CN111647018B - Preparation method of phosphorus center chiral compound - Google Patents

Preparation method of phosphorus center chiral compound Download PDF

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CN111647018B
CN111647018B CN202010501171.8A CN202010501171A CN111647018B CN 111647018 B CN111647018 B CN 111647018B CN 202010501171 A CN202010501171 A CN 202010501171A CN 111647018 B CN111647018 B CN 111647018B
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CN111647018A (en
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崔玉明
徐利文
马伟扬
林燕
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Hangzhou Normal University
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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
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
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    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
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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
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    • C07F9/65616—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 containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
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Abstract

The invention discloses a preparation method of a phosphorus center chiral compound, which specifically comprises the following steps: in the presence of an oxidant, a palladium salt and an N-single protection chiral amino acid ligand, carrying out C-H bond olefination reaction on 2-pyridyl diaryl phosphine oxide shown in a formula (II) and olefin derivatives shown in a formula (III) to generate a phosphorus center chiral compound shown in a formula (I). The method has better adaptability to various 2-pyridyl diaryl phosphine oxides and different substituent groups in olefin, especially olefin with larger steric hindrance, and has stable yield and excellent enantioselectivity.

Description

Preparation method of phosphorus center chiral compound
Technical Field
The invention relates to the technical field of asymmetric chemical synthesis, in particular to a preparation method of a phosphorus center chiral compound.
Background
Chiral phosphorus compounds have played an important role as chiral ligands and catalysts in various types of asymmetric catalytic reactions. Since the difficulty in constructing the phosphorus chiral center is great, chemists have focused more on the construction of the chiral carbon skeleton in the early stage of research, and the phosphorus chiral center is often ignored.
Over the last decade and so forth, great efforts have been made by chemists with continuous efforts to produce asymmetric syntheses of chiral compounds at the phosphorus center, and in particular to produce such compounds by novel asymmetric catalytic reactions. Such as cross-coupling reactions of secondary phosphine oxides with aromatic hydrocarbons containing a leaving group, and the like. However, the related synthetic routes often require the preparation of a substrate containing a functional group in advance, and the atom economy and step economy of the reaction routes are poor. In addition, these catalytic reactions suffer from problems such as limited range of substrates, low turnover and low stereoselectivity.
It is well known that the C-H bond is a chemical bond that is widely present in various types of organic compounds. The C-H bond activation strategy is known as an effective method for directly and quickly constructing C-C bonds and C-heteroatom bonds, the economical efficiency of reaction atoms is improved, meanwhile, the synthetic route is greatly shortened, the waste emission is reduced, and the method belongs to a green chemical process.
With the continuous and intensive research of chemists in the field in recent years, a plurality of efficient catalytic systems have been developed, regioselective and stereoselective functionalization is realized on a substrate aryl C-H bond with a specific structure, and the synthesis of a phosphorus center chiral compound is successfully realized. Higher yields and enantioselectivities were achieved in the catalytic Synthesis of phosphorus-centered chiral compounds by using intramolecular asymmetric arylC-H bond Arylation as described by Staglad et al (Palladium-Catalyzed Enantioselective C-H Arylation for the Synthesis of P-Stereogenic compounds, angew. Chem. Int. Ed.2015,54, 6265). Korean-Foster et al synthesized a series of phosphorus-centered chiral compounds using phosphoramide directed intermolecular asymmetric arylC-H bond Arylation reactions with moderate to good yields and excellent enantioselectivity (Palladium-Catalyzed Enantioselective Synthesis of P-Stereogenic Phosphonamides via Desymmetic C-H aryl, J.Am.chem.Soc., 2015137, 632).
However, no report has been found on the study of synthesizing chiral compounds at phosphorus centers by using the transition metal to catalyze the enantioselective C-H bond olefination reaction between molecules starting from achiral raw materials.
Disclosure of Invention
The invention provides a preparation method of a phosphorus center chiral compound, which is characterized in that under the existence of a complex formed by an oxidant, palladium salt and an N-single protection chiral amino acid ligand, 2-pyridyl diaryl phosphine oxide and an olefin derivative are used as raw materials to carry out intermolecular asymmetric C-H bond olefination reaction to synthesize the phosphorus center chiral compound.
The technical scheme provided by the invention for solving the technical problems is as follows:
a preparation method of a phosphorus center chiral compound comprises the following steps that in the presence of an oxidant, a palladium salt and an N-single protection chiral amino acid ligand, C-H bond olefination reaction is carried out on 2-pyridyl diaryl phosphine oxide shown in a formula (II) and an olefin derivative shown in a formula (III) to generate the phosphorus center chiral compound shown in the formula (I);
Figure BDA0002524728850000021
wherein,
m is 0,1, 2, 3 or 4;
n is 0,1, 2 or 3;
R 1 is H, C 1～6 Alkyl or C 6～10 Aryl radical, said C 1～10 Alkyl or C 6～10 Aryl is optionally substituted by 1 to 3 halogens, methyl, OH or NH 2 Substitution; or two adjacent R 1 Together with the pyridyl group to which it is attached to form a quinolinyl group;
R 2 is H, halogen, C 1～6 Alkyl radical, C 1～6 Alkoxy or C 6～10 Aryl radical, said C 1～6 Alkyl radical, C 1～6 Alkoxy or C 6～10 Aryl is optionally substituted by 1 to 3 halogens, methyl, OH or NH 2 Substitution; or two adjacent R 2 Together with the phenyl group to which it is attached form a naphthyl group;
R 3 is H, C 1～6 Alkyl, -C (= O) O-C 1～6 Alkyl radical, C 1～6 alkyl-CHO, -C (= O) -C 1～6 Alkyl, -P (= O) - (O-C) 1～6 Alkyl radical) 3 、-S(＝O) 2 -C 1～6 Alkyl, -S (= O) 2 -C 6～20 Aryl, -Si (C) 1～6 Alkyl radical) 3 、C 6～20 Aryl radical, said C 6～20 Aryl is optionally substituted by 1-3 halogens, methyl, heteroaryl, OH, NH 2 or-N (Ph) 2 Substituted, said C 1～6 Alkyl, -S (= O) 2 -C 6～20 Aryl, -Si (C) 1～6 Alkyl radical) 3 Optionally substituted by 1 to 3 halogens, methyl, OH or NH 2 And (4) substitution.
Preferably, R is 1 Is H, C 1～4 Alkyl or phenyl, said C 1～4 Alkyl or phenyl is optionally substituted with 1 to 3 halogens.
Preferably, R is 1 Is H, methyl, tert-butyl or phenyl, the methyl, tert-butyl or phenyl is optionally substituted by 1 to 3 halogens.
Two adjacent R 1 Together with the pyridyl group to which it is attached form a quinolinyl group, said quinolinyl group being
Figure BDA0002524728850000022
Figure BDA0002524728850000023
The two adjacent R 2 Together with the phenyl group to which it is attached form a naphthyl group, said naphthyl group being
Figure BDA0002524728850000024
Preferably, R is 2 Is H, halogen, C 1～4 Alkyl radical, C 1～4 Alkoxy or phenyl, said C 1～4 Alkyl radical, C 1～4 Alkoxy or phenyl is optionally substituted with 1 to 3 halogens.
Preferably, R is 2 Is H, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, methoxy, ethoxy, propoxy or phenyl, the methyl, ethyl, propyl, methoxy, ethoxy, propoxy or phenyl being optionally substituted with 1 to 3 halogens.
In the preparation process of the chiral compound at the phosphorus center, olefin with large steric hindrance can also smoothly react. Preferably, R is 3 Is H, methyl ester, ethyl ester, n-butyl ester, tert-butyl ester, p-methoxyphenyl, p-nitrophenyl, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, p-methylphenyl, phenylsulfonyl, dimethyl phosphate, diethyl phosphate, trimethylsilyl, diphenylaminophenyl, naphthyl, anthryl, phenanthryl, pyrenyl or
Figure BDA0002524728850000031
The naphthyl, anthryl, phenanthryl or pyrenyl group is optionally substituted by 1 to 3 halogens.
The palladium salt is palladium acetate, palladium bis (acetylacetonate), palladium trifluoroacetate, palladium tetrakis (acetonitrile) tetrafluoroborate or palladium chloride.
The N-single protection chiral amino acid ligand is
Figure BDA0002524728850000032
Figure BDA0002524728850000033
The oxidant is copper acetate, silver carbonate, silver oxide or benzoquinone.
The reaction temperature of the C-H bond olefination reaction is 40-80 ℃, and the reaction time is 6-48H.
The reaction medium of the C-H bond olefination reaction is methanol, tetrahydrofuran, tert-amyl alcohol, toluene or hexafluoroisopropanol. The solvent is preferably tert-amyl alcohol, in which case the reaction gives the desired product in higher yield and enantioselectivity.
The preparation method of the phosphorus center chiral compound also comprises the following post-treatment steps, after the reaction is finished, the mixture is diluted by water, and after extraction, an organic phase is separated by silica gel column chromatography to obtain the phosphorus center chiral compound shown in the formula (I).
The concentration of the 2-pyridyl diaryl phosphine oxide shown in the formula (II) is 0.1-0.5 mol/L.
The molar ratio of the oxidant to the 2-pyridyl diaryl phosphine oxide shown in the formula (II) is 1.1-3: 1.
the mole ratio of the palladium salt to the 2-pyridyl diaryl phosphine oxide shown in the formula (II) is 0.01-0.1: 1.
the molar ratio of the N-single protection chiral amino acid ligand to the 2-pyridyl diaryl phosphine oxide shown in the formula (II) is 0.01-0.2: 1.
the mol ratio of the olefin derivative shown in the formula (III) to the 2-pyridyl diaryl phosphine oxide shown in the formula (II) is 1.1-3: 1.
the molar ratio of the oxidant, the palladium salt, the N-single protection chiral amino acid ligand, the 2-pyridyl diaryl phosphine oxide shown in the formula (II) and the olefin derivative shown in the formula (III) is 1.1-3: 0.01 to 0.1:0.01 to 0.2:1:1.1 to 3.
Unless otherwise specified, the term "substituted" means that any one or more hydrogen atoms on a particular atom is replaced with a substituent, including variations of deuterium and hydrogen, so long as the valence of the particular atom is normal and the substituted compound is stable. When the substituent is keto (i.e = O), it means that two hydrogen atoms are substituted. The keto substitution does not occur on the aromatic group.
The term "optionally substituted" means that it may or may not be substituted, and the kind and number of the substituents may be arbitrary on the basis of chemical realization.
Unless otherwise specified, when any variable (e.g., R) occurs more than one time in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2R, the group may optionally be substituted with up to two R, and there are separate options for R in each case. Furthermore, combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
Unless otherwise specified, the term "C 1-10 Alkyl "is intended to mean a straight or branched saturated hydrocarbon group consisting of 1 to 8 carbon atoms. Said C is 1-10 The alkyl group including C 1-10 、C 1-9 、C 1-8 、C 1-6 、C 1-5 、C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-4 、C 10 、C 9 、C 8 、C 7 、C 6 And C 5 Alkyl, etc.; it may be monovalent (e.g. methyl), divalent (e.g. methylene) or polyvalent (e.g. methine). C 1-10 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl)S-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, heptyl, octyl and the like.
Compounds are named according to the conventional naming principles in the art or using software, and commercially available compounds are referred to by the supplier's catalog name.
Compared with the prior art, the invention has the advantages that:
1. the catalyst palladium salt and the N-single protection chiral amino acid ligand of the preparation method are commercial reagents, and the raw materials of the 2-pyridyl diaryl phosphine oxide and the olefin derivative are cheap and easy to obtain.
2. The preparation method has the advantages of good yield and enantioselectivity, simple operation, and convenient post-treatment, and the crude product is subjected to rapid column chromatography for impurity removal and then is subjected to reduced pressure concentration to obtain a pure product.
3. The preparation method has better adaptability to various 2-pyridyl diaryl phosphine oxides and different substituent groups in olefin, especially the olefin with larger steric hindrance, stable yield and excellent enantioselectivity.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers.
Example 1: synthesis of diphenyl (pyridin-2-yl) phosphine oxide
Figure BDA0002524728850000041
To a 100mL Schlenk reaction flask, diphenylphosphine oxide (4.04g, 20mmol), 2-bromopyridine (2.38mL, 25mmol), and K were added in this order under a nitrogen atmosphere 2 CO 3 (3.45g,25mmol)。Ni(PPh 3 ) 2 Cl 2 (261.7mg, 0.4mmol), DMF (15 mL) and stirred at 90 ℃ for 24h. After the reaction was completed, the mixture was diluted with water and extracted three times with ethyl acetate. Saturated chlorine for organic phaseWashed with sodium hydroxide solution, dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography, eluted with petroleum ether/ethyl acetate =1, and then dried by suction to obtain a white solid (3.77g, 13.5 mmol) in 67.5% yield.
1 H NMR(400MHz,CDCl3)δ8.75(d,J＝3.9Hz,1H),8.29(t,J＝6.4Hz,1H),7.90(dd,J＝11.6,7.7Hz,4H),7.84–7.72(m,1H),7.55–7.37(m,6H),7.37–7.24(m,1H)。
13 C NMR(101MHz,CDCl3)δ156.3(d),150.1(d),136.2(d),132.2(d),132.1(d),131.9(d),128.3(d),128.2(s),125.3(d)。
HRMS(ESI):m/z:[M+H]+calculated for C 17 H 15 NOP:280.0886,Found:280.0891。
Example 2 Synthesis of (3-methylpyridin-2-yl) diphenylphosphine oxide
Figure BDA0002524728850000051
To a 100mL Schlenk reaction flask, diphenylphosphine oxide (4.04g, 20mmol), 2-bromo-3-methylpyridine (2.79mL, 25mmol), and K were added in this order under a nitrogen atmosphere 2 CO 3 (3.45g,25mmol)。Ni(PPh 3 ) 2 Cl 2 (261.7mg, 0.4mmol), DMF (15 mL) and stirred at 90 ℃ for 24h. After the reaction was completed, the mixture was diluted with water and extracted three times with ethyl acetate. The organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography, eluting with petroleum ether/ethyl acetate =1, to obtain a white solid (4.04g, 13.8mmol) by suction, in 69.2% yield.
1 H NMR(400MHz,CDCl3)δ8.50(d,J＝4.1Hz,1H),7.85–7.68(m,4H),7.61–7.36(m,7H),7.27(dd,J＝7.9,4.2Hz,1H),2.65(s,3H)。
13 C NMR(101MHz,CDCl3)δ153.3(d),146.5(d),140.6(d),139.3(d),132.89(d),132.1(d),131.7(d),128.3(d),125.1(d),19.2(s)。
HRMS(ESI):m/z:[M+H]+calculated for C 18 H 16 NOP:294.0970,Found:294.1044。
Example 3: synthesis of diphenyl (quinolin-2-yl) phosphine oxide
Figure BDA0002524728850000052
To a 100mL Schlenk reaction flask, diphenylphosphine oxide (4.04g, 20mmol), 2-bromoquinoline (5.21mL, 25mmol), and K were added under a nitrogen atmosphere 2 CO 3 (3.45g,25mmol)，Ni(PPh 3 ) 2 Cl 2 (654.2 mg, 1mmol), DMF (15 mL), and stirred at 90 ℃ for 24h. After the reaction was completed, the mixture was diluted with water and extracted three times with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography, eluting with petroleum ether/ethyl acetate =1, to obtain a white solid (3.62g, 11mmol) by suction drying, with a yield of 55%.
1 H NMR(400MHz,CDCl3)δ8.32(ddd,J＝20.7,8.3,4.0Hz,2H),8.15(d,J＝8.5Hz,1H),8.07–7.90(m,4H),7.84(d,J＝8.2Hz,1H),7.78–7.66(m,1H),7.59(t,J＝7.5Hz,1H),7.54–7.34(m,6H)。
13 C NMR(101MHz,CDCl3)δ157.1(d),148.1(d),136.2(d),132.5(d),132.2(d),131.9(d),130.2(d),128.3(d),128.2(s),127.9(d),123.4(d). 31 P NMR(202MHz,CDCl3)δ20.59(s)。
HRMS(ESI):m/z:[M+Na]+calculated for C 21 H 14 F 2 NOP:352.0971,Found:352.0863。
Example 4: synthesis of bis (4-fluorophenyl) (quinolin-2-yl) phosphine oxide
Figure BDA0002524728850000053
To a 100mL Schlenk reaction flask, bis (p-fluoro) phenylphosphoric oxide (4.76g, 20mmol), 2-bromoquinoline (5.21mL, 25mmol), and K were added under a nitrogen atmosphere 2 CO 3 (4.14g,30mmol)，Ni(PPh 3 ) 2 Cl 2 (261.7mg, 0.4mmol), DMF (15 mL) and stirred at 90 ℃ for 24h. After the reaction was completed, the mixture was diluted with water and extracted three times with ethyl acetate. Is provided withThe organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography, eluting with petroleum ether/ethyl acetate =2, to obtain a white solid (4.20g, 11.5mmol) by suction drying, with a yield of 57.5%.
1 H NMR(400MHz,CDCl 3 )δ8.34(d,J＝3.9Hz,2H),8.14(d,J＝8.5Hz,1H),7.99(ddd,J＝11.4,7.9,5.8Hz,4H),7.88(d,J＝8.2Hz,1H),7.77(t,J＝7.7Hz,1H),7.63(t,J＝7.5Hz,1H),7.14(t,J＝8.2Hz,4H)。
13 C NMR(101MHz,CDCl 3 )δ166.43(s),163.88(s),157.31(s),155.99(s),148.22(s),148.00(s),136.41(s),134.92–134.25(m),130.24(d,J＝10.2Hz),128.82(s),128.35(d,J＝9.6Hz),127.88(d,J＝19.5Hz),123.32(s),123.10(s),115.77(dd,J＝21.4,13.3Hz)。
HRMS(ESI):m/z:[M+Na]+calculated for C 21 H 14 F 2 NOP:388.0781,Found:388.0674。
Example 5: synthesis of bis (4-fluorophenyl) (3-methylpyridin-2-yl) phosphine oxide
Figure BDA0002524728850000061
To a 100mL Schlenk reaction flask, bis (p-fluorophenyl) phosphorus oxide (0.952g, 5 mmol), 1-bromoisoquinoline (1.04g, 5 mmol), and K were sequentially added under a nitrogen atmosphere 2 CO 3 (1.38g,10mmol)，Ni(PPh 3 ) 2 Cl 2 (159.3mg, 0.25mmol), DMF (5 mL), and stirred at 90 ℃ for 24h. After the reaction was completed, the mixture was diluted with water and extracted three times with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography, eluting with petroleum ether/ethyl acetate =2, and dried by suction to give a white solid (1.10g, 3mmol) with a yield of 60%.
1 H NMR(400MHz,CDCl 3 )δ9.42(d,J＝8.5Hz,1H),8.62(d,J＝5.5Hz,1H),7.90–7.82(m,5H),7.76(dd,J＝5.6,2.8Hz,1H),7.71(d,J＝7.2Hz,1H),7.65(dd,J＝11.4,4.1Hz,1H),7.14(td,J＝8.7,2.1Hz,4H)。
13 C NMR(101MHz,CDCl 3 )δ166.30(s),163.79(s),155.95(s),154.63(s),136.22(d,J＝7.4Hz),134.70(s),131.58(d,J＝22.6Hz),130.80(s),129.41(s),128.41(d,J＝22.3Hz),127.21(d,J＝24.2Hz),123.28(s),115.72(dd,J＝21.3,13.2Hz)。
HRMS(ESI):m/z:[M+Na]+calculated for C 21 H 14 F 2 NOP:388.0781,Found:388.0674。
Example 6: synthesis of bis (4-fluorophenyl) (6-methylpyridin-2-yl) phosphine oxide
Figure BDA0002524728850000062
To a 100mL Schlenk reaction flask, bis (p-fluorophenyl) phosphorus oxide (0.952g, 5 mmol), 2-bromo-6-methylpyridine (0.68mL, 6 mmol), and K were sequentially added under a nitrogen atmosphere 2 CO 3 (1.38g,10mmol)。Ni(PPh 3 )Cl 2 (159.25mg, 0.25mmol), DMF (5 mL) and stirred at 90 ℃ for 24h. After the reaction was completed, the mixture was diluted with water and extracted three times with ethyl acetate. The organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography, eluting with petroleum ether/ethyl acetate =2, and dried by suction to obtain a white solid (0.89g, 2.7 mmol) in 54% yield.
1 H NMR(400MHz,CDCl 3 )δ8.00(t,J＝6.7Hz,1H),7.85(ddd,J＝11.4,8.2,5.9Hz,4H),7.66(td,J＝7.7,4.2Hz,1H),7.18(d,J＝9.6Hz,1H),7.06(dd,J＝8.6,7.2Hz,4H),2.51(s,3H)。
13 C NMR(101MHz,CDCl 3 )δ166.35(s),163.83(s),159.26(d,J＝19.4Hz),136.39(s),134.64(d,J＝10.1Hz),129.01(s),127.91(s),125.42(d,J＝20.0Hz),115.67(dd,J＝21.3,13.0Hz),24.65(s)。
HRMS(ESI):m/z:[M+Na]+calculated for C 18 H 14 F 2 NOP:352.0789,Found:352.0763。
Example 7: synthesis of bis (4-methoxyphenyl) (pyridin-2-yl) phosphine oxide
Figure BDA0002524728850000071
To a 100mL Schlenk reaction flask, bis (p-methoxyphenyl) phosphorus oxide (0.952g, 5 mmol), 2-bromopyridine (0.60mL, 6 mmol), and K were added under a nitrogen atmosphere 2 CO 3 (1.38g,10mmol)。Ni(PPh 3 )Cl 2 (159.25mg, 0.25mmol), DMF (5 mL), and stirred at 90 ℃ for 24h. After the reaction was completed, the mixture was diluted with water and extracted three times with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography, eluting with petroleum ether/ethyl acetate =2, to obtain a white solid (0.85g, 2.5 mmol) by suction drying, with a yield of 50%.
1 H NMR(400MHz,CDCl 3 )δ8.68(d,J＝3.6Hz,1H),8.20(t,J＝6.4Hz,1H),7.80–7.64(m,5H),7.29(s,1H),6.87(d,J＝7.5Hz,4H),3.74(s,6H)。
13 C NMR(101MHz,CDCl 3 )δ162.47(s),136.12(s),133.94(s),128.21(s),125.06(s),124.08(s),122.97(s),114.03(s),113.90(s),55.30(d)。
HRMS(ESI):m/z:[M+Na]+calculated for C 19 H 18 NO 3 P:362.1026,Found:362.0917。
Example 8: synthesis of bis (4-methoxyphenyl) (3-methylpyridin-2-yl) phosphine oxide
Figure BDA0002524728850000072
To a 100mL Schlenk reaction flask, di (p-methoxy) phenylphosphoric oxide (0.952g, 5 mmol), 2-bromo-3-methylpyridine (0.60mL, 6 mmol), and K were sequentially added under a nitrogen atmosphere 2 CO 3 (1.38g,10mmol)。Ni(PPh 3 )Cl 2 (159.25mg, 0.25mmol), DMF (5 mL) and stirred at 90 ℃ for 24h. After the reaction was completed, the mixture was diluted with water and extracted three times with ethyl acetate. The organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography, eluted with petroleum ether/ethyl acetate =2, and dried by suction to give a white solid (0.88g, 2.5 mmol) in 5% yield0％。
1 H NMR(400MHz,CDCl 3 )δ8.49(d,J＝4.4Hz,1H),7.66(dd,J＝11.2,8.7Hz,4H),7.62–7.50(m,2H),6.94(dd,J＝8.7,2.0Hz,4H),3.82(s,6H),2.64(s,3H). 13 C NMR(101MHz,CDCl 3 )δ162.21(s),154.72(s),153.38(s),140.17(s),139.16(s),133.83(s),124.94(s),123.83(s),113.85(d),55.27(s),19.29(s)。
HRMS(ESI):m/z:[M+Na]+calculated for C 20 H 20 NO 3 P:376.1181,Found:376.1073。
Example 9: synthesis of bis (4-methoxyphenyl) (6-methylpyridin-2-yl) phosphine oxide
Figure BDA0002524728850000081
To a 100mL Schlenk reaction flask, bis (p-methoxyphenyl) phosphorus oxide (0.952g, 5 mmol), 2-bromo-6-methylpyridine (0.60mL, 6 mmol), and K were sequentially added under a nitrogen atmosphere 2 CO 3 (1.38g,10mmol)。Ni(PPh 3 )Cl 2 (159.3mg, 0.25mmol), DMF (5 mL) and stirred at 90 ℃ for 24h. After the reaction was completed, the mixture was diluted with water and extracted three times with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography, eluting with petroleum ether/ethyl acetate =2, to obtain a white solid (0.93g, 2.65mmol) by suction drying, with a yield of 53%.
1 H NMR(400MHz,CDCl 3 )δ9.41(t,J＝6.6Hz,1H),9.21(dd,J＝11.3,8.7Hz,4H),9.10(td,J＝7.7,4.0Hz,1H),8.62(d,J＝7.6Hz,1H),8.36(dd,J＝8.7,2.1Hz,4H),5.23(s,6H),3.98(s,3H)。
13 C NMR(101MHz,CDCl 3 )δ162.36(d),159.10(d),155.82(d),136.15(s),134.00(d),125.12(d),123.77(d),113.86(d),100.00(s),55.28(d,),24.63(s)。
HRMS(ESI):m/z:[M+Na]+calculated for C 20 H 20 NO 3 P:376.1181,Found:376.1075。
Example 10: synthesis of bis (4-methoxyphenyl) (quinolin-2-yl) phosphine oxide
Figure BDA0002524728850000082
To a 100mL Schlenk reaction flask, bis (p-methoxyphenyl) phosphorus oxide (0.952g, 5 mmol), 2-bromoquinoline (1.25g, 6 mmol), and K were added in this order under a nitrogen atmosphere 2 CO 3 (1.38g,10mmol)。Ni(PPh 3 )Cl 2 (159.3mg, 0.25mmol), DMF (5 mL), and stirred at 90 ℃ for 24h. After the reaction was completed, the mixture was diluted with water and extracted three times with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography, eluting with petroleum ether/ethyl acetate =2, to obtain a white solid (0.82g, 2.1mmol) by suction, in 42% yield.
1 H NMR(400MHz,CDCl 3 )δ8.27–8.18(m,1H),8.12(s,1H),8.02(s,1H),7.83(dd,J＝14.3,5.6Hz,4H),7.69–7.47(m,2H),7.38(d,J＝6.5Hz,1H),6.83(d,J＝1.9Hz,4H),3.67–3.53(m,6H)。
13 C NMR(101MHz,CDCl 3 )δ162.36(d),158.37(s),157.07(s),148.10(s),147.89(s),136.12(d),133.98(dd),130.02(s),127.92(d,),124.23(s),123.14(s),122.94(s),113.89(d),55.16(d)。
HRMS(ESI):m/z:[M+Na]+calculated for C 23 H 20 NO 3 P:412.1181,Found:412.1073。
Example 11: synthesis of isoquinolin-1-yl bis (4-methoxyphenyl) phosphine oxide
Figure BDA0002524728850000091
To a 100mL Schlenk reaction flask, bis (p-methoxyphenyl) phosphorus oxide (0.952g, 5 mmol), 1-bromoisoquinoline (1.04g, 6 mmol), and K were added under a nitrogen atmosphere 2 CO 3 (1.38g,10mmol)。Ni(PPh 3 )Cl 2 (159.3mg, 0.25mmol), DMF (5 mL) and stirred at 90 ℃ for 24h. After the reaction was completed, the mixture was diluted with water and extracted three times with ethyl acetate. Is provided withThe organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography, eluting with petroleum ether/ethyl acetate =2, to obtain a white solid (0.86g, 2.2mmol) in 44% yield by suction drying.
1 H NMR(400MHz,CDCl 3 )δ9.43(d,J＝8.5Hz,1H),8.61(d,J＝5.5Hz,1H),7.85(d,J＝8.1Hz,1H),7.78–7.69(m,6H),7.65–7.59(m,1H),6.95(dd,J＝8.8,2.2Hz,4H),3.82(s,6H)。
13 C NMR(101MHz,CDCl 3 )δ162.29(s),157.27(s),136.12(s),134.09(s),131.56(s),130.55(s),128.19(s),127.19(s),125.03(s),123.92(s),122.85(s),113.94(s),113.81(s),55.27(s)。
HRMS(ESI):m/z:[M+Na]+calculated for C 23 H 20 NO 3 P:412.1181,Found:412.1071。
Example 12: synthesis of quinolin-2-yl di-p-tolyl phosphine oxide
Figure BDA0002524728850000092
To a 100mL Schlenk reaction flask, bis (p-methylphenyl) phosphorus oxide (1.15g, 5mmol), 2-bromoquinoline (1.04g, 6 mmol), and K were added in this order under a nitrogen atmosphere 2 CO 3 (1.38g,10mmol)。Ni(PPh 3 )Cl 2 (159.3mg, 0.25mmol), DMF (5 mL) and stirred at 90 ℃ for 24h. After the reaction was completed, the mixture was diluted with water and extracted three times with ethyl acetate. The organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography, eluting with petroleum ether/ethyl acetate =2, and dried by suction to give a white solid (0.61g, 1.7 mmol) with a yield of 34%.
1 H NMR(400MHz,CDCl 3 )δ8.21(qd,J＝8.4,4.0Hz,1H),8.05(d,J＝8.5Hz,1H),7.76(dd,J＝11.6,8.1Hz,4H),7.65–7.55(m,2H),7.52–7.41(m,2H),7.36(td,J＝7.4,2.7Hz,1H),7.17–7.13(m,3H),2.28(d,J＝8.3Hz,6H)。
13 C NMR(101MHz,CDCl 3 )δ158.21(s),156.92(s),148.16(d),142.24(d),136.06(d),132.13(dd),130.33(s),129.89(d),129.05(d),128.77(s),128.52(d),128.23–127.78(m),123.30(d),21.60(s)。
HRMS(ESI):m/z:[M+Na]+calculated for C 23 H 20 NOP:380.1283,Found:380.1176。
Example 13: synthesis of bis (3-methoxyphenyl) (pyridin-2-yl) phosphine oxide
Figure BDA0002524728850000101
To a 100mL Schlenk reaction flask, bis (m-methoxyphenyl) phosphorus oxide (0.952g, 5 mmol), 2-bromopyridine (0.60mL, 6 mmol), and K were sequentially added under a nitrogen atmosphere 2 CO 3 (1.38g,10mmol)。Ni(PPh 3 )Cl 2 (159.3mg, 0.25mmol), DMF (5 mL) and stirred at 90 ℃ for 24h. After the reaction was completed, the mixture was diluted with water and extracted three times with ethyl acetate. The organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography, eluting with petroleum ether/ethyl acetate =2, and dried by suction to give a white solid (0.61g, 1.7 mmol) with a yield of 34%.
1 H NMR(400MHz,CDCl 3 )δ8.77(d,J＝4.0Hz,1H),8.25(t,J＝6.7Hz,1H),7.86–7.78(m,1H),7.43(dd,J＝10.8,9.2Hz,4H),7.39–7.30(m,3H),7.03(d,J＝7.3Hz,2H),3.77(s,6H)。
13 C NMR(101MHz,CDCl 3 )δ159.38(d),156.42(d),150.16(d),136.13(d),133.47(d),129.56(d),128.31(d),125.27(d),124.44(d),118.17(d),116.75(d),55.39(s)。
HRMS(ESI):m/z:[M+Na]+calculated for C 19 H 18 NO 3 P:362.1024,Found:362.0925。
Example 14: synthesis of bis ([ 1,1' -biphenyl ] -4-yl) (pyridin-2-yl) phosphine oxide
Figure BDA0002524728850000102
Under nitrogen atmosphere, two were added in sequence to a 100mL Schlenk reaction flask(p-phenylphenyl) phosphorus oxide (1.77g, 5 mmol), 2-bromopyridine (0.60mL, 6 mmol), K 2 CO 3 (1.38g,10mmol)。Ni(PPh 3 )Cl 2 (159.3mg, 0.25mmol), DMF (5 mL), and stirred at 90 ℃ for 24h. After the reaction was completed, the mixture was diluted with water and extracted three times with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography, eluting with petroleum ether/ethyl acetate =4, to obtain a white solid (0.99g, 2.3 mmol) by suction drying, with a yield of 46%.
1 H NMR(400MHz,CDCl 3 )δ8.84(d,J＝4.5Hz,1H),8.41–8.35(m,1H),8.00(dd,J＝11.6,8.3Hz,4H),7.90(ddd,J＝7.7,6.2,3.8Hz,1H),7.69(dd,J＝8.3,2.6Hz,4H),7.62–7.57(m,4H),7.48–7.42(m,5H),7.41–7.35(m,2H)。
13 C NMR(101MHz,CDCl 3 )δ150.23(d),144.74(d),140.07(s),136.28(d),132.64(d),132.11(d),131.37(s),130.32(s),128.92(s),128.62–128.16(m),128.08(s),127.44–126.97(m),125.36(s)。
HRMS(ESI):m/z:[M+Na]+calculated for C 29 H 22 NOP:454.1493,Found:454.1333。
Example 15: synthesis of bis (naphthalen-1-yl) (pyridin-2-yl) phosphine oxides
Figure BDA0002524728850000111
To a 100mL Schlenk reaction flask, bis (o-phenylphenyl) phosphorus oxide (1.51g, 5 mmol), 2-bromopyridine (0.60mL, 6 mmol), and K were added in this order under a nitrogen atmosphere 2 CO 3 (1.38g,10mmol)。Ni(PPh 3 )Cl 2 (159.3mg, 0.25mmol), DMF (5 mL) and stirred at 90 ℃ for 24h. After the reaction was completed, the mixture was diluted with water and extracted three times with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography, eluting with petroleum ether/ethyl acetate =4, to obtain a white solid (0.80g, 2.1 mmol) in 42% yield by suction drying.
1 H NMR(400MHz,CDCl 3 )δ8.74(d,J＝8.4Hz,2H),8.68(d,J＝4.5Hz,1H),8.49–8.45(m,1H),8.02(d,J＝8.2Hz,2H),7.90(d,J＝8.1Hz,2H),7.61–7.35(m,10H)。
13 C NMR(101MHz,CDCl 3 )δ157.68(s),156.36(s),150.02(d),136.46(d),133.83(dd),133.24(d),129.13(d),128.83(s),127.78(s),127.56(d),127.25(s),126.37(s),125.23(d),124.55(s),124.41(s)。
HRMS(ESI):m/z:[M+Na]+calculated for C 25 H 18 NOP:402.1125,Found:402.1017。
Example 16: synthesis of ethyl 3- (2- (phenyl (pyridin-2-yl) phosphoryl) phenyl) acrylate
Figure BDA0002524728850000112
A25 mL Schlenk reaction flask was charged with diphenylyl (pyridine-2-yl) phosphine oxide (83.7 mg,0.3 mmol), ethyl acrylate (45.1mg, 0.45mmoL), palladium acetate (3.4 mg, 0.015mmoL), silver carbonate (165.5mg, 0.6 mmol), ac-Ala-OH (3.9mg, 0.03mmoL), and dissolved thoroughly in methanol (3 mL). The mixture was stirred at room temperature for 10 minutes, then at 80 ℃ for 24h. The mixture was diluted with ethyl acetate (10 mL), washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography, eluted with petroleum ether/ethyl acetate =1, and dried by suction to give a white solid in 65% yield.
1 H NMR(400MHz,CDCl 3 )δ8.72(d,J＝4.3Hz,1H),8.38(t,J＝6.6Hz,1H),8.26(d,J＝15.7Hz,1H),8.01(dd,J＝11.5,7.8Hz,2H),7.86(dd,J＝11.2,7.9Hz,1H),7.72–7.57(m,1H),7.57–7.31(m,7H),6.09(d,J＝15.7Hz,1H),4.15(q,J＝7.1Hz,2H),1.28(t,J＝6.9Hz,3H)。
13 C NMR(101MHz,CDCl 3 )δ165.91(s),156.60(d),150.04(d),142.81(d),139.03(d),136.28(d),133.53(d),132.81(s),132.38(d),132.20–131.54(m),130.61(s),129.56(d),129.00–128.62(m),128.43(t),127.82(d),125.29(s),121.22(d),60.36(s),14.29(s)。
HRMS(ESI):m/z:[M+H]+calculated for C 22 H 21 NO 3 P:378.1254,Found:378.1249。
The enantiomeric excess was determined by UPLC (Chiralpak INB column) (hexane: 2-propanol =80, 0.5ml/min,254nm,98% ee). The major enantiomer tr =11.45 min and the minor enantiomer tr =12.57 min.
[α] D 20 ＝70.60(c＝0.012,CHCl 3 )。
Example 17: synthesis of ethyl 3- (2- (((3-methylpyridin-2-yl) (phenyl) phosphoryl) phenyl) acrylate
Figure BDA0002524728850000121
To a 25mL Schlenk reaction flask was added (3-methylpyridin-2-yl) diphenylphosphinoxide (87.9mg, 0.3mmol), ethyl acrylate (45.1mg, 0.45mmoL), palladium acetate (3.4 mg, 0.015mmoL), copper acetate (108.9mg, 0.6 mmol), ac-Ala-OH (3.9mg, 0.03mmoL), and methanol (2 mL) was added to dissolve sufficiently. The solution was stirred at room temperature for 10 minutes, then at 50 ℃ for 48h. The mixture was diluted with ethyl acetate (20 mL), washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography, eluted with petroleum ether/ethyl acetate =1, and then drained to give a yellow solid in a yield of 57%.
1 H NMR(400MHz,CDCl 3 )δ8.45(d,J＝4.3Hz,1H),8.19(d,J＝15.7Hz,1H),7.88(dt,J＝18.9,9.6Hz,2H),7.62(dd,J＝7.6,4.1Hz,1H),7.58–7.32(m,8H),7.25–7.22(m,1H),6.11(d,J＝15.7Hz,1H),4.11(dt,J＝12.4,7.1Hz,2H),2.75(s,3H),1.25(t,J＝7.1Hz,6H)。
13 C NMR(101MHz,CDCl 3 )δ165.88(d),146.67(d,),144.13(s),143.08(d),140.67(d),139.25(d),138.58(s),134.37(s),133.35(s),132.72(dd),132.13(d),129.43(s),128.83(d),128.37(t),127.65(d),124.94(s),120.83(s),60.33(s),19.20(s),14.24(s)。
HRMS(ESI):m/z:[M+Na]+calculated for C 23 H 22 NO 3 P:414.1337,Found:414.1231。
The enantiomeric excess was determined by UPLC (Chiralpak INB column) (hexane: 2-propanol =80:20,0.5ml/min,254nm, 99.5% ee). The major enantiomer tr =8.90 min and the minor enantiomer tr =10.48 min.
[α] D 20 ＝12.40(c＝0.027,CHCl 3 )。
Example 18: synthesis of ethyl 3- (2- (phenyl (quinolin-2-yl) phosphoryl) phenyl) acrylate
Figure BDA0002524728850000122
Diphenyl (quinolin-2-yl) phosphine oxide (101.7 mg,0.3 mmol), ethyl acrylate (45.1mg, 0.45mmoL), palladium acetate (3.4 mg, 0.015mmoL), silver carbonate (91mg, 0.33mmol), ac-Ala-OH (3.9mg, 0.03mmoL) were added to a 25mL Schlenk reaction flask, and sufficiently dissolved by adding methanol (3 mL). The solution was stirred at room temperature for 10 minutes, then at 60 ℃ for 48h. The mixture was diluted with ethyl acetate (20 mL), washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography, eluted with petroleum ether/ethyl acetate =1, and then dried by suction to give a yellow solid in 59% yield.
1 H NMR(400MHz,CDCl 3 )δ8.39(ddd,J＝24.5,8.4,4.0Hz,3H),8.11–7.96(m,3H),7.87(d,J＝8.1Hz,1H),7.77–7.70(m,1H),7.70–7.58(m,3H),7.49(ddd,J＝11.4,9.9,5.6Hz,5H),7.38(d,J＝7.3Hz,1H),6.07(d,J＝15.7Hz,1H),4.11(q,J＝7.1Hz,2H),1.26–1.21(m,3H)。
13 C NMR(101MHz,CDCl 3 )δ165.96(s),143.28(s),136.26(s),133.65(s),132.49(d),132.44(s),132.30(s),132.06(s),130.29(s),130.09(s),128.88(s),128.42(s),128.30(s),127.88(s),127.72(s),123.71(s),123.49(s),121.08(s),60.33(s),14.25(s)。
HRMS(ESI):m/z:[M+Na]+calculated for C 26 H 22 NO 3 P:450.1337,Found:450.1230。
Enantiomeric excess was determined by UPLC (Chiralpak INB column) (hexane: 2-propanol =80:20,0.5mL/min,254nm, 97% ee). The major enantiomer tr =11.57 min and the minor enantiomer tr =12.64 min.
[α] D 20 ＝16.31(c＝0.005,CHCl 3 )。
Example 19: synthesis of butyl-3- (5-fluoro-2- ((4-fluorophenyl) (3-methylpyridin-2-yl) phosphoryl) phenyl) acyl acrylate
Figure BDA0002524728850000131
To a 25mL Schlenk reaction flask was added bis (4-fluorophenyl) (3-methylpyridin-2-yl) phosphine oxide (98.7mg, 0.3mmol), butyl acrylate (76.9mg, 0.60mmoL), palladium acetate (3.4 mg, 0.015mmoL), silver oxide (173.8mg, 0.75mmol), boc-Val-OH (6.5mg, 0.03mmoL), and the mixture was dissolved thoroughly in methanol (1 mL). The solution was stirred at room temperature for 10 minutes, then at 60 ℃ for 36h. The mixture was diluted with ethyl acetate (10 mL), washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography, eluted with petroleum ether/ethyl acetate =1, and then dried by suction to give a yellow solid with a yield of 59%.
1 H NMR(400MHz,CDCl 3 )δ8.36(d,J＝3.6Hz,1H),8.04(d,J＝15.7Hz,1H),7.83–7.74(m,2H),7.52–7.46(m,1H),7.25(ddd,J＝24.6,13.4,6.2Hz,4H),7.08(t,J＝8.0Hz,2H),6.96(t,J＝7.9Hz,1H),6.03(d,J＝15.7Hz,1H),4.01(t,J＝6.4Hz,2H),2.64(s,3H),1.55–1.49(m,2H),1.27(dd,J＝14.9,7.3Hz,2H),0.85(t,J＝7.2Hz,3H)。
13 C NMR(101MHz,CDCl 3 )δ166.07(s),165.72(s),163.75(d),153.36(s),152.01(s),146.71(d),141.63(s),140.88(s),140.66(s),139.44(d),135.14(dd),129.48(d,J＝103.1Hz),127.40(d,J＝106.7Hz),125.24(s),122.13(s),115.77(dd),115.04(s),64.44(s),30.65(s),19.08(s),13.69(s)。
HRMS(ESI):m/z:[M+Na]+calculated for C 25 H 24 F 2 NO 3 P:478.1462,Found:478.1354。
The enantiomeric excess was determined by UPLC (Chiralpak INB column) (hexane: 2-propanol =80, 0.5ml/min,254nm,98% ee). The major enantiomer tr =11.21 min and the minor enantiomer tr =13.51 min.
[α] D 20 ＝79.41(c＝0.002,CHCl 3 )。
Example 20: (E) Synthesis of butyl (E) -3- (5-fluoro-2- (((4-fluorophenyl) (6-methylpyridin-2-yl) phosphoryl) phenyl) acrylate
Figure BDA0002524728850000141
To a 25mL Schlenk reaction flask was added bis (4-fluorophenyl) (6-methylpyridin-2-yl) phosphine oxide (98.7 mg,0.3 mmol), butyl acrylate (76.9mg, 0.60mmoL), palladium acetate (3.4 mg, 0.015mmoL), silver oxide (173.8mg, 0.75mmol), boc-Val-OH (6.5mg, 0.03mmoL), and methanol (3 mL) was added to dissolve sufficiently. The solution was stirred at room temperature for 10 minutes, then at 60 ℃ for 24h. The mixture was diluted with ethyl acetate (20 mL), washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography, eluted with petroleum ether/ethyl acetate =1, and suction-dried to give a yellow solid in 52% yield.
1 H NMR(400MHz,CDCl 3 )δ8.26(d,J＝15.8Hz,1H),8.13(t,J＝6.6Hz,1H),7.95(ddd,J＝11.3,8.7,5.6Hz,2H),7.74(td,J＝7.7,4.3Hz,1H),7.67–7.55(m,1H),7.31–7.21(m,3H),7.14(td,J＝8.8,2.2Hz,2H),7.05(t,J＝8.1Hz,1H),6.08(d,J＝15.7Hz,1H),4.11(t,J＝6.7Hz,2H),2.52(s,3H),1.61(dd,J＝14.6,6.8Hz,2H),1.38(dd,J＝15.0,7.4Hz,2H),0.95(t,J＝7.4Hz,3H)。
13 C NMR(101MHz,CDCl 3 )δ165.72(s),159.25(d),154.78(d,J＝136.1Hz),142.01(s),136.40(s),134.87(s),129.09–128.58(m),128.15(s),127.95–127.65(m),126.00(s),125.79(s),125.32(s),122.21(s),115.93(s),115.79(s),115.58(s),64.47(s),30.70(s),24.48(s),19.12(s),13.72(s).
HRMS(ESI):m/z:[M+Na]+calculated for C 25 H 24 F 2 NO 3 P:478.1462,Found:478.1355。
Enantiomeric excess was determined by UPLC (Chiralpak INB column) (hexane: 2-propanol =80, 0.5ml/min,254nm,84% ee); m/z (MH +). The major enantiomer tr =14.61 min and the minor enantiomer tr =17.43 min.
[α] D 20 ＝46.83(c＝0.004,CHCl 3 )。
Example 21: synthesis of butyl-3- (5-fluoro-2- ((4-fluorophenyl) (quinolin-2-yl) phosphoryl) phenyl) acrylate
Figure BDA0002524728850000142
A25 mL Schlenk reaction flask was charged with bis (4-fluorophenyl) (quinolin-2-yl) phosphine oxide (147.3mg, 0.3mmol), butyl acrylate (76.9mg, 0.60mmoL), palladium acetate (3.4 mg, 0.015mmoL), silver oxide (173.8mg, 0.75mmol), boc-Val-OH (6.5mg, 0.03mmoL), and dissolved thoroughly in THF (3 mL). The solution was stirred at room temperature for 10 minutes, then at 40 ℃ for 48h. The mixture was diluted with ethyl acetate (10 mL), washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography, eluted with petroleum ether/ethyl acetate =1, and suction-dried to give a yellow solid in 52% yield.
1 H NMR(400MHz,CDCl 3 )δ9.39(d,J＝8.4Hz,1H),8.55(d,J＝5.5Hz,1H),8.12(d,J＝15.7Hz,1H),7.94–7.85(m,3H),7.73(dd,J＝8.5,5.7Hz,2H),7.69–7.61(m,1H),7.44–7.28(m,2H),7.19–7.10(m,2H),7.03(t,J＝8.2Hz,1H),6.07(d,J＝15.7Hz,1H),3.99–3.82(m,2H),1.45–1.35(m,2H),1.22(dd,J＝14.9,7.3Hz,2H),0.85(t,J＝7.3Hz,3H)。
13 C NMR(101MHz,CDCl 3 )δ166.30(d),165.48(s),163.77(d),155.81(s),154.48(s),141.71(d),141.51–141.25(m),136.20(d),135.76–134.92(m),131.59(s),131.36(s),130.80(s),130.03(s),128.94(s),128.54(s),128.06(s),127.35(s),127.05(s),123.38(s),122.37(s),115.84(dd),115.00(dd),64.31(s),30.44(s),18.98(s),13.69(s)。
HRMS(ESI):m/z:[M+Na]+calculated for C 28 H 24 F 2 NO 3 P:514.1462,Found:514.1357
Enantiomeric excess was determined by UPLC (Chiralpak INB column) (hexane: 2-propanol =80, 0.5ml/min,254nm,84% ee); the major enantiomer tr =16.96 min and the minor enantiomer tr =23.33 min.
[α] D 20 ＝50.35(c＝0.018,CHCl 3 )。
Example 22: synthesis of butyl-3- (5-fluoro-2- ((4-fluorophenyl) (isoquinolin-1-yl) phosphoryl) phenyl) acrylate
Figure BDA0002524728850000151
To a 25mL Schlenk reaction flask was added bis (4-fluorophenyl) (isoquinolin-1-yl) phosphine oxide (147.3mg, 0.3mmol), butyl acrylate (76.9mg, 0.60mmoL), palladium acetate (3.4 mg, 0.015mmoL), silver oxide (173.8mg, 0.75mmol), boc-Val-OH (6.5mg, 0.03mmoL), and THF (6 mL) was added and dissolved sufficiently. The solution was stirred at room temperature for 10 minutes, and then at 40 ℃ for 36 hours. The mixture was diluted with ethyl acetate (10 mL), washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography, eluted with petroleum ether/ethyl acetate =1, and then dried by suction to obtain a yellow solid with a yield of 52%.
1 H NMR(400MHz,CDCl 3 )δ8.33(d,J＝15.0Hz,2H),8.07(d,J＝9.0Hz,1H),8.05–7.97(m,3H),7.88(d,J＝7.7Hz,1H),7.76(t,J＝7.7Hz,1H),7.67–7.61(m,2H),7.15(s,3H),7.07(t,J＝8.1Hz,1H),6.08(d,J＝15.7Hz,1H),4.08(t,J＝6.7Hz,2H),1.62–1.56(m,2H),1.35(dd,J＝12.9,5.1Hz,2H),0.93(t,J＝7.4Hz,3H)。
13 C NMR(101MHz,CDCl 3 )δ165.66(s),135.00(s),130.19(s),128.51(s),127.93(s),122.37(s),115.82(s),64.47(s),30.67(s),19.10(s),13.71(s)。
HRMS(ESI):m/z:[M+Na]+calculated for C 28 H 24 F 2 NO 3 P:514.1462,Found:514.1356。
Enantiomeric excess was determined by UPLC (Chiralpak INB column) (hexane: 2-propanol = 90: 10,0.5ml/min,254nm,% ee); the major enantiomer tr =42.10 min and the minor enantiomer tr =45.47 min.
[α] D 20 ＝120(c＝0.0006,CHCl 3 )。
Example 23: synthesis of butyl 3- (5-methoxy-2- (((4-methoxyphenyl) (pyridin-2-yl) phosphoryl) phenyl) acrylate
Figure BDA0002524728850000161
To a 25mL Schlenk reaction flask, bis (4-methoxyphenyl) (pyridin-2-yl) phosphine oxide (98.7mg, 0.3mmol), butyl acrylate (76.9mg, 0.60mmoL), palladium acetate (3.4 mg, 0.015mmoL), benzoquinone (97.3mg, 0.9mmol), boc-Val-OH (6.5mg, 0.03mmoL) were added, and THF (0.5 mL) was added and dissolved sufficiently. The solution was stirred at room temperature for 10 minutes, then at 80 ℃ for 24h. The mixture was diluted with ethyl acetate (10 mL), washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography, eluted with petroleum ether/ethyl acetate =1, and then, suction-dried to obtain a yellow solid with a yield of 56%.
1 H NMR(400MHz,CDCl 3 )δ8.70(d,J＝4.1Hz,1H),8.33(t,J＝6.6Hz,1H),8.21(d,J＝15.7Hz,1H),7.93–7.78(m,3H),7.42–7.30(m,2H),7.08(s,1H),6.96(d,J＝6.9Hz,2H),6.84(d,J＝8.4Hz,1H),6.08(d,J＝15.7Hz,1H),4.08(t,J＝6.6Hz,2H),3.83(d,J＝2.2Hz,6H),1.61(dd,J＝14.6,6.9Hz,2H),1.39(dd,J＝15.0,7.4Hz,2H),0.95(t,J＝7.4Hz,3H)。
13 C NMR(101MHz,CDCl 3 )δ164.07(s),160.52(d),148.08(s),147.89(s),140.93(d),138.99(s),134.20(d),133.62(d),132.24(d),126.46(s),126.26(s),123.05(s),121.07(s),119.35(s),112.09(s),111.96(s),111.47(d),62.33(s),53.39(d),28.74(s),17.17(s),11.80(s)。
HRMS(ESI):m/z:[M+Na]+calculated for C 26 H 28 NO 5 P:488.1705,Found:488.1596。
Enantiomeric excess was determined by UPLC (Chiralpak INB column) (hexane: 2-propanol =75, 25,1ml/min,254nm,99.9% ee); m/z (MH +). The major enantiomer tr =11.54 min and the minor enantiomer tr =23.5 min.
Figure BDA0002524728850000163
Example 24: synthesis of butyl-3- (5-methoxy-2- ((4-methoxyphenyl) (3-methylpyridin-2-yl) phosphoryl) phenyl) acrylate
Figure BDA0002524728850000162
To a 25mL Schlenk reaction flask, bis (4-methoxyphenyl) (pyridin-2-yl) phosphine oxide (105.9 mg,0.3 mmol), butyl acrylate (76.9 mg, 0.60mmoL), palladium acetate (3.4 mg, 0.015mmoL), benzoquinone (97.3 mg,0.9 mmol), boc-Val-OH (6.5mg, 0.03mmoL) were added and dissolved sufficiently in THF (3 mL). The solution was stirred at room temperature for 10 minutes, then at 80 ℃ for 24h. The mixture was diluted with ethyl acetate (10 mL), washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography, eluted with petroleum ether/ethyl acetate =1, and then dried by suction to obtain a yellow solid with a yield of 56%.
1 H NMR(400MHz,CDCl 3 )δ8.44(d,J＝4.1Hz,1H),8.14(d,J＝15.7Hz,1H),7.75(dd,J＝10.9,8.8Hz,2H),7.56–7.49(m,1H),7.30(d,J＝8.6Hz,1H),7.22(d,J＝3.0Hz,1H),7.11(s,1H),6.96(d,J＝6.8Hz,2H),6.84(d,J＝8.6Hz,1H),6.10(d,J＝15.7Hz,1H),4.06(t,J＝6.6Hz,2H),3.83(d,J＝1.7Hz,6H),2.70(s,3H),1.62–1.54(m,2H),1.34(dd,J＝15.0,7.4Hz,2H),0.92(t,J＝7.4Hz,3H)。
13 C NMR(101MHz,CDCl 3 )δ166.16(s),162.40(s),162.13(s),153.31(s),146.59(d),143.13(d),140.46(s),140.25(s),139.14(d),134.82(d),134.35(d),126.22(s),124.79(s),123.62(s),120.88(s),113.94(t),113.26(d),64.26(s),55.34(d),30.68(s),19.21(d),13.77(s)。
HRMS(ESI):m/z:[M+Na]+calculated for C 27 H 30 NO 5 P:502.1863,Found:502.1753。
Enantiomeric excess was determined by UPLC (Chiralpak INB column) (hexane: 2-propanol =93, 7,0.6ml/min,254nm,99.9% ee); m/z. The major enantiomer tr =27.00 min and the minor enantiomer tr =30.25 min.
[α] D 20 ＝53.59(c＝0.005,CHCl 3 )。
Example 25: synthesis of butyl-3- (5-methoxy-2- ((4-methoxyphenyl) (6-methylpyridin-2-yl) phosphoryl) phenyl) acrylate
Figure BDA0002524728850000171
To a 25mL reaction tube was added bis (4-methoxyphenyl) (6-methylpyridin-2-yl) phosphine oxide (105.9 mg,0.3 mmol), butyl acrylate (76.9 mg, 0.60mmoL), palladium bis (acetylacetonate) (9.1 mg, 0.03mmol), boc-Phe-OH (15.9 mg, 0.06mmol), silver acetate (150.2 mg,0.9 mmol), and isopropanol (3 mL) was added. The reaction tube was moved to an oil bath at 80 ℃ for reaction for 48h. The mixture was diluted with ethyl acetate (20 mL), washed with saturated aqueous sodium chloride, the organic phase was dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography and concentrated under reduced pressure to give the product in 67% yield.
1 H NMR(400MHz,CDCl 3 )δ8.27(d,J＝15.7Hz,1H),8.08(t,J＝6.6Hz,1H),7.86(dd,J＝11.1,8.7Hz,2H),7.68(td,J＝7.7,4.1Hz,1H),7.52(dd,J＝13.1,8.6Hz,1H),7.18(d,J＝7.7Hz,1H),7.07(d,J＝2.5Hz,1H),6.96–6.91(m,2H),6.86(d,J＝8.6Hz,1H),6.07(d,J＝15.7Hz,1H),4.08(t,J＝6.7Hz,2H),3.82(d,J＝3.4Hz,6H),2.51(s,3H),1.65–1.57(m,2H),1.38(dd,J＝14.9,7.4Hz,2H),0.94(t,J＝7.4Hz,3H)。
13 C NMR(101MHz,CDCl 3 )δ166.16(s),162.33(d),158.92(d),156.76(s),155.43(s),143.55(d),140.86(d),136.13(d),135.69(d),134.20(d),125.51(d),124.88(d),123.87(s),122.78(s),120.93(s),113.88(dd),113.30(d),64.26(s),55.33(d),30.72(s),24.53(s),19.14(s),13.76(s)。
HRMS(ESI):m/z:[M+Na]+calculated for C 27 H 30 NO 5 P:502.1863,Found:502.1754。
Enantiomeric excess was determined by UPLC (Chiralpak INB column) (hexane: 2-propanol =85, 15,0.8ml/min,254nm,99.9% ee); m/z (MH +). The major enantiomer tr =26.52 min and the minor enantiomer tr =31.59 min.
[α] D 20 ＝19.23(c＝0.007,CHCl 3 )。
Example 26: synthesis of butyl-3- (5-methoxy-2- ((4-methoxyphenyl) (quinolin-2-yl) phosphoryl) phenyl) acrylate
Figure BDA0002524728850000181
To a 25mL reaction tube was added bis (4-methoxyphenyl) (quinolin-2-yl) phosphine oxide (116.7mg, 0.3mmol), butyl acrylate (76.9mg, 0.60mmoL), palladium bis (acetylacetonate) (9.1mg, 0.03mmol), ac-Ala-OH (7.9mg, 0.06mmoL), silver acetate (150.2mg, 0.9mmol), and isopropanol (3 mL) was added. The reaction tube was moved to an oil bath at 80 ℃ for reaction for 48h. The mixture was diluted with ethyl acetate (20 mL), washed with saturated aqueous sodium chloride, the organic phase was dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography and then concentrated under reduced pressure to give the product in 67% yield.
1 H NMR(400MHz,CDCl 3 )δ9.35(d,J＝8.5Hz,1H),8.48(d,J＝5.5Hz,1H),8.09(d,J＝15.7Hz,1H),7.81–7.68(m,3H),7.62(t,J＝5.7Hz,2H),7.55(t,J＝7.5Hz,1H),7.30–7.17(m,1H),7.08–7.02(m,1H),6.87(dd,J＝8.7,2.0Hz,2H),6.76(d,J＝8.5Hz,1H),6.01(d,J＝15.7Hz,1H),3.75(d,J＝4.1Hz,6H),1.35–1.26(m,2H),1.13(dd,J＝15.0,7.4Hz,2H),0.77(t,J＝7.3Hz,3H)。
13 C NMR(101MHz,CDCl 3 )δ165.94(s),162.48(d),162.23(d),156.50(d),143.08(d),141.71(d),140.73(d),136.12(d),135.03(d),134.42(d),131.36(d),130.52(s),128.17(s),127.49(s),127.18(s),126.14(s),125.06(s),123.66(s),122.87(d),122.56(s),121.12(s),113.95(dd),113.37(d),64.11(s),55.34(d),30.44(s),18.98(s),13.71(s)。
HRMS(ESI):m/z:[M+Na]+calculated for C 30 H 30 NO 5 P:538.1862,Found:538.1752。
Enantiomeric excess was determined by UPLC (Chiralpak INB column) (hexane: 2-propanol =75, 1ml/min,254nm,87.4% ee); m/z (MH +). The major enantiomer tr =9.99 min and the minor enantiomer tr =20.45 min.
[α] D 20 ＝17.83(c＝0.005,CHCl 3 )。
Example 27: synthesis of butyl-3- (2- (isoquinolin-1-yl (4-methoxyphenyl) phosphoryl) -5-methoxyphenyl) acrylate
Figure BDA0002524728850000182
To a 25mL reaction tube was added isoquinolin-1-ylbis (4-methoxyphenyl) phosphine oxide (116.7mg, 0.3mmol), butyl acrylate (76.9mg, 0.60mmoL), palladium bis (acetylacetonate) (9.1mg, 0.03mmoL), ac-Ala-OH (7.9mg, 0.06mmoL), silver acetate (150.2mg, 0.9mmol), and methanol (3 mL). The reaction tube was moved to a 40 ℃ oil bath for reaction for 48h. The mixture was diluted with ethyl acetate (20 mL), washed with saturated aqueous sodium chloride, the organic phase was dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography and concentrated under reduced pressure to give the product in 56% yield.
1 H NMR(400MHz,CDCl 3 )δ8.34(qd,J＝8.4,3.9Hz,3H),8.07(d,J＝8.5Hz,1H),7.92(dd,J＝11.0,8.8Hz,2H),7.84(d,J＝8.1Hz,1H),7.75–7.50(m,4H),7.09(s,1H),6.95(d,J＝6.9Hz,2H),6.87(d,J＝8.6Hz,1H),6.07(d,J＝15.7Hz,1H),4.05(t,J＝6.6Hz,2H),3.82(d,J＝4.5Hz,6H),1.61–1.53(m,2H),1.33(dd,J＝14.9,7.5Hz,2H),0.91(t,J＝7.4Hz,3H)。
13 C NMR(101MHz,CDCl 3 )δ163.79(s),160.19(d),156.10(s),154.78(s),145.73(d),141.10(d),138.61(d,),133.85(d),133.46(d),132.03(d),129.82(d),127.99(s),127.66(s),126.23(d),125.69(d),125.49–125.40(m),121.53(s),121.18(d),121.04–120.93(m),120.16(s),118.82(s),111.68(dd),111.08(d),61.97(s),53.06(d),28.39(s),16.83(s),11.47(s)。
HRMS(ESI):m/z:[M+Na]+calculated for C 30 H 30 NO 5 P:538.1862,Found:538.1755。
Enantiomeric excess was determined by UPLC (Chiralpak INB column) (hexane: 2-propanol =75, 25,1ml/min,254nm,99.3% ee); the major enantiomer tr =12.92 min and the minor enantiomer tr =32.82 min.
[α] D 20 ＝15.42(c＝0.003,CHCl 3 )。
Example 28: (E) Synthesis of butyl (E) -3- (2- (isoquinolin-3-yl (p-tolyl) phosphoryl) -5-methylphenyl) acrylate
Figure BDA0002524728850000191
To a 25mL reaction tube was added isoquinolin-1-ylbis (4-methylphenyl) phosphine oxide (107.1mg, 0.3mmol), butyl acrylate (115.4 mg, 0.9mmol), palladium tetrakis (acetonitrile) tetrafluoroborate (6.7 mg, 0.015), ac-Ala-OH (3.9mg, 0.03mmoL), silver acetate (150.2mg, 0.9mmol), and methanol (0.6 mL) was added. The reaction tube was moved to a 40 ℃ oil bath for 32h. The mixture was diluted with ethyl acetate (10 mL), washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography and concentrated under reduced pressure to give a product in 68% yield.
1 H NMR(400MHz,CDCl 3 )δ8.35–8.19(m,3H),7.99(d,J＝8.5Hz,1H),7.85–7.75(m,3H),7.64(t,J＝7.2Hz,1H),7.56–7.42(m,2H),7.35(d,J＝3.1Hz,1H),7.18(d,J＝6.1Hz,2H),7.10(d,J＝7.8Hz,1H),6.01(d,J＝15.7Hz,1H),3.97(t,J＝6.6Hz,2H),2.30(s,6H),1.54–1.45(m,2H),1.26(dd,J＝15.0,7.4Hz,2H),0.84(t,J＝7.4Hz,3H)。
13 C NMR(101MHz,CDCl 3 )δ163.82(s),155.77(s),154.47(s),145.78(s),145.57(s),141.15(d),140.27(s),140.07(s),136.59(d),133.79(d),131.51(d),130.10(d),127.96(s),127.59(s),127.23(d),126.74(d),126.13(d),125.78(s),125.48(s),121.28(s),121.07(s),118.39(s),61.82(s),28.35(s),19.23(d),16.77(s),11.42(s)。
HRMS(ESI):m/z:[M+Na] + calculated for C 30 H 30 NO 3 P:506.1963,Found:506.1856。
Enantiomeric excess was determined by UPLC (Chiralpak INB column) (hexane: 2-propanol =90/10,0.5ml/min,254nm,70% ee); the major enantiomer tr =14.6 min and the minor enantiomer tr =16.0 min.
[α] D 20 ＝39.69(c＝0.013,CHCl 3 )。
Example 29: (E) Synthesis of butyl (E) -3- (4-methoxy-2- (((3-methoxyphenyl) (pyridin-2-yl) phosphoryl) phenyl) acrylate
Figure BDA0002524728850000201
To a 25mL reaction tube was added bis (3-methoxyphenyl) (pyridin-2-yl) phosphine oxide (101.7mg, 0.3mmol), butyl acrylate (115.4mg, 0.9mmol), palladium acetate (6.7mg, 0.03mmol), ac-Ala-OH (7.9mg, 0.06mmoL), silver acetate (150.2mg, 0.9mmol), and methanol (2 mL) was added. The reaction tube was moved to a 40 ℃ oil bath for reaction for 48h. The mixture was diluted with ethyl acetate (20 mL), washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography and concentrated under reduced pressure to give the product in 62% yield.
1 H NMR(400MHz,CDCl 3 )δ8.73(d,J＝4.4Hz,1H),8.34(t,J＝6.7Hz,1H),8.18(d,J＝15.7Hz,1H),7.89–7.82(m,1H),7.56(ddd,J＝18.7,10.4,6.5Hz,3H),7.38(dt,J＝7.5,3.9Hz,2H),7.09–6.98(m,3H),6.04(d,J＝15.7Hz,1H),4.07(t,J＝6.7Hz,2H),3.81(s,3H),3.73(s,3H),1.60(dd,J＝14.6,6.9Hz,2H),1.37(dd,J＝15.0,7.5Hz,2H),0.94(t,J＝7.4Hz,3H)。
13 C NMR(101MHz,CDCl 3 )δ166.38(s),159.90(s),159.75(s),159.53(s),159.38(s),150.16(s),149.97(s),142.25(d),136.31(d),130.96(s),129.52(dd),128.67(s),128.46(s),125.35(s),124.70(d),119.67(d),119.04(s),118.65(s),117.32(s),116.72(d),64.14(s),55.41(d),30.73(s),19.14(s),13.77(s)。
HRMS(ESI):m/z:[M+Na] + calculated for C 26 H 28 NO 5 P:488.1704,Found:488.1596。
Enantiomeric excess was determined by UPLC (Chiralpak INB column) (hexane: 2-propanol =85/15,0.5mL/min,254nm,93.3% ee); the major enantiomer tr =18.7 min and the minor enantiomer tr =22.2 min.
[α] D 20 ＝36.50(c＝0.005,CHCl 3 )。
Example 30: butyl (E) -3- (4- ([ [1,1 '-biphenyl ] -4-yl (pyridin-2-yl) phosphoryl) - [1,1' -biphenyl ] -3-yl) acyl acrylate
Figure BDA0002524728850000202
To a 25mL reaction tube was added bis ([ 1,1' -biphenyl ] -4-yl) (pyridin-2-yl) phosphine oxide (129.3mg, 0.3mmol), butyl acrylate (115.4mg, 0.9mmol), palladium acetate (2.0mg, 0.009mmol), ac-Ala-OH (2.4mg, 0.018mmol), silver acetate (150.2mg, 0.9mmol), and methanol (1.5 mL) was added. The reaction tube was moved to a 50 ℃ oil bath for reaction for 36h. The mixture was diluted with ethyl acetate (10 mL), washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography and concentrated under reduced pressure to give the product in 67% yield.
1 H NMR(400MHz,CDCl 3 )δ8.77(d,J＝4.2Hz,1H),8.43(t,J＝6.6Hz,1H),8.33(d,J＝15.7Hz,1H),8.09(dd,J＝11.1,8.3Hz,2H),7.89(d,J＝3.1Hz,1H),7.82(d,J＝2.8Hz,1H),7.71(d,J＝6.2Hz,2H),7.64–7.56(m,6H),7.46(t,J＝7.3Hz,4H),7.42–7.36(m,3H),6.20(d,J＝15.7Hz,1H),4.09(t,J＝6.6Hz,2H),1.67–1.57(m,2H),1.39(dd,J＝14.9,7.4Hz,2H),0.94(t,J＝7.3Hz,3H)。
13 C NMR(101MHz,CDCl 3 )δ165.98(s),157.45(s),156.13(s),150.11(d),145.20(s),144.83(s),142.96(d),139.98(s),139.64(d),139.45(s),136.37(d),134.21(d),132.91(d),131.34(s),130.32(s),128.90(t),128.48(d),128.15(s),127.72–126.89(m),126.65(d),125.33(s),121.59(s),64.33(s),30.73(s),19.14(s),13.74(s)。
HRMS(ESI):m/z:[M+Na] + calculated for C 36 H 32 NO 3 P:580.2120,Found:580.2013。
Enantiomeric excess was determined by UPLC (Chiralpak INB column) (hexane: 2-propanol =85/15,0.5mL/min,254nm,99.9% ee); the major enantiomer tr =29.3 min and the minor enantiomer tr =25.2 min.
[α] D 20 ＝33.96(c＝0.006,CHCl 3 )。
Example 31: (E) Synthesis of butyl (E) -3- (1- (naphthalen-1-yl (pyridin-2-yl) phosphoryl) naphthalen-2-yl) acrylate
Figure BDA0002524728850000211
To a 25mL reaction tube was added bis (naphthalen-1-yl) (pyridin-2-yl) phosphine oxide (113.7mg, 0.3mmol), butyl acrylate (38.5mg, 0.3mmol), palladium chloride (5.3mg, 0.03mmol), ac-Ala-OH (7.9mg, 0.06mmoL), silver acetate (150.2mg, 0.9mmol), and methanol (1 mL) was added. The reaction tube was moved to a 40 ℃ oil bath for reaction for 48h. The mixture was diluted with ethyl acetate (10 mL), washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography and then concentrated under reduced pressure to give the product in 34% yield.
1 H NMR(400MHz,CDCl 3 )δ9.13(d,J＝8.6Hz,1H),8.69(d,J＝4.4Hz,1H),8.45–8.38(m,1H),8.30(d,J＝8.5Hz,1H),8.09(d,J＝15.7Hz,1H),8.01–7.92(m,2H),7.87–7.79(m,3H),7.62–7.53(m,1H),7.50–7.40(m,3H),7.39–7.32(m,3H),7.32–7.26(m,1H),5.50(d,J＝15.8Hz,1H),4.00–3.88(m,2H),1.59–1.50(m,2H),1.34(dd,J＝14.8,7.4Hz,2H),0.93(t,J＝7.4Hz,3H)。
13 C NMR(101MHz,CDCl 3 )δ165.67(s),158.19(s),156.88(s),150.23(d),146.05(d),139.69(d),136.47(d),134.88(d),134.14–133.32(m),133.25(s),132.35(d),131.56(s),130.54(s),129.02(s),128.91–128.38(m),128.38–127.84(m),127.17(d),126.59(dd),125.81(dd,),125.28–125.17(m),124.68(d),120.38(s),118.21(s),64.01(s),30.62(s),19.15(s),13.79(s)。
HRMS(ESI):m/z:[M+Na] + calculated for C 32 H 28 NO 3 P:528.1807,Found:528.1702。
Enantiomeric excess was determined by UPLC (Chiralpak INB column) (hexane: 2-propanol =85/15,0.5mL/min,254nm,98% ee); m/z. The major enantiomer tr =21.6 min and the minor enantiomer tr =16.2 min.
[α] D 20 ＝75.76(c＝0.011,CHCl 3 )。
Example 32: (E) Synthesis of t-butyl (E) -3- (2- (((3-methylpyridin-2-yl) (phenyl) phosphoryl) phenyl) acrylate
Figure BDA0002524728850000221
To a 25mL reaction tube was added (3-methylpyridin-2-yl) diphenylphosphine oxide (87.9 mg,0.3 mmol), tert-butyl acrylate (115.4 mg,0.9 mmol), bis (acetylacetonate) palladium (9.1 mg, 0.03mmol), cbz-Val-OH (15.1 mg, 0.06mmol), silver acetate (150.2 mg,0.9 mmol), and HFIP (3 mL) was added. The reaction tube was moved to a 40 ℃ oil bath for reaction for 32h. The mixture was diluted with ethyl acetate (20 mL), washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography and concentrated under reduced pressure to give the product in 56% yield.
1 H NMR(400MHz,CDCl3)δ8.37(d,J＝4.4Hz,1H),7.98(d,J＝15.7Hz,1H),7.78(dd,J＝11.5,7.9Hz,2H),7.55–7.35(m,7H),7.29(dd,J＝18.6,5.5Hz,2H),7.20–7.14(m,1H),5.93(d,J＝15.7Hz,1H),2.65(s,3H),1.35(s,9H)。
13 C NMR(101MHz,CDCl3)δ165.27(s),153.99(s),152.66(s),146.75(s),146.55(s),142.16(d),140.70(s),140.49(s),139.12(dd),133.93(s),133.14–132.43(m),132.33(s),131.85(dd),128.41(dd),127.69(d),124.91(d),122.98(s),80.25(s),28.07(s),19.29(s)。
HRMS(ESI):m/z:[M+Na] + calculated for C 25 H 26 NO 3 P:442.1650,Found:442.1542。
Enantiomeric excess was determined by UPLC (Chiralpak INB column) (hexane: 2-propanol =80/20,0.5ml/min,254nm,99.9% ee); the major enantiomer tr =7.8 min and the minor enantiomer tr =6.7 min.
[α] D 20 ＝68.41(c＝0.006,CHCl 3 )。
Example 33: (E) Synthesis of (3-methylpyridin-2-yl) (phenyl) (2-styrylphenyl) phosphine oxide
Figure BDA0002524728850000222
To a 25mL reaction tube was added (3-methylpyridin-2-yl) diphenylphosphine oxide (87.9mg, 0.3mmol), styrene (62.5mg, 0.6mmol), palladium acetate (3.4mg, 0.015mmol), BOC-Val-OH (6.5mg, 0.03), silver acetate (150.2mg, 0.9mmol), and toluene (3 mL) was added. The reaction tube was moved to a 45 ℃ oil bath for reaction for 48h. The mixture was diluted with ethyl acetate (15 mL), washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography and then concentrated under reduced pressure to give the product in 88% yield.
1 H NMR(400MHz,CDCl3)δ8.42(d,J＝4.4Hz,1H),7.86(dd,J＝11.5,7.7Hz,2H),7.73(dd,J＝7.7,4.4Hz,1H),7.67(d,J＝16.0Hz,1H),7.54–7.39(m,6H),7.29–7.12(m,8H),6.80(d,J＝16.0Hz,1H),2.68(s,3H)。
13 C NMR(101MHz,CDCl3)δ154.52(s),153.19(s),146.68(s),146.48(s),141.67(d),140.39(s),140.17(s),139.14(d),137.04(s),133.16–132.46(m),132.01(d),131.87–131.23(m),131.16(s),130.61(s),129.22(s),128.50–127.98(m),127.72(s),127.42(d),127.00–126.35(m),124.85(d),19.24(s)。
HRMS(ESI):m/z:[M+Na] + calculated for C 26 H 22 NOP:418.1439,Found:418.1334。
Enantiomeric excess was determined by UPLC (Chiralpak INB column) (hexane: 2-propanol =80/20,0.5mL/min,254nm,99.9% ee); m/z. The major enantiomer tr =13.9 min and the minor enantiomer tr =16.2 min.
[α] D 20 ＝73.33(c＝0.006,CHCl 3 )。
Example 34: (E) Synthesis of (3-methylpyridin-2-yl) (2- (4-methylstyryl) phenyl) (phenyl) phosphine oxide
Figure BDA0002524728850000231
To a 25mL reaction tube was added (3-methylpyridin-2-yl) diphenylphosphine oxide (87.9mg, 0.3mmol), p-methylstyrene (53mg, 0.45mmol), tetrakis (acetonitrile) palladium tetrafluoroborate (2.7mg, 0.006mmol), ac-Ala-OH (1.6mg, 0.012mmoL), silver acetate (150.2mg, 0.9mmol), hexafluoroisopropanol: ethylene glycol dimethyl ether =1 (3 mL). The reaction tube was moved to a 40 ℃ oil bath for 48 hours. The mixture was diluted with ethyl acetate (20 mL), washed with saturated aqueous sodium chloride, the organic phase was dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography and concentrated under reduced pressure to give the product in 77% yield.
1 H NMR(400MHz,CDCl 3 )δ8.43(d,J＝4.4Hz,1H),7.86(dd,J＝11.5,7.7Hz,2H),7.73(dd,J＝7.7,4.4Hz,1H),7.61(d,J＝16.0Hz,1H),7.53–7.40(m,7H),7.18–7.09(m,4H),7.05(d,J＝7.9Hz,2H),6.79(d,J＝16.0Hz,1H),2.68(s,3H),2.31(s,3H)。
13 C NMR(101MHz,CDCl 3 )δ154.62(s),153.29(s),146.67(s),146.47(s),141.81(d),140.35(s),140.14(s),139.11(d),137.63(s),134.29(s),132.95(d),132.62(d),131.97(s),131.54(d),131.03(s),130.46(s),129.12(s),128.14(d),126.87–126.13(m),124.82(s),21.24(s),19.25(s)。
HRMS(ESI):m/z:[M+Na] + calculated for C 27 H 24 NOP:432.1596,Found:432.1489。
Enantiomeric excess was determined by UPLC (Chiralpak INB column) (hexane: 2-propanol =80/20,0.5ml/min,254nm,96% ee); the major enantiomer tr =13.3 min and the minor enantiomer tr =11.9 min.
[α] D 20 ＝32.00(c＝0.009,CHCl 3 )。
Example 35: (E) Synthesis of (2- (4-fluorophenylethenyl) phenyl) (3-methylpyridin-2-yl) (phenyl) phosphine oxide
Figure BDA0002524728850000232
To a 25mL reaction tube were added (3-methylpyridin-2-yl) diphenylphosphine oxide (87.9mg, 0.3mmol), p-fluorostyrene (54.9mg, 0.45mmol), palladium acetate (6.7mg, 0.03mmol), cbz-Val-OH (15.1mg, 0.06mmol), silver acetate (55.1mg, 0.33mmol), and methanol (2 mL) was added. The reaction tube was moved to a 40 ℃ oil bath for reaction for 48h. The mixture was diluted with ethyl acetate (10 mL), washed with saturated aqueous sodium chloride, the organic phase was dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography and concentrated under reduced pressure to give the product in 74% yield.
1 H NMR(400MHz,CDCl 3 )δ8.34(d,J＝4.3Hz,1H),7.77(dd,J＝11.5,7.7Hz,2H),7.62(dd,J＝7.6,4.3Hz,1H),7.53(d,J＝16.0Hz,1H),7.46–7.27(m,7H),7.13–7.05(m,3H),6.85(t,J＝8.5Hz,2H),6.67(d,J＝16.0Hz,1H),2.59(s,3H)。
13 C NMR(101MHz,CDCl 3 )δ162.38(d,J＝247.5Hz),153.83(d,J＝134.2Hz),146.56(d),141.57(d),140.40(s),140.19(s),139.14(d),133.26(d),133.13–132.67(m),132.57(d),132.02(d),131.68(dd),130.59(s),129.87(s),128.22(t),127.30(d),126.81(d),126.47(d),124.85(d),115.46(s),115.25(s),19.23(s)。
HRMS(ESI):m/z:[M+Na] + calculated for C 26 H 21 FNOP:436.1345,Found:436.1247。
Enantiomeric excess (hexane: 2-propanol =90/10,1ml/min,254nm,99.9% ee) was determined by UPLC (Chiralpak INB column); the major enantiomer tr =21.2 min and the minor enantiomer tr =14.3 min.
[α] D 20 ＝67.14(c＝0.007,CHCl 3 )。
Example 36: (E) Synthesis of (2- (4-chlorostyryl) phenyl) (3-methylpyridin-2-yl) (phenyl) phosphine oxide
Figure BDA0002524728850000241
To a 25mL reaction tube was added (3-methylpyridin-2-yl) diphenylphosphine oxide (87.9mg, 0.3mmol), p-chlorostyrene (62.4mg, 0.45mmol), palladium acetate (6.7mg, 0.03mmol), ac-Ala-OH (7.9mg, 0.06mmoL), silver oxide (83.4mg, 0.36mmol), and methanol (2 mL) was added. The reaction tube was moved to a 40 ℃ oil bath for 28h. The mixture was diluted with ethyl acetate (10 mL), washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography and then concentrated under reduced pressure to give the product in 71% yield.
1 H NMR(400MHz,CDCl 3 )δ8.34(d,J＝4.3Hz,1H),7.81–7.72(m,2H),7.62(dd,J＝13.9,6.7Hz,2H),7.46–7.28(m,6H),7.23–7.16(m,1H),7.16–7.03(m,5H),6.67(d,J＝16.0Hz,1H),2.60(s,3H)。
13 C NMR(101MHz,CDCl 3 )δ154.42(s),153.09(s),146.69(s),146.49(s),141.34(d),140.42(s),140.21(s),139.18(d),135.58(s),133.30(s),133.13–132.41(m),132.03(d),131.71(d),130.74(s),129.70(s),128.60(s),128.10(dd),126.98(d),126.53(d),124.89(d),19.25(s)。
HRMS(ESI):m/z:[M+Na] + calculated for C 26 H 21 ClNOP:452.1049,Found:452.0944。
Enantiomeric excess was determined by UPLC (Chiralpak INB column) (hexane: 2-propanol =80/20,0.5ml/min,254nm,99.8% ee); m/z. The major enantiomer tr =16.7 min and the minor enantiomer tr =27.8 min.
[α] D 20 ＝42.83(c＝0.015,CHCl 3 )。
Example 37: (E) Synthesis of (3-methylpyridin-2-yl) (2- (2- (naphthalen-2-yl) vinyl) phenyl) (phenyl) phosphine oxide
Figure BDA0002524728850000251
To a 25mL reaction tube was added (3-methylpyridin-2-yl) diphenylphosphine oxide (87.9mg, 0.3mmol), 2-vinylnaphthalene (92.5mg, 0.6mmol), bis (acetylacetonato) palladium (9.1mg, 0.03mmol), boc-Tle-OH (13.9mg, 0.06mmol), silver acetate (50mg, 0.3mmol), and tert-amyl alcohol (2 mL) was added. The reaction tube was moved to a 40 ℃ oil bath for 48 hours. The mixture was diluted with ethyl acetate (10 mL), washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography and concentrated under reduced pressure to give the product in 64% yield.
1 H NMR(400MHz,CDCl 3 )δ8.44(d,J＝4.1Hz,1H),7.90(dd,J＝11.3,7.5Hz,2H),7.84–7.69(m,5H),7.60(s,1H),7.58–7.37(m,9H),7.28(dd,J＝14.2,6.6Hz,2H),7.16–7.10(m,1H),6.97(d,J＝16.0Hz,1H),2.71(s,3H)。
13 C NMR(101MHz,CDCl 3 )δ146.73(s),146.53(s),141.63(s),140.41(s),140.19(s),139.17(d),134.61(s),133.47(s),133.00(d),132.64(d),132.07(s),131.72(s),131.14(s),128.45–127.74(m),127.65(s),126.86(d),126.50(d),126.23(s),125.97(s),124.85(s),123.79(s),19.29(s)。
HRMS(ESI):m/z:[M+Na] + calculated for C 30 H 24 NOP:468.1596,Found:468.149。
Enantiomeric excess was determined by UPLC (Chiralpak INB column) (hexane: 2-propanol =80/20,0.5mL/min,254nm,99.9% ee); the major enantiomer tr =18.6 min and the minor enantiomer tr =23.6 min.
[α] D 20 ＝72.05(c＝0.008,CHCl 3 )。
Example 38: (E) Synthesis of (3-methylpyridin-2-yl) (phenyl) (2- (2- (trimethylsilyl) vinyl) phenyl) phosphine oxide
Figure BDA0002524728850000252
To a 25mL reaction tube was added (3-methylpyridin-2-yl) diphenylphosphine oxide (87.9 mg,0.3 mmol), trimethylvinylsilane (60mg, 0.6 mmol), palladium trifluoroacetate (10mg, 0.03mmol), ac-Ala-OH (7.9 mg, 0.06mmoL), silver acetate (150.2 mg,0.9 mmol), and tetrahydrofuran (3 mL) was added. The reaction tube was moved to a 40 ℃ oil bath for reaction for 48h. The mixture was diluted with ethyl acetate (10 mL), washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography and then concentrated under reduced pressure to give the product in 70% yield.
1 H NMR(400MHz,CDCl 3 )δ8.34(d,J＝4.3Hz,1H),7.77–7.67(m,2H),7.57(dd,J＝7.6,4.3Hz,1H),7.48–7.29(m,6H),7.16(ddd,J＝14.6,13.2,7.4Hz,3H),6.16(d,J＝18.7Hz,1H),2.59(s,3H),-0.20(s,9H)。
13 C NMR(101MHz,CDCl 3 )δ156.04(s),154.71(s),148.20(s),147.99(s),144.33(d),143.69(d),141.88(s),141.67(s),140.65(d),134.70(s),134.15(dt),133.45(d),133.13(t),132.83(s),131.81(s),129.60(d),128.51(d),128.10(d),126.30(d),20.85(s),0.00(s)。
HRMS(ESI):m/z:[M+Na] + calculated for C 23 H 26 NOPSi:414.1521,Found:414.1402。
Enantiomeric excess was determined by UPLC (Chiralpak INB column) (hexane: 2-propanol =90/10,0.5ml/min,254nm,99.3% ee); m/z. The major enantiomer tr =9.9 min and the minor enantiomer tr =8.7 min.
[α] D 20 ＝37.05(c＝0.027,CHCl 3 )。
Example 40: (E) Synthesis of (3-methylpyridin-2-yl) (phenyl) (2- (2- (phenylsulfonyl) ethenyl) phenyl) phosphine oxide
Figure BDA0002524728850000261
To a 25mL reaction tube was added (3-methylpyridin-2-yl) diphenylphosphine oxide (87.9mg, 0.3mmol), phenylvinylsulfone (151.4mg, 0.9mmol), palladium acetate (6.7mg, 0.03mmol), ac-Ala-OH (7.9mg, 0.06mmoL), silver acetate (150.2mg, 0.9mmol), and tert-amyl alcohol (3 mL). The reaction tube was moved to an oil bath at 80 ℃ for reaction for 48h. The mixture was diluted with ethyl acetate (10 mL), washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography and then concentrated under reduced pressure to give the product in 87% yield.
1 H NMR(400MHz,CDCl 3 )δ8.43(d,J＝4.4Hz,1H),8.23(d,J＝15.2Hz,1H),7.84–7.74(m,4H),7.62–7.45(m,10H),7.37(dd,J＝7.7,4.6Hz,2H),7.31–7.27(m,1H),6.68(d,J＝15.2Hz,1H),2.74(s,3H)。
13 C NMR(101MHz,CDCl 3 )δ146.81(s),146.61(s),141.60(d),141.01(s),140.79(s),140.31(s),139.60(d),133.19(d,J＝10.7),132.46(d),132.02(d),129.67(d),129.20(s),128.54(d),128.12(d),127.80(s),125.29(s),19.18(s)。
HRMS(ESI):m/z:[M+Na] + calculated for C 26 H 22 NOPS:482.1058,Found:482.0949。
Enantiomeric excess was determined by UPLC (Chiralpak INB column) (hexane: 2-propanol =80/20,0.5mL/min,254nm,97.3% ee); m/z. The major enantiomer tr =32.7 min and the minor enantiomer tr =28.2 min.
[α] D 20 ＝36.81(c＝0.011,CHCl 3 )。
Example 41: (E) Synthesis of (2- (4- (4- (diphenylamino) styryl) phenyl) (3-methylpyridin-2-yl) (phenyl) phosphine oxide
Figure BDA0002524728850000271
To a 25mL reaction tube was added (3-methylpyridin-2-yl) diphenylphosphine oxide (87.9mg, 0.3mmol), N, N-diphenyl-4-vinylaniline (122.1mg, 0.45mmol), palladium tetrakis (acetonitrile) tetrafluoroborate (6.7mg, 0.015mmol), ac-Ala-OH (7.9mg, 0.06mmoL), benzoquinone (32.4mg, 0.9mmol), and methanol (3 mL) was added. The reaction tube was moved to a 40 ℃ oil bath for reaction for 45h. The mixture was diluted with ethyl acetate (20 mL), washed with saturated aqueous sodium chloride, the organic phase was dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography and concentrated under reduced pressure to give the product in 56% yield.
1 H NMR(400MHz,CDCl 3 )δ8.33(d,J＝4.3Hz,1H),7.76(dd,J＝11.1,7.7Hz,2H),7.64(dd,J＝7.6,4.4Hz,1H),7.45–7.30(m,7H),7.16(t,J＝7.7Hz,5H),7.08(ddd,J＝7.3,4.4,2.5Hz,1H),7.01–6.91(m,8H),6.84(d,J＝8.5Hz,2H),6.70(d,J＝16.0Hz,1H),2.57(s,3H)。
13 C NMR(101MHz,CDCl 3 )δ154.72(s),153.39(s),147.47(d),146.72(s),146.51(s),141.83(d),140.34(s),140.13(s),139.16(d),133.03(d),132.62(d),132.17–131.84(m),131.63(d),131.23(d),130.55(s),130.21(s),129.31(s),128.18(d),127.71(s),126.35(dd),125.70(d),124.87(d),124.56(s),123.13(d),19.32(s)。
HRMS(ESI):m/z:[M+Na] + calculated for C 38 H 31 N 2 OP:582.2179,Found:582.2066。
Enantiomeric excess was determined by UPLC (Chiralpak INB column) (hexane: 2-propanol =80/20,0.6mL/min,365nm,99.9% ee); the major enantiomer tr =104.9 min and the minor enantiomer tr =56.8 min.
[α] D 20 ＝30.55(c＝0.014,CHCl 3 )。
Example 42: (E) Synthesis of (3-methylpyridin-2-yl) (phenyl) (2- (2- (pyridin-1-yl) ethenyl) phenyl) phosphine oxide
Figure BDA0002524728850000272
To a 25mL reaction tube was added (3-methylpyridin-2-yl) diphenylphosphine oxide (87.9mg, 0.3mmol), 1-vinylpyrene (102.6mg, 0.45mmol), palladium acetate (6.7mg, 0.03mmol), ac-Ala-OH (7.9mg, 0.06mmoL), silver acetate (150.2mg, 0.9mmol), and then pivalol (3 mL). The reaction tube was moved to a 70 ℃ oil bath for reaction for 48h. The mixture was diluted with ethyl acetate (10 mL), washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography and then concentrated under reduced pressure to give the product in a yield of 72%.
1 H NMR(400MHz,CDCl 3 )δ8.43(d,J＝4.3Hz,1H),8.29(d,J＝9.3Hz,1H),8.16(d,J＝7.3Hz,2H),8.08–7.88(m,11H),7.62(t,J＝7.5Hz,1H),7.51–7.42(m,4H),7.34(dd,J＝7.3,4.7Hz,2H),7.05(ddd,J＝7.3,4.4,2.6Hz,1H),2.68(s,3H)。
13 C NMR(101MHz,CDCl 3 )δ142.15(d),140.48(s),140.26(s),139.10(d),133.01(d),132.69(d),132.12(s),131.92–131.33(m),131.29–130.85(m),130.85–130.75(m),130.55(d),128.40–128.08(m),127.39(d),126.95(d),125.96(s),125.30(s),124.89(dd),124.03(s),123.01(s),19.22(s)。
HRMS(ESI):m/z:[M+Na] + calculated for C 36 H 26 N 2 OP:542.1752,Found:542.1644。
Enantiomeric excess was determined by UPLC (Chiralpak INB column) (hexane: 2-propanol =80/20,0.6ml/min,365 nm); the major enantiomer tr =30.1 min and the minor enantiomer tr =60.9 min.
[α] D 20 ＝62.82(c＝0.013,CHCl 3 )。
Example 43: (E) Synthesis of (2- (4- (5, 5-difluoro-1, 3,7, 9-tetramethyl-5H-4 l4,5l 4-dipyrrolo [1,2-c:2',1' -f ] [1,3,2] -diazaborin-10-yl) styryl) phenyl) (3-methylpyridin-2-yl) (phenyl) phosphine oxide
Figure BDA0002524728850000281
To a 25mL reaction tube was added (3-methylpyridin-2-yl) diphenylphosphine oxide (87.9mg, 0.3mmol), 5-difluoro-1, 3,7, 9-tetramethyl-10- (4-vinylphenyl) -5H-4l4, 5l4-dipyrrolo [1,2-c:2',1' -f ] [1,3,2] Diazaboronamine (210mg, 0.6 mmol), palladium tetrakis (acetonitrile) tetrafluoroborate (13.3mg, 0.03), ac-Ala-OH (7.9mg, 0.06mmoL), silver carbonate (248.2mg, 0.9mmol), and pivanol (3 mL) was added. The reaction tube was moved to a 40 ℃ oil bath for reaction for 48h. The mixture was diluted with ethyl acetate (10 mL), washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography and then concentrated under reduced pressure to give the product in 70% yield.
1 H NMR(400MHz,CDCl 3 )δ8.43(d,J＝4.0Hz,1H),7.91–7.71(m,4H),7.57–7.25(m,10H),7.16(d,J＝7.9Hz,3H),6.82(d,J＝16.0Hz,1H),5.98(s,2H),2.69(s,3H),2.55(s,6H),1.40(s,6H)。
13 C NMR(101MHz,CDCl 3 )δ155.49(s),146.73(s),146.52(s),143.01(s),141.49(s),140.48(s),139.15(d),137.76(s),134.21(s),132.92(d),132.60(d),132.12(s),131.71(s),131.38(s),130.29(s),128.68(s),128.21(d),127.37(s),127.26–126.73(m),126.70(s),124.80(s),121.22(s),31.94(s),29.72(s),29.34(s),27.23(s),22.71(s),19.27(s),14.58(s),14.14(s),1.05(s)。
HRMS(ESI):m/z:[M+Na] + calculated for C 39 H 35 BF 2 N 3 OP:642.2658,Found:642.2645。
Enantiomeric excess was determined by UPLC (Chiralpak INB column) (hexane: 2-propanol =80/20,0.5ml/min,254nm,96.5% ee); the major enantiomer tr =39.886 minutes and the minor enantiomer tr =27.001 minutes.

Claims (4)

1. A preparation method of a phosphorus center chiral compound is characterized by comprising the following steps:
in the presence of an oxidizing agent, a palladium salt andN-2-pyridyldiarylphosphine oxide of formula (II) and alkene derivative of formula (III) in the presence of a mono-protected chiral amino acid ligandC-HCarrying out a bond olefination reaction to generate a phosphorus center chiral compound shown in a formula (I); saidC-HThe reaction temperature of the bond olefination reaction is 40-80 ℃, and the reaction time is 6-48 h;
Figure QLYQS_1
；
wherein,
m is 0,1, 2, 3 or 4;
n is 0,1, 2 or 3;
R 1 is H, methyl, tert-butyl or phenyl, said methyl, tert-butyl or phenyl being optionally substituted by 1 to 3 halogens;
R 2 is H, fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, or phenyl, said methyl, ethyl, propyl, methoxy, ethoxy, propoxy, or phenyl being optionally substituted with 1 to 3 halogens;
R 3 is H, methyl ester, ethyl ester, n-butyl ester, tert-butyl ester, p-methoxyphenyl, p-nitrophenyl, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, p-methylphenyl,
Figure QLYQS_2
Phenyl sulfone group, trimethyl phosphate, triethyl phosphate, trimethylsilyl group, diphenylaminophenyl group, naphthyl group, anthryl group, phenanthryl group or pyrenyl group, wherein the naphthyl group, anthryl group, phenanthryl group or pyrenyl group is optionally substituted by 1 to 3 halogens, heteroaryl groups or-N (Ph) 2 Substitution;
the oxidant is copper acetate, silver carbonate, silver oxide or benzoquinone;
the palladium salt is palladium acetate, palladium bis (acetylacetonate), palladium trifluoroacetate, palladium tetrakis (acetonitrile) tetrafluoroborate or palladium chloride;
saidN-a mono-protected chiral amino acid ligand is
Figure QLYQS_4
、
Figure QLYQS_6
、
Figure QLYQS_8
、
Figure QLYQS_5
、
Figure QLYQS_7
、
Figure QLYQS_9
、
Figure QLYQS_10
Or>
Figure QLYQS_3
。/>
2. The method for preparing chiral compounds of phosphorus center as claimed in claim 1, wherein said chiral compounds are prepared by reacting a compound of formula (I) with a compound of formula (II) selected from the group consisting ofC-HThe reaction medium of the bond olefination reaction is methanol and tetraHydrogen furan, tert-amyl alcohol, toluene or hexafluoroisopropanol.
3. The process for preparing a phosphorus-centered chiral compound according to claim 1, characterized in that the oxidant, palladium salt,N-the molar ratio of the mono-protected chiral amino acid ligand to the 2-pyridyldiarylphosphine oxide of formula (II) is 1.1 to 3:0.01 to 0.1:0.01 to 0.2:1.
4. the method for preparing a phosphorus-centered chiral compound according to claim 1, wherein the molar ratio of the 2-pyridyldiarylphosphine oxide represented by the formula (II) to the olefin derivative represented by the formula (III) is 1:1.1 to 3.
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