马灿亮
董晓阳
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Southern University of Science and Technology
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    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
    • B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
    • B01J31/2442—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems
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    • C07—ORGANIC CHEMISTRY
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    • C07C2/86—Preparation of hydrocarbons from hydrocarbons containing a smaller number of carbon atoms by condensation between a hydrocarbon and a non-hydrocarbon
    • C07C2/861—Preparation of hydrocarbons from hydrocarbons containing a smaller number of carbon atoms by condensation between a hydrocarbon and a non-hydrocarbon the non-hydrocarbon contains only halogen as hetero-atoms
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    • 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
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
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    • 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
    • B01J2231/4266—Sonogashira-type, i.e. RY + HC-CR' triple bonds, in which R=aryl, alkenyl, alkyl and R'=H, alkyl or aryl
    • 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
    • B01J2531/10—Complexes comprising metals of Group I (IA or IB) as the central metal
    • B01J2531/16—Copper
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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    • C07B2200/07—Optical isomers

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Abstract

The invention belongs to the field of organic chemical ligands, and discloses a nitrogen-phosphorus ligand, which has a structure shown in a general formula I:wherein R is1Is hydrogen or alkoxy, R is cyclohexyl, naphthyl, optionally substituted phenyl, R is2Is hydrogen, phenyl or alkyl. The invention also discloses four synthetic methods of the nitrogen and phosphorus ligands and application of the nitrogen and phosphorus ligands in Sonogashira asymmetric cross-coupling reaction. The invention takes quinine and cinchonine as core skeletons, and synthesizes a class of compounds through derivationThe nitrogen-phosphorus compound with a novel structure can be used as a ligand of asymmetric reaction, especially because the electronic effect and the steric effect of phosphorus on the ligand can be regulated and controlled, the nitrogen-phosphorus compound has unique advantages in the free radical asymmetric reaction: high catalytic efficiency, wide substrate application range, high yield and good enantioselectivity.

Description

Nitrogen-phosphorus ligand and preparation method and application thereof
Technical Field
The invention belongs to the field of organic chemical ligands, and particularly relates to a nitrogen-phosphorus ligand, and a preparation method and application thereof.
Background
The cortex Cinchonae contains more than 30 alkaloids, wherein quinine is mainly contained in the cortex Cinchonae,the second is quinidine, cinchonidine, cinchonine, etc. Quinine, also known as cinchona cream, is chemically known as cinchona alkaloid and has a molecular formula C20H24N2O2Has important biological activity, is a medicament for treating and preventing malaria and treating scorched insects, and is widely applied.
Meanwhile, cinchona alkaloid is used as an important catalyst and ligand in chemical synthesis and applied to various catalytic reactions, particularly asymmetric catalysis. Due to the unique chiral molecular structure of the compounds, various catalysts designed by taking the compounds as a matrix have made outstanding progress in the fields of chiral primary amine catalysis, thiourea catalysis, base catalysis, phase transfer catalysis and the like in recent years.
However, the structural modifications to cinchona alkaloid have mostly focused on the transformation of certain groups thereof, such as substitution reactions on the hydroxyl group at the 9-position, quaternization on the quinuclidine nitrogen atom, etc. Therefore, the skeleton structure of the catalyst is further modified to obtain a novel cinchona alkaloid compound, and the catalyst has important theoretical and application values for enriching the types of the catalyst and expanding the application range of the catalyst.
Disclosure of Invention
The invention aims to provide a nitrogen-phosphorus ligand which is based on cinchona alkaloid and has a novel structure.
The invention also aims to provide a preparation method of the nitrogen-phosphorus ligand.
The invention also aims to provide the application of the nitrogen-phosphorus ligand.
In order to achieve one of the purposes, the invention adopts the following technical scheme;
a nitrogen phosphorus ligand having the structure of formula i:
wherein R is1Is a hydrogen or an alkoxy group,
r is cyclohexyl, naphthyl, optionally substituted phenyl,
R2is hydrogen, phenyl or alkyl。
Further, the R is selected from the following structures:
a cyclohexyl group which is a group having a ring-opening structure,
a naphthyl group,
a phenyl group,
wherein R is3Selected from alkyl, alkoxy, trifluoromethyl, halogen, phenyl and phenoxy, m represents an integer of 1-5, when m is more than or equal to 2, more than 2R exist3The same or different.
Further, the R is selected from the following structures:
a cyclohexyl group which is a group having a ring-opening structure,
a naphthyl group,
a phenyl group,
wherein R is3Selected from methyl, propyl, butyl, methoxy, trifluoromethyl, fluorine, phenyl and phenoxy, m represents an integer of 1-5, when m is more than or equal to 2, more than 2R exist3The same or different.
Further, the R is selected from the following structures:
a cyclohexyl group which is a group having a ring-opening structure,
a naphthyl group,
a phenyl group,
wherein, when m is 1, R3Selected from propyl, butyl, methoxy, phenyl, phenoxy; when m is 2, R3Selected from butyl, trifluoromethyl, methoxy, phenyl; when m is 3, R3Selected from methyl, propyl, butyl, methoxy, fluoro; when m is 5, R3Is selected from methyl; when m.gtoreq.2, more than 2R are present3The same or different.
Further, R1Is hydrogen or methoxy.
Further, R2Is hydrogen, phenyl or butyl.
Further, R2When hydrogen, R is not phenyl.
Further, the nitrogen phosphorus ligand is selected from the following compounds:
the preparation method of the nitrogen-phosphorus ligand comprises the following steps:
r is optionally substituted phenyl and is not 2,4-6-tri-iPrC6H2，
Reacting the compound S1 with diethyl phosphite to obtain an intermediate S2;
reacting the intermediate S2 with copper trifluoromethanesulfonate and TMDS to obtain an intermediate S3;
reacting the intermediate S3 with o-fluorobenzoic acid methyl ester and KHMDS to obtain an intermediate S4; hydrolysis of intermediate S4 affords intermediate S5;
and carrying out condensation reaction on the intermediate S5 and a quinine derivative S6 to obtain the ligand.
The preparation method of the nitrogen-phosphorus ligand comprises the following steps:
r is a naphthyl group,
reacting the compound S7 with diethyl phosphite to obtain an intermediate S8;
intermediate S8 and O-Bromobenzoic acid methyl ester, Pd (OAc)2And dppp reaction to obtain an intermediate S9;
reacting the intermediate S9 with trichlorosilane and triethylamine to obtain an intermediate S10;
hydrolysis of intermediate S10 affords intermediate S11;
and carrying out condensation reaction on the intermediate S11 and a quinine derivative S6 to obtain the ligand.
The preparation method of the nitrogen-phosphorus ligand comprises the following steps:
r is 2,4-6-tri-iPrC6H2，
Reacting a compound S12 with n-butyl lithium and phosphorus trichloride, and reacting the obtained product with CuCl. LiCl and a compound S19 to obtain an intermediate S13;
reacting the intermediate S13 with trichlorosilane and triethylamine to obtain an intermediate S14;
hydrolysis of intermediate S14 affords intermediate S15;
and carrying out condensation reaction on the intermediate S15 and a quinine derivative S6 to obtain the ligand.
The preparation method of the nitrogen-phosphorus ligand comprises the following steps:
r is a cyclohexyl group,
reacting the compound S16 with n-butyllithium and carbon dioxide to obtain an intermediate S17;
carrying out condensation reaction on the intermediate S17 and a quinine derivative S6 to obtain an intermediate S18;
intermediate S18 was reacted with DMAP to give the ligand.
The application of the ligand in the reaction of synthesizing alkyne by asymmetric cross coupling.
As used herein, "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted phenyl" includes both "unsubstituted phenyl" and "substituted phenyl". It will be understood by those skilled in the art that, for any group containing one or more substituents, such groups are not intended to introduce any substitution or substitution pattern that is sterically impractical, not readily synthesized, and/or inherently unstable.
As used herein, "substituted" means that any one or more hydrogens on the designated atom or group is replaced with a (substituent) selected from the designated group, provided that the designated atom's normal valence is not exceeded.
The "substitution" of the "substituted phenyl" as described herein is mono-or poly-substituted, i.e. includes two possibilities: (1) the benzene ring has a substituent; (2) the benzene ring has two or more same or different substituents;
as used herein, "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-methylpentyl.
As used herein, "alkoxy" refers to-O- (alkyl) and-O- (cycloalkyl), where alkyl, cycloalkyl are defined herein, and non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentyloxy, 2-pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, 2-hexyloxy, 3-methylpentyloxy, cyclopropyloxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. Alkoxy groups typically have 1 to 7 carbon atoms connected by an oxygen bridge.
The term "halogen" as used herein refers to fluorine, chlorine, bromine and iodine.
As used herein, "phenoxy" refers to the group-O-phenyl, wherein phenyl is as defined herein.
As used herein, "phenyl" refers to
"naphthyl" as used herein refers toIncluding 1-naphthyl and 2-naphthyl.
As used herein, "propyl" includes n-propyl, isopropyl.
"butyl" as used herein includes n-butyl, sec-butyl, isobutyl, tert-butyl.
TMDS means tetramethyldisiloxane, KHMDS means potassium bis (trimethylsilyl) amide, EDCI means 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, DMAP means 4-dimethylaminopyridine, dppp means 1, 3-bis (diphenylphosphino) propane, Cy means cyclohexyl, 1-Naph means 1-naphthyl, 2-Naph means 2-naphthyl.
The invention has the following beneficial effects:
the invention takes quinine and cinchonine as core skeletons, synthesizes nitrogen and phosphorus compounds with novel structures through derivation, can be used as ligands of asymmetric reaction, and has unique advantages in free radical asymmetric reaction particularly because the electronic effect and steric effect of phosphorus on the ligands can be regulated and controlled: high catalytic efficiency, wide substrate application range, high yield and good enantioselectivity.
Detailed Description
All reactions were carried out under an argon atmosphere. Unless otherwise indicated, chemicals were purchased from commercial products and were not further purified. Tetrahydrofuran, dichloromethane and toluene used in the experiment are all anhydrous solvents. Wherein anhydrous tetrahydrofuran and toluene are subjected to reflux dehydration by using sodium, and anhydrous dichloromethane is subjected to reflux dehydration by using calcium hydride. Thin Layer Chromatography (TLC) used 60F254 silica gel plates. The silica gel column chromatography uses Qingdao marine silica gel (particle size 0.040-0.063 mm). TLC color development was performed with UV light (254nm) or iodine. NMR spectra were characterized using a Bruker DPX 400 or DPX 500 nuclear magnetic resonance apparatus,1the HNMR is 400 or 500MHz,31PNMR was 162MHz, solvent was deuterated chloroform, and Tetramethylsilane (TMS) was used as an internal standard. Chemical shifts are in ppm and coupling constants are in Hz. In that1In HNMR, δ represents the chemical shiftS represents a singlet, d represents a doublet, t represents a triplet, q represents a quartet, p represents a quintet, m represents a multiplet, br represents a broad peak.
Example 1
Scheme 1:
step 1: diethyl phosphite (1.0mmol) was slowly added dropwise to a stirred solution of Grignard reagent S1(3.0mmol) in tetrahydrofuran at 0 ℃. The reaction mixture was then warmed to room temperature and stirred for 12 hours. After complete conversion (monitored by TLC), the crude mixture was directly purified by silica gel column chromatography (50: 1 ratio of petroleum ether to ethyl acetate) to give pure S2 (50-80% yield).
Step 2: to a stirred solution of S2(1.0mmol) in toluene was added copper triflate (0.1mmol) and 1,1,3, 3-tetramethyldisiloxane TMDS (2.0mmol) at room temperature. The reaction mixture was stirred and heated to reflux for 12 hours. After cooling to room temperature, the toluene solvent was removed under reduced pressure to give crude product S3, which was directly subjected to the next reaction.
And step 3: dissolving the crude product S3 obtained in the last step into tetrahydrofuran, cooling to-78 ℃, and stirring. KHMDS (1.0mmol) was added to the reaction at this temperature, and the reaction was stirred for 30 minutes at room temperature. Then cooling to-78 ℃, adding the o-fluorobenzoic acid methyl ester into the reaction system, slowly heating to room temperature for reaction, and stirring for 24 hours. The mixture was quenched with dilute hydrochloric acid (1M). The organic layer was separated, dried, filtered and concentrated in vacuo. The residue thus obtained was purified by silica gel column chromatography (ratio of petroleum ether to ethyl acetate 20:1) to give S4 (40-60% yield).
And 4, step 4: lithium hydroxide (2.0mmol) was added to a mixed solution of S4(1.0mmol) in tetrahydrofuran and water, and the reaction system was heated to 70 ℃ and refluxed for 24 hours, and then cooled. The organic layer was separated, dried, filtered and concentrated in vacuo. The residue thus obtained was purified by silica gel column chromatography (ratio of petroleum ether to ethyl acetate 1:1) to give S5 (70-80% yield).
And 5: to a solution of S5(1.0mmol) and quinine-derived S6(1.0mmol) (S6 and several other derivatives of amines of the backbone synthesis references: Chinese chem. Lett.2014,25,557.) in dichloromethane were added EDCI (1.2mmol) and DMAP (0.1 mmol). The reaction was stirred at room temperature for 24 hours and quenched by addition of water. The organic layer was separated, dried, filtered and concentrated in vacuo. The residue thus obtained was purified by silica gel column chromatography (ratio of petroleum ether to ethyl acetate 1:2) to obtain ligand 1 (60-80% yield).
Characterization data for ligand 1:
1H NMR(400MHz,CDCl3)δ8.69(d,J＝4.4Hz,1H),7.98(d,J＝9.2Hz,1H),7.71(s,1H),7.63-7.15(m,23H),7.06-6.95(m,1H),6.02-5.64(m,2H),5.12-4.97(m,2H),3.92(s,3H),3.77(s,1H),3.49(s,1H),3.30-3.20(m,1H),3.04-2.88(m,1H),2.84-2.70(m,1H),2.48-2.31(m,1H),1.88-1.55(m,4H),1.10-0.92(m,1H)；13C NMR(100MHz,CDCl3)δ169.2,158.2,147.6,144.9,141.4,141.3,140.4,139.1,136.1,134.4,134.3,134.2,134.1,131.7,130.7,129.0,128.9,127.7,127.2,127.1,127.0,122.2,116.1,102.1,56.1,55.0,41.4,38.2,27.2,26.4,25.6；31P NMR(162MHz,CDCl3)δ-11.3。
the ligands 1-10, 12-15, 19-23 can be synthesized by the synthetic route 1.
Example 2
Characterization data for ligand 2:
1H NMR(400MHz,CDCl3)δ8.73-8.58(m,1H),8.08-7.92(m,1H),7.73-7.61(m,2H),7.40-7.21(m,5H),7.09-6.93(m,4H),6.89-6.71(m,5H),5.79-5.66(m,1H),5.62-5.30(m,1H),5.06-4.89(m,2H),3.97(s,3H),3.76(s,6H),3.11-2.94(m,3H),2.70-2.54(m,2H),2.29-2.19(m,1H),1.67-1.50(m,3H),1.48-1.38(m,1H),0.92-0.79(m,1H)；13C NMR(101MHz,CDCl3)δ168.7,160.0,159.9,157.6,147.4,144.6,141.3,135.2,135.0,134.9,134.7,133.5,131.3,130.0,128.3,121.5,114.3,114.2,114.1,114.03,113.95,102.1,55.8,55.6,55.00,54.98,40.9,39.4,27.7,27.3,26.1；31P NMR(162MHz,CDCl3):δ-13.74。
example 3
Characterization data for ligand 3:
1H NMR(400MHz,CDCl3)δ8.69(d,J＝4.4Hz,1H),8.01(d,J＝9.2Hz,1H),7.71(d,J＝2.4Hz,1H),7.66-7.58(m,1H),7.43-7.27(m,9H),7.17-6.80(m,15H),5.83-5.64(m,1H),5.64-5.36(m,1H),5.09-4.90(m,2H),3.97(s,3H),3.36-3.00(m,3H),2.73-2.57(m,2H),2.41-2.19(m,1H),1.76-1.54(m,3H),1.51-1.37(m,1H),1.03-0.81(m,1H)；13C NMR(100MHz,CDCl3)δ169.0,158.5,158.3,157.9,156.3,156.2,147.6,144.8,141.2,135.5,135.33,135.28,135.1,134.1,129.9,124.02,123.97,121.8,119.8,119.7,118.4,118.3,118.2,114.8,102.3,56.0,55.8,41.2,39.5,27.8,27.5,26.3；31P NMR(162MHz,CDCl3)δ-13.4。
example 4
Characterization data for ligand 4:
1H NMR(400MHz,CDCl3)δ8.65(d,J＝4.4Hz,1H),8.01(d,J＝9.2Hz,1H),7.70(d,J＝2.6Hz，1H)，7.66-7.58(m，1H)，7.38-7.25(m，8H)，7.08(t，J＝7.8Hz，2H)，7.02(t，J＝7.8Hz，2H),6.98-6.95(m,1H),5.74-5.65(m,1H),5.47(brs,1H),4.97-4.93(m,2H),3.97(s,3H),3.15-2.94(m,3H),2.59-2.45(m,2H),2.25-2.19(m,1H),1.61-1.54(m,3H),1.43-1.32(m,1H),1.30(s,9H),1.29(s,9H),0.92-0.87(m,1H)；13C NMR(100MHz,CDCl3)δ169.0,157.7,151.7,151.5,147.6,144.7,141.8(d,J＝27.9Hz),141.5,135.7(d,J＝20.8Hz),134.4,133.7(d,J＝9.8Hz),133.6,133.43,133.36,133.2,133.6,130.1,128.7,128.5,125.7(d,J＝6.8Hz),125.5(d,J＝6.8Hz),121.7,114.5,102.2,56.0,55.7,48.9,41.0,39.6,34.7,34.6,33.9,31.31,31.30,28.0,27.4,26.2,25.6,25.0；31P NMR(162MHz,CDCl3)δ-14.4。
example 5
Characterization data for ligand 5:
1H NMR(400MHz,CDCl3)δ8.53(s,1H),7.99(d,J＝9.2Hz,1H),7.69(s,1H),7.59(s,1H),7.44-7.20(m,9H),7.12-7.00(m,2H),6.99-6.88(m,1H),6.88-6.71(m,1H),5.74-5.53(m,1H),5.34(br,1H),5.00-4.83(m,2H),3.94(s,1H),3.75-3.53(m,2H),3.20-2.14(m,8H),1.74-1.49(m,4H),1.13-0.96(m,12H)；13C NMR(100MHz,CDCl3)δ168.7,157.7,147.8,144.6,141.3,135.1,133.9,131.7,129.4,128.7,126.2,125.70,125.66,125.6,121.3,114.4,102.2,55.8,55.6,41.0,39.6,31.5,31.4,31.3,31.1,28.0,27.4,27.0,24.0；31P NMR(162MHz,CDCl3):δ-30.4。
example 6
Characterization data for ligand 6:
1H NMR(400MHz,CDCl3)δ8.58(d,J＝4.4Hz,1H),8.01(d,J＝9.2Hz,1H),7.70(d,J＝2.3Hz,2H),7.63(s,1H),7.44–7.35(m,4H),7.34–7.29(m,1H),7.18(s,1H),7.13–7.07(m,2H),7.00(dd,J＝7.9,1.7Hz,2H),6.90(dd,J＝7.1,3.9Hz,1H),5.67(ddd,J＝17.5,10.3,7.6Hz,1H),5.44(s,1H),5.02–4.87(m,2H),4.00(s,3H),3.06(dd,J＝13.8,10.1Hz,2H),2.86(s,1H),2.58(s,1H),2.52–2.42(m,1H),2.19(d,J＝22.4Hz,2H),1.65–1.51(m,3H),1.23(d,J＝15.7Hz,36H),0.95(dd,J＝13.1,6.5Hz,1H)；13C NMR(101MHz,CDCl3)δ168.8,157.6,150.7,150.6,147.6,144.5,141.4,136.0,135.9,134.2,131.6,130.0,128.6,128.1,127.9,127.7,122.4,122.3,121.3,114.4,102.0,60.3,56.0,55.6,40.8,39.6,34.9,34.8,31.4,31.3,28.0,27.3,25.6,21.0,14.2；31P NMR(162MHz,CDCl3)δ-8.63。
example 7
Characterization data for ligand 7:
1H NMR(400MHz,CDCl3)δ8.67(d,J＝4.3Hz,1H),8.01(d,J＝9.1Hz,1H),7.87(s,1H),7.80–7.68(m,3H),7.60(dd,J＝24.6,5.9Hz,4H),7.39(dd,J＝21.2,6.8Hz,4H),6.85(s,1H),5.75(dt,J＝17.3,8.9Hz,1H),5.48(s,1H),5.09–4.88(m,2H),3.90(s,3H),3.36–3.06(m,3H),2.84–2.61(m,2H),2.33(s,1H),1.62(dd,J＝43.9,20.1Hz,4H),1.05-0.95(m,1H)；13C NMR(101MHz,CDCl3)δ167.7,157.9,147.4,144.7,141.6,141.4,141.2,140.9,140.7,139.9,139.7,134.4,134.2,133.6,133.4,133.1,132.9,132.4,132.2,132.1,132.1,132.0,131.9,131.8,131.7,131.6,131.6,131.5,131.4,131.3,131.21,131.15,130.1,128.6,128.5,127.73,127.69,127.1,127.0,124.4,124.3,122.9,122.8,121.7,121.6,118.9,118.9,114.6,102.1,56.0,55.5,41.0,39.4,27.7,27.3,26.5；19F NMR(376MHz,CDCl3)δ-62.97,-63.00；31P NMR(162MHz,CDCl3)δ-7.28。
example 8
Characterization data for ligand 8:
1H NMR(400MHz,CDCl3)δ8.67(d,J＝3.8Hz,1H),7.99(d,J＝9.0Hz,1H),7.72-7.61(m,2H),7.39-7.21(m,5H),6.95(s,1H),6.43-6.25(m,6H),5.77-5.65(m,1H),5.47(s,1H),5.02-4.91(m,2H),3.97(s,3H),3.67(s,12H),3.21-3.07(m,2H),3.05-2.89(m,1H),2.70-2.59(m,1H),2.56-2.46(m,1H),2.23(s,2H),1.63-1.55(m,2H),1.44-1.36(m,1H),0.94-0.82(m,1H)；13C NMR(101MHz,CDCl3)δ168.8,160.7,160.62,160.60,160.5,157.7,157.6,147.4,144.6,141.3,141.1,138.9,134.2,131.4,130.3,128.9,128.2,121.5,114.4,111.45,111.41,111.24,111.19,102.0,100.8,100.7,55.7,55.6,55.2,40.9,39.4,27.8,27.3,26.1；31P NMR(162MHz,CDCl3)δ-6.57。
example 9
Characterization data for ligand 9:
1H NMR(400MHz,CDCl3)δ8.61(d,J＝4.4Hz,1H),7.94(d,J＝9.2Hz,1H),7.78(s,1H),7.74-7.65(m,2H),7.56-7.48(m,12H),7.46-7.27(m,18H),7.18-7.12(m,1H),5.67-5.52(m,1H),5.44(brs,1H),4.93-4.80(m,2H),3.89(s,3H),3.20-2.81(m,3H),2.60-2.49(m,1H),2.47-2.39(m,1H),2.22-2.12(m,1H),1.67-1.44(m,3H),1.39-1.29(m,1H),0.95-0.81(m,1H)；13C NMR(100MHz,CDCl3)δ171.3,169.0,157.8,147.7,144.8,142.0,141.9,141.4,140.7,140.0,138.8,138.6,138.5,135.3,134.6,131.6,131.4,130.7,128.9,128.5,127.7,127.3,126.9,126.7,121.6,114.5,102.2,55.9,55.7,41.0,39.6,28.0,27.4,21.2；31P NMR(162MHz,CDCl3):δ-8.6。
example 10
Characterization data for ligand 10:
1H NMR(400MHz,CDCl3)δ8.61(s,1H),8.36(d,J＝4.6Hz,1H),7.97(d,J＝9.2Hz,1H),7.90(t,J＝6.5Hz,1H),7.68(d,J＝2.8Hz,1H),7.37–7.31(m,2H),7.24–7.14(m,2H),6.87(d,J＝3.1Hz,2H),6.77(d,J＝3.2Hz,2H),6.60(s,1H),5.75(ddd,J＝17.5,10.4,7.4Hz,1H),5.53(d,J＝10.8Hz,1H),5.03–4.94(m,2H),3.96(s,3H),3.24(qd,J＝10.5,6.1Hz,2H),2.91(d,J＝9.3Hz,1H),2.77–2.65(m,2H),2.31(d,J＝2.8Hz,6H),2.11(s,6H),1.94(s,6H),1.82(d,J＝31.5Hz,2H),1.61(ddq,J＝16.0,6.6,3.0Hz,2H),1.44–1.33(m,1H),0.93–0.84(m,1H)；13C NMR(101MHz,CDCl3)δ168.1,157.7,147.6,144.5,143.6,143.5,142.6,142.4,141.6,138.9,138.1,133.3,131.5,130.3,130.3,130.2,130.2,130.0,128.4,121.4,114.4,101.8,41.2,39.7,28.0,27.5,26.0,23.0,22.9,22.6,22.5,21.0,20.9；31P NMR(162MHz,CDCl3)δ-30.28。
example 11
Characterization data for ligand 12:
1H NMR(400MHz,CDCl3)δ8.64(s,1H),8.43(d,J＝4.8Hz,1H),7.97(d,J＝9.2Hz,1H),7.94-7.84(m，1H)，7.68(d，J＝2.8Hz，1H)，7.40-7.30(m，2H)，7.25-7.12(m，2H)，6.80-6.39(m，5H)，5.89-5.68(m，1H)，5.60(br，1H)，5.15-4.87(m，2H)，3.95(s，3H)，3.81(s，6H)，3.41-3.19(m，2H)，2.86-2.67(m，2H)，2.11(s，6H)，1.92(s，6H)，1.74-1.51(m，4H)，0.95-0.78(m，3H)；31P NMR(162MHz，CDCl3)δ-31.6。
example 12
Characterization data for ligand 13:
1H NMR(400MHz,CDCl3)δ8.55(d,J＝4.6Hz,1H),7.92(d,J＝9.2Hz,1H),7.67–7.56(m,3H),7.54(d,J＝9.7Hz,1H),7.51–7.45(m,1H),7.43–7.34(m,1H),7.33–7.21(m,4H),6.96(d,J＝7.6Hz,2H),6.87(d,J＝7.7Hz,2H),6.80–6.73(m,1H),5.58(ddd,J＝17.5,10.3,7.6Hz,1H),5.36(s,1H),4.91–4.76(m,2H),3.91(s,3H),3.60(d,J＝4.3Hz,6H),2.99(dd,J＝13.9,10.0Hz,2H),2.83(s,1H),2.57–2.32(m,2H),2.14(d,J＝5.4Hz,1H),1.78(s,2H),1.51(d,J＝22.4Hz,3H),1.22(d,J＝11.9Hz,36H)；31PNMR(162MHz,)δ-11.22。
example 13
Characterization data for ligand 14:
1H NMR(400MHz,CDCl3):δ8.79(d,J＝4.4Hz,1H),8.05(d,J＝9.2Hz,1H),7.79(d,J＝4Hz，1H)，7.64(s，1H)，7.50-7.39(m，6H)，7.24-7.18(m，2H)，7.04-6.99(m，1H)，6.10-6.05(m，1H)，5.91-5.83(m，1H)，5.37-5.24(m，3H)，4.14-4.07(m，2H)，3.93(s，4H)，3.61-3.55(m，1H)，3.36-3.32(m，1H)，2.76(s，1H)，2.04-2.03(m，3H)，1.14-1.11(m，1H)；13C NMR(100MHz，CDCl3) (C-P coupling not removed): δ 169.0, 158.5, 152.6-152.3(m), 150.2-149.9(m), 147.8, 144.6, 140.9(d, J ═ 7.1Hz), 140.1, 136.5, 133.5, 132.9(d, J ═ 12.7Hz), 131.8, 129.6(d, J ═ 13.2Hz), 129.2, (d, J ═ 9.8Hz), 127.8, 125.5, 124.4, 122.0, 120.3, 117.8, 117.1-116.8(m), 116.2-115.9(m), 101.1, 58.8, 55.9, 53.4, 48.4, 42.8, 36.7, 26.6, 24.9, 24.4;19F NMR(376MHz，CDCl3)δ-129.5，-129.8，-151.4；31P NMR(162MHz，CDCl3)：δ29.9。
example 14
Characterization data for ligand 15:
1H NMR(400MHz,CDCl3)δ8.99(d,J＝5.8Hz,1H),8.21(d,J＝4.4Hz,1H),8.02-7.96(m，1H)，7.92(d，J＝9.2Hz，1H)，7.68(d，J＝2.5Hz，1H)，7.33-7.27(m，2H)，7.23-7.15(m，2H)，6.30(s，1H)，5.78-5.68(m，1H)，5.54(d，J＝9.0Hz，1H)，4.98(d，J＝8.3Hz，1H)，4.94(s，1H)，3.96(s，3H)，3.30-3.19(m，2H)，2.85(d，J＝7.2Hz，1H)，2.76-2.66(m，2H)，2.27(s，6H)，2.25-2.21(m,1H),2.17(s,12H),2.07(s,6H),1.94(s,6H),1.62-1.51(m,3H),1.33(t,J＝11.7Hz,1H),0.81(dd,J＝13.6,6.7Hz,1H)；13C NMR(101MHz,CDCl3)δ167.7,157.,147.3,145.1,144.2,141.5,138.8,138.7,137.4,137.2,137.1,136.8,136.3,135.2,133.1,133.0,132.9,132.9,131.2,130.9,130.1,128.6,127.7,121.2,114.2,101.7,55.9,55.5,41.0,39.5,27.8,27.3,25.9,19.9,19.8,19.7,19.5,17.2,17.1,17.00,16.98；31P NMR(162MHz,CDCl3)δ-23.94。
example 15
Characterization data for ligand 19:
1H NMR(400MHz,CDCl3)δ8.25(d,J＝7.1Hz,2H),8.14-8.04(m,2H),7.71-7.63(m,2H),7.47-7.34(m，6H)，7.29-7.12(m，13H)，7.01-6.95(m，1H)，5.81-5.33(m，2H)，4.96-4.88(m，2H)，3.97(s，3H)，3.19-2.81(m，3H)，2.63-2.52(m，1H)，2.40-2.31(m，1H)，2.23-2.15(m，1H)，1.62-1.49(m，3H)，1.40(t，J＝11.6Hz，1H)，1.02-0.90(m，1H)；13C NMR(101MHz，CDCl3)δ168.9，157.5，154.6，142.0，141.8，141.3，140.0，136.9，136.8，134.4，133.6，133.4，133.2，131.8，130.0，128.8，128.64，128.58，128.54，128.45，128.37，128.32，128.2，127.42，127.40，121.5，114.3，99.8，60.2，55.7，55.5，40.8，39.4，27.8，27.2，26.0；31P NMR(162MHz，CDCl3)δ-12.34。
example 16
Characterization data for ligand 20:
1H NMR(400MHz,CDCl3):δ7.98(d,J＝7.5Hz,1H),7.74-7.60(m,2H),7.44-7.11(m,15H)，6.96(s，1H)，5.91-5.19(m，2H)，5.04-4.86(m，2H)，4.24-4.01(m，1H)，3.94(s，3H)，3.17-2.90(m，4H)，2.69-2.43(m，2H)，2.30-2.12(sm，1H)，2.03-1.97(m，1H)，1.91-1.72(m，2H)，1.65-1.38(m，6H)，1.26-1.18(m，1H)，0.99-0.88(m，3H)；13C NMR(101MHz，CDCl3)：δ168.6，159.5，156.8，144.2，141.8，141.5，141.1，137.1，136.9，136.8，134.1，133.4，133.3，133.2，133.1，130.6,129.8,128.5,128.3,128.2,128.1,128.0,127.9,120.9,114.0,102.1,60.0,55.5,55.3,40.7,39.2,38.6,32.0,27.6,27.1,26.0,22.4,20.7,13.8；31P NMR(162MHz,CDCl3):δ-11.60。
example 17
Characterization data for ligand 21:
1H NMR(400MHz,CDCl3)δ8.53(d,J＝4.6Hz,1H),7.97(d,J＝9.2Hz,1H),7.76-7.55(m,3H),7.44-7.31(m,4H),7.17-7.09(m,3H),6.97(dd,J＝7.9,1.8Hz,2H),6.88(t,J＝4.0Hz,1H),5.92-5.82(m,1H),5.38(s,1H),5.14-5.00(m,2H),3.98(s,3H),3.54-3.42(m,1H),2.96-2.52(m,5H),2.26-2.15(m,1H),1.97-1.88(m,2H),1.60-1.52(m,2H),1.24(s,18H),1.18(s,18H)；13C NMR(100MHz,CDCl3)δ168.8,157.7,156.9,150.9,147.7,144.5,140.6,136.4,136.0(d,J＝10.5Hz),135.7(d,J＝21.3Hz),134.4,131.6,130.0,128.7,128.2,128.0,127.9,127.69,122.68,122.4,121.8,114.7,101.3,55.5,49.1,48.9,47.1,39.1,35.0,34.9,34.0,31.42,31.36,27.4,26.6,25.6,25.0；31P NMR(162MHz,CDCl3)δ-9.0。
example 18
Characterization data for ligand 22:
1H NMR(400MHz,CDCl3):δ8.75(d,J＝4.6Hz,1H),8.44(d,J＝8.5Hz,1H),8.13(dd,J＝8.5，1.3Hz，1H)，7.81-7.65(m，3H)，7.62-7.57(m，1H)，7.48-7.42(m，2H)，7.38(td，J＝7.5，1.4Hz，1H)，7.33-7.27(m，2H)，7.20(dd，J＝7.9，1.8Hz，2H)，7.02(dd，J＝7.9，1.8Hz，2H)，6.95-6.88(m，1H)，5.89(ddd，J＝17.1，10.5，6.5Hz，1H)，5.47(s，1H)，5.25-5.00(m，2H)，2.98-2.50(m，5H)，2.38-2.14(m，1H)，1.63-1.33(m，4H)，1.29(s，18H)，1.23(s，18H)，0.88-0.72(m，1H)；13C NMR(101MHz，CDCl3)δ169.0，151.0(d，J＝6.6Hz)，150.8(d，J＝6.3Hz)，150.2，148.4，140.3，136.5(d，J＝9.8Hz)，136.0(d，J＝10.4Hz)，135.7(d，J＝21.6Hz)，134.4，132.1(d，J＝9.9Hz),132.0(d,J＝3.1Hz),130.3,130.1,129.2,128.84,128.75,128.6,128.5,128.3,128.1,127.9,127.7,126.4,123.4,122.7,122.4,114.9,48.9,47.0,39.3,35.0,34.9,31.5,31.4,27.4,26.6,25.7,25.0,24.8；31P NMR(162MHz,CDCl3):δ-9.0。
example 19
Characterization data for ligand 23:
1H NMR(400MHz,CDCl3)δ8.71(s,1H),8.51-8.39(m,1H),8.17-8.04(m,1H),7.77-7.65(m，3H)，7.61-7.55(m，1H)，7.44-7.33(m，3H)，7.29-7.22(m，2H)，7.15-7.06(m，2H)，7.02-6.94(m，2H)，6.92-6.83(m，1H)，5.66-5.55(m，1H)，5.52-5.32(m，1H)，4.93-4.84(m，2H)，3.10-2.94(m，2H)，2.90-2.73(m，1H)，2.59-2.51(m，1H)，2.45-2.37(m，1H)，2.29-2.11(m，2H)，1.61-1.47(m，3H)，1.26-1.17(m，36H)，0.93-0.87(m，1H)；13C NMR(101MHz，CDCl3)δ171.0，150.83，150.77，150.70，150.6，150.1，148.31，141.32，136.0，134.2，130.2，130.0，128.8，128.6，128.1，127.9，127.7，126.4，123.4，122.4，122.3，114.4，55.9，40.6，39.6，34.9，34.8，31.3，31.3，27.8，27.2，25.4；31P NMR(162MHz，CDCl3)δ-8.84。
example 20
Scheme 2:
step 1: diethyl phosphite (1.0mmol) was slowly added dropwise to a stirred solution of Grignard reagent S7(3.0mmol) in tetrahydrofuran at 0 ℃. The reaction mixture was then warmed to room temperature and stirred for 12 hours. After complete conversion (monitored by TLC), the crude mixture was directly purified by silica gel column chromatography (50: 1 ratio of petroleum ether to ethyl acetate) to give pure S8 (50-80% yield).
Step 2: to a stirred solution of S8(1.0mmol) in toluene was added palladium acetate (0.1mmol), 1, 3-bis (diphenylphosphino) propane (0.12mmol) and methyl o-bromobenzoate (1.2mmol) at room temperature. The reaction mixture was stirred and heated to reflux for 12 hours. After cooling to room temperature, the toluene solvent was removed under reduced pressure to give crude product S9, which was directly subjected to the next reaction.
And step 3: the crude product S9 obtained in the previous step was dissolved in toluene, and trichlorosilane (1.2mmol) and triethylamine (1.2mmol) were added thereto, followed by heating and refluxing for 24 hours. The temperature was reduced to room temperature and the mixture was quenched with dilute hydrochloric acid (1M). The organic layer was separated, dried, filtered and concentrated in vacuo. The residue thus obtained was purified by silica gel column chromatography (ratio of petroleum ether to ethyl acetate 20:1) to give S10 (50-60% yield).
And 4, step 4: lithium hydroxide (2.0mmol) was added to a mixed solution of S10(1.0mmol) in tetrahydrofuran and water, and the reaction system was heated to 70 ℃ and refluxed for 24 hours, and then cooled. The organic layer was separated, dried, filtered and concentrated in vacuo. The residue thus obtained was purified by silica gel column chromatography (ratio of petroleum ether to ethyl acetate 1:1) to give S11 (70-80% yield).
And 5: EDCI (1.2mmol) and DMAP (0.1mmol) were added to a solution of S11(1.0mmol) and commercial S6(1.0mmol) in dichloromethane. The reaction was stirred at room temperature for 24 hours and quenched by addition of water. The organic layer was separated, dried, filtered and concentrated in vacuo. The residue thus obtained was purified by silica gel column chromatography (ratio of petroleum ether to ethyl acetate 1:2) to give ligand 16 (60-80% yield).
Characterization data for ligand 16:
1H NMR(400MHz,CDCl3)δ8.46(d,J＝4.4Hz,1H),7.94(d,J＝9.2Hz,1H),7.80(t,J＝8.6Hz,2H),7.76-7.64(m,7H),7.62(d,J＝2.4Hz,1H),7.52-7.38(m,5H),7.33-7.18(m,6H),7.00-6.97(m,1H),5.67-5.59(m,1H),5.39(brs,1H),4.93-4.87(m,2H),3.90(s,3H),3.04-2.90(m,3H),2.54-2.47(m,1H),2.35-2.31(m,1H),2.20-2.17(m,1H),1.59-1.57(m,1H),1.50-1.47(m,2H),1.36-1.31(m,1H),0.84-0.79(m,1H)；13C NMR(100MHz,CDCl3)δ168.8,157.6,147.3,144.6,141.4,141.2,134.43,134.36,134.3,134.2,134.1(d,J＝4Hz),133.8,133.4,133.34,133.25,133.23,133.15,131.4,130.3,130.1,130.0,128.9,128.5,128.1,128.0,127.9(d,J＝7.3Hz),127.6(d,J＝8Hz),126.7(d,J＝10.4Hz),126.3(d,J＝8.4Hz),121.5,114.4,102.0,55.6,40.9,39.3,27.7,27.3,26.0；31P NMR(162MHz,CDCl3)δ-9.4。
ligand 17 can be synthesized using scheme 2.
Example 21
Characterization data for ligand 17:
1H NMR(400MHz,CDCl3)δ8.44-8.21(m,3H),7.92(d,J＝9.2Hz,1H),7.86-7.70(m,5H),7.65(d,J＝1.8Hz,1H),7.49-7.25(m,8H),7.19(t,J＝7.5Hz,1H),7.12(td,J＝7.6,0.7Hz,1H),7.01(s,2H),6.91-6.85(m,2H),5.64-5.31(m,2H),4.90-4.80(m,2H),3.86(s,3H),3.13(s,1H),3.01-2.92(m,1H),2.90-2.43(m,2H),2.40-2.20(m,1H),2.15(s,1H),1.57-1.41(m,3H),1.32-1.25(m,1H),0.77(d,J＝6.5Hz,1H)；13C NMR(101MHz,CDCl3)δ168.7,157.5,147.2,144.3,141.0,135.2,135.1,135.04,134.99,134.8,133.32,133.28,132.6,131.3,130.2,129.6,129.5,129.0,128.5,128.4,126.3,126.2,126.2,126.05,125.97,125.94,125.87,125.6,125.5,121.3,114.2,101.7,55.4,40.7,39.2,27.6,27.1,25.7,25.6；31P NMR(162MHz,CDCl3)δ-28.24。
example 22
Scheme 3:
step 1: to a stirred solution of bromide S12(3.0mmol) in tetrahydrofuran was slowly added n-butyllithium solution (2.4M, 1.5mL) dropwise at-78 ℃. After stirring for 30 minutes, phosphorus trichloride was added and the reaction mixture was allowed to warm to room temperature and stirred for 12 hours. After complete conversion (monitored by TLC), the now prepared CuCl. LiCl complex and zinc chloride lithium benzoate complex were added to the reaction. The reaction was continued for 12 hours and quenched by addition of water. The organic layer was separated, dried, filtered and concentrated in vacuo. The residue thus obtained was purified by silica gel column chromatography (ratio of petroleum ether to ethyl acetate 20:1) to give S13 (72% yield).
Step 2: the product S13 obtained in the previous step was dissolved in toluene, and trichlorosilane (1.2mmol) and triethylamine (1.2mmol) were added thereto, followed by heating and refluxing for 24 hours. The temperature was reduced to room temperature and the mixture was quenched with dilute hydrochloric acid (1M). The organic layer was separated, dried, filtered and concentrated in vacuo. The residue thus obtained was purified by silica gel column chromatography (20: 1 ratio of petroleum ether to ethyl acetate) to give S14 (56% yield).
And step 3: lithium hydroxide (2.0mmol) was added to a mixed solution of S14(1.0mmol) in tetrahydrofuran and water, and the reaction system was heated to 70 ℃ and refluxed for 24 hours, and then cooled. The organic layer was separated, dried, filtered and concentrated in vacuo. The residue thus obtained was purified by silica gel column chromatography (ratio of petroleum ether to ethyl acetate 1:1) to give S15 (72% yield).
And 4, step 4: EDCI (1.2mmol) and DMAP (0.1mmol) were added to a solution of S15(1.0mmol) and commercial S6(1.0mmol) in dichloromethane. The reaction was stirred at room temperature for 24 hours and quenched by addition of water. The organic layer was separated, dried, filtered and concentrated in vacuo. The residue thus obtained was purified by silica gel column chromatography (ratio of petroleum ether to ethyl acetate 1:2) to give ligand 11 (65% yield).
Characterization data for ligand 11:
1H NMR(400MHz,CDCl3)δ10.08(s,1H),8.15(s,1H),8.04(s,1H),7.94(d,J＝9.2Hz,1H),7.69–7.66(m,1H),7.47–7.43(m,1H),7.35–7.31(m,2H),7.27–7.23(m,1H),7.06(s,2H),7.00(d,J＝2.9Hz,2H),6.63(s,1H),5.70–5.57(m,2H),4.95–4.87(m,2H),3.99(s,3H),3.24–3.16(m,2H),3.04–2.97(m,1H),2.90(dt,J＝9.2,6.9Hz,2H),2.73–2.58(m,2H),2.25(s,1H),2.10(s,1H),1.61(s,3H),1.34–1.17(m,24H),1.05–0.93(m,5H),0.75–0.42(m,12H)；13C NMR(101MHz,CDCl3)δ167.3,157.7,154.4,154.2,153.1,152.9,150.9,149.5,147.7,146.6,144.3,141.4,136.7,136.5,134.2,131.8,131.4,130.0,129.6,128.6,128.2,122.7,121.2,119.3,114.3,101.6,60.3,55.9,55.5,51.8,41.1,39.7,34.1,34.0,32.2,32.0,28.1,27.4,25.5,24.2,23.8,23.8,23.7；31P NMR(162MHz,CDCl3)δ-40.16。
example 23
Scheme 4:
step 1: to a solution of S16(1.0mmol) in tetrahydrofuran was added slowly a solution of butyllithium (2.4M, 0.5mL) at-78 deg.C, stirred for 30 min and allowed to warm to room temperature. Carbon dioxide gas was slowly bubbled into the reaction system for 6 hours until no starting material remained. The reaction solution was directly concentrated to obtain a crude product S17.
Step 2: EDCI (1.2mmol) and DMAP (0.1mmol) were added to a solution of S17(1.0mmol) and commercial S6(1.0mmol) in dichloromethane. The reaction was stirred at room temperature for 24 hours and quenched by addition of water. The organic layer was separated, dried, filtered and concentrated in vacuo. The residue thus obtained was purified by silica gel column chromatography (ratio of petroleum ether to ethyl acetate 1:2) to give S18 (50% yield).
And step 3: DMAP (3.0mmol) was added to a solution of S18(1.0mmol) in toluene, and the reaction was heated to 80 ℃. After 12 hours, the crude product was concentrated and the residue thus obtained was purified by silica gel column chromatography (1: 1 ratio of petroleum ether to ethyl acetate) to give ligand 18 (80% yield).
Characterization data for ligand 18:
1H NMR(400MHz,CDCl3)δ8.92–8.69(m,1H),8.55(s,1H),8.05(d,J＝9.2Hz,1H),7.85(s,1H),7.74(s,1H),7.56–7.38(m,3H),7.37–7.29(m,2H),6.13(s,1H),5.84(s,1H),5.29–5.05(m,2H),4.06(s,4H),3.52(s,2H),3.15(s,1H),2.68(s,1H),2.01–1.54(m,14H),1.44–0.79(m,12H)；13C NMR(100MHz,CDCl3)δ170.6,158.4,147.9,144.9,144.4,144.0,143.5,140.0,137.4,137.3,132.5,131.7,129.0,125.4,122.2,119.9,117.5,102.1,59.2,56.0,54.2,53.5,49.2,42.2,37.3,34.5(d,J＝12Hz),33.8(d,J＝12Hz),30.7–30.3(4C),29.7,29.3,27.1–26.9(4C),26.3,26.2,25.2；31P NMR(162MHz,CDCl3)δ-8.7。
example 24
The ligands of the invention are used in the free radical asymmetric Sonogashira reaction:
to an oven-dried Schlenk tube equipped with a magnetic stir bar, CuTc (cuprous thiophene-2-carboxylate, 10 mol% equiv.), ligand L2(15 mol%), cesium carbonate (2.0 equiv.), and diethyl ether (1.0mL) were added under argon. Then, (1-bromoethyl) benzene (0.05mmol) and phenylacetylene (0.075mmol) were added successively to the mixture and reacted at 29 ℃ for 24 h. After completion of the reaction (monitored by TLC), the precipitate was filtered off and washed with solvent, then the solution was evaporated and purified by silica gel column chromatography (petroleum ether ═ 100) to give the product in 83% yield, 85% ee.
Characterization data of the product: is colorless oil, [ alpha ]]D 27＝-29(c 1.4,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 99.5/0.5, flow rate 1.0mL/min,. lambda.254 nm), tR(minor)＝12.30min,tR(major)＝17.52min。1H NMR(400MHz,CDCl3)δ7.52–7.41(m,4H),7.36(t,J＝7.6Hz,2H),7.32–7.27(m,3H),7.26–7.24(m,1H),4.00(q,J＝7.1Hz,1H),1.59(d,J＝7.2Hz,3H)。13C NMR(100MHz,CDCl3) δ 143.3,131.6,128.6,128.2,127.8,127.0126.7,123.7,92.6,82.4,32.5, 24.6. HRMS (ESI) m/z accurate mass calculation C16H15[M+H]+207.1168, found 207.1161.
Results of other ligands used in the free radical asymmetric Sonogashira reaction:
ligands Yield (%) ee(％)
L1 88 88
L3 67 93
L4 79 83
L5 92 89
L6 90 94
L7 75 75
L8 70 80
L9 64 86
L10 50 89
L11 83 91
L12 74 94
L13 89 78
L14 58 90
L15 86 87
L16 82 80
L17 75 92
L18 93 89
L19 76 88
L20 81 88
L23 77 83
It can be seen that the ligand of the invention can be used as a catalyst with copper salt for Sonogashira C (sp) -C (sp) of terminal alkyne and racemic alkyl halide3) Asymmetric cross-coupling reaction, chiral C-C bond construction, good yield and excellent enantioselectivity.
The above description is only an embodiment of the present invention, but the scope of the present invention is not limited thereto, and any changes or substitutions that can be easily conceived by those skilled in the art within the technical scope of the present invention are included in the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.

Claims (12)

1. A nitrogen phosphorus ligand having the structure of formula i:
wherein R is1Is a hydrogen or an alkoxy group,
r is cyclohexyl, naphthyl, optionally substituted phenyl,
R2is hydrogen, phenyl or alkyl.
2. The nitrogen phosphorus ligand of claim 1, wherein R is selected from the structures:
a cyclohexyl group which is a group having a ring-opening structure,
a naphthyl group,
a phenyl group,
wherein R is3Selected from alkyl, alkoxy, trifluoromethyl, halogen, phenyl and phenoxy, m represents an integer of 1-5, when m is more than or equal to 2, more than 2 existR3The same or different.
3. The nitrogen phosphorus ligand of claim 2, wherein R is selected from the structures:
a cyclohexyl group which is a group having a ring-opening structure,
a naphthyl group,
a phenyl group,
wherein R is3Selected from methyl, propyl, butyl, methoxy, trifluoromethyl, fluorine, phenyl and phenoxy, m represents an integer of 1-5, when m is more than or equal to 2, more than 2R exist3The same or different.
4. The nitrogen phosphorus ligand of claim 3, wherein R is selected from the structures:
a cyclohexyl group which is a group having a ring-opening structure,
a naphthyl group,
a phenyl group,
wherein, when m is 1, R3Selected from propyl, butyl, methoxy, phenyl, phenoxy; when m is 2, R3Selected from butyl, trifluoromethyl, methoxy, phenyl; when m is 3, R3Selected from methyl, propyl, butyl, methoxy, fluoro; when m is 5, R3Is selected from methyl; when m.gtoreq.2, more than 2R are present3The same or different.
5. The nitrogen phosphorus ligand of claim 1, wherein R is1Is hydrogen or methoxy.
6. The nitrogen phosphorus ligand of claim 1, wherein R is2Is hydrogen, phenyl or butyl.
7. The nitrogen-phosphorus ligand according to any one of claims 1 to 6, wherein the structure is selected from the following compounds:
8. the preparation method of the nitrogen-phosphorus ligand as defined in any one of claims 1 to 7, comprising the following steps:
r is optionally substituted phenyl and is not 2,4-6-tri-iPrC6H2，
Reacting the compound S1 with diethyl phosphite to obtain an intermediate S2;
reacting the intermediate S2 with copper trifluoromethanesulfonate and TMDS to obtain an intermediate S3;
reacting the intermediate S3 with o-fluorobenzoic acid methyl ester and KHMDS to obtain an intermediate S4;
hydrolysis of intermediate S4 affords intermediate S5.
9. The preparation method of the nitrogen-phosphorus ligand as defined in any one of claims 1 to 7, comprising the following steps:
r is a naphthyl group,
reacting the compound S7 with diethyl phosphite to obtain an intermediate S8;
intermediate S8 and O-Bromobenzoic acid methyl ester, Pd (OAc)2And dppp reaction to obtain an intermediate S9;
reacting the intermediate S9 with trichlorosilane and triethylamine to obtain an intermediate S10;
hydrolysis of intermediate S10 affords intermediate S11.
10. The preparation method of the nitrogen-phosphorus ligand as defined in any one of claims 1 to 7, comprising the following steps:
r is 2,4-6-tri-iPrC6H2，
Reacting a compound S12 with n-butyl lithium and phosphorus trichloride, and reacting the obtained product with CuCl. LiCl and a compound S19 to obtain an intermediate S13;
reacting the intermediate S13 with trichlorosilane and triethylamine to obtain an intermediate S14;
hydrolysis of intermediate S14 affords intermediate S15.
11. The preparation method of the nitrogen-phosphorus ligand as defined in any one of claims 1 to 7, comprising the following steps:
r is a cyclohexyl group,
reacting the compound S16 with n-butyllithium and carbon dioxide to obtain an intermediate S17;
and carrying out condensation reaction on the intermediate S17 and a quinine derivative S6 to obtain an intermediate S18.
12. Use of the ligand of any one of claims 1 to 7 in asymmetric cross-coupling alkyne synthesis reactions.
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CN114213460A (en) * 2021-11-01 2022-03-22 贵州医科大学 Chiral nitrogen phosphine compound for ketone asymmetric hydrogenation reaction or transfer hydrogenation reaction, preparation method and application
CN114213460B (en) * 2021-11-01 2024-01-30 贵州医科大学 Chiral nitrogen-phosphine compound for ketone asymmetric hydrogenation reaction or transfer hydrogenation reaction, preparation method and application
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