Preparation method of P-chiral benzo five-membered cyclic phosphine compound

Abstract

The invention discloses a preparation method of a P-chiral benzo five-membered cyclic phosphine compound, which belongs to the technical field of organic synthesis, and comprises the following steps: in an argon atmosphere, placing substrates (2-bromophenyl) divinyl phosphine oxide with different substituent groups, a catalyst, a ligand and alkali in a solvent, and reacting at the temperature of 60-80 DEG C for 1-2 hours to obtain the P-chiral benzo five-membered cyclic phosphine compound. And reacting at 50 DEG C for 12 hours, and heating to obtain a product (S)-vinyl phosphino-indole oxide with different substituent groups. The P-chiral benzo five-membered cyclic phosphine compound prepared by the invention can be used as a skeleton of a novel chiral phosphine ligand, and has potential application value in organic synthesis and natural product synthesis; in the preparation process, the reaction condition is mild, the catalyst dosage is small, and the product has the characteristics of high yield and high selectivity. The raw materials are simple and easy to obtain, and the method is simple and convenient to operate.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, in particular to a method for preparing a P-chiral benzo five-membered cyclic phosphine compound. Background Art

[0002] Organophosphine compounds are widely used in a variety of fields, including pesticides, pharmaceuticals, materials, and chemical synthesis. In particular, p-chiral heterocyclic compounds, such as TangPhos, Duanphos, Zhangphos, and BIBOP, which can serve as chiral ligands, play an important role in asymmetric catalytic synthesis. Therefore, the development of efficient and highly selective methods for the synthesis of p-chiral heterocyclic compounds has attracted widespread attention.

[0003] In recent years, the construction of p-chiral compounds using transition metal-catalyzed asymmetric synthesis has made considerable progress. However, there are few reports on the synthesis of p-chiral benzo-pentacyclic phosphine compounds. This significantly restricts the application of the skeletal structure of p-chiral benzo-pentacyclic phosphine compounds. To address this issue, a method for preparing a p-chiral benzo-pentacyclic phosphine compound was proposed.

[0004] The above information disclosed in this background technology is only for enhancing understanding of the background technology of the present invention and therefore it may contain information that does not constitute the prior art that is already known to a person of ordinary skill in the art. Summary of the Invention

[0005] The present invention aims to solve at least one of the technical problems existing in the prior art. To this end, one object of the present invention is to provide a method for preparing a P-chiral benzo-pentacyclic phosphine compound.

[0006] To achieve the above object, the present invention provides the following technical solutions:

[0007] A method for preparing a P-chiral benzo-pentacyclic phosphine compound comprises the following steps:

[0008] Under an argon atmosphere, a substrate (2-bromophenyl) divinylphosphine oxide (Formula 1) with different substituents, a catalyst, a ligand, and a base are placed in a solvent and reacted at 50° C. for 12 h. The product (S)-vinylphosphine dole oxide (Formula 2) with different substituents is obtained by heating. The reaction formula is as follows:

[0009]

[0010] Wherein, R is an alkyl, alkoxy, fluorine, chlorine, or trifluoromethyl substituent.

[0011] As a further optimization scheme of the present invention, the catalyst is allyl palladium (II) chloride dimer (Pd2(Alyl)Cl2), and commercial reagents can be used without special treatment; the amount used is based on 6.0% equivalents of the (2-bromophenyl) divinyl phosphine oxide (Formula 1).

[0012] As a further optimization scheme of the present invention, the ligand structural formula is Commercial reagents can be used without special treatment; the amount used is 12.0% equivalent based on the (2-bromophenyl)divinylphosphine oxide (Formula 1).

[0013] As a further optimized solution of the present invention, the base is triethylamine, and a commercial reagent can be used without special treatment; the amount used is based on 4.0 equivalents of the (2-bromophenyl)divinylphosphine oxide (Formula 1).

[0014] As a further optimized solution of the present invention, the solvent is chloroform, and the amount of the solvent is measured at 5.0 mL of solvent per millimole of (2-bromophenyl)divinylphosphine oxide (Formula 1).

[0015] Compared with the prior art, the present invention has the following beneficial effects:

[0016] The P-chiral benzo-pentacyclic phosphine compound prepared by the present invention can serve as a novel chiral phosphine ligand framework and has potential applications in organic synthesis and natural product synthesis. The preparation process utilizes mild reaction conditions, requires minimal catalyst, and exhibits high yield and selectivity. Furthermore, the raw materials involved in the present invention are readily available, and the method is simple to operate.

[0017] The above summary is for illustrative purposes only and is not intended to be limiting in any way. In addition to the illustrative aspects, embodiments and features described above, further aspects, embodiments and features of the present invention will be readily apparent by reference to the accompanying drawings and the following detailed description. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 is the hydrogen nuclear magnetic resonance spectrum of compound (S)-2a in Example 1 of the present invention;

[0019] Figure 2 is the carbon NMR spectrum of compound (S)-2a in Example 1 of the present invention;

[0020] Figure 3 is the hydrogen nuclear magnetic resonance spectrum of compound (S)-2b in Example 1 of the present invention;

[0021] Figure 4 is the carbon NMR spectrum of compound (S)-2b in Example 1 of the present invention;

[0022] Figure 5 is the nuclear magnetic resonance phosphine spectrum of compound (S)-2b in Example 1 of the present invention;

[0023] Figure 6 is the hydrogen nuclear magnetic resonance spectrum of compound (S)-2c in Example 1 of the present invention;

[0024] Figure 7 is the carbon NMR spectrum of compound (S)-2c in Example 1 of the present invention;

[0025] Figure 8 is the nuclear magnetic resonance phosphine spectrum of compound (S)-2c in Example 1 of the present invention;

[0026] Figure 9 is the hydrogen nuclear magnetic resonance spectrum of compound (S)-2d in Example 1 of the present invention;

[0027] Figure 10 is the carbon NMR spectrum of compound (S)-2d in Example 1 of the present invention;

[0028] Figure 11 This is the nuclear magnetic resonance phosphine spectrum of compound (S)-2d in Example 1 of the present invention. DETAILED DESCRIPTION

[0029] The following will clearly and completely describe the technical solutions in the embodiments of the present invention in conjunction with the accompanying drawings. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0030] A method for preparing a P-chiral benzo-pentacyclic phosphine compound comprises the following steps:

[0031] Under an argon atmosphere, a substrate (2-bromophenyl) divinylphosphine oxide (Formula 1) with different substituents, a catalyst, a ligand, and a base are placed in a solvent and reacted at 50° C. for 12 h. The product (S)-vinylphosphine dole oxide (Formula 2) with different substituents is obtained by heating. The reaction formula is as follows:

[0032]

[0033] Wherein, R is an alkyl, alkoxy, fluorine, chlorine, or trifluoromethyl substituent.

[0034] Example 1

[0035] Synthesis of Compound (S)-Vinylphosphine Indole Oxide (S)-2a

[0036] Under argon protection, (2-bromophenyl)divinylphosphine oxide (51.4 mg, 0.20 mmol), Pd2(Alyl)Cl2 (4.39 mg, 12 μmol, 6.0 mol% Pd), ligand (12.2 mg, 24 μmol), NEt3 (80.8 mg, 0.80 mmol) and chloroform (1.0 mL) were added to a dry reaction tube and stirred in an oil bath at 50°C for 12 h.

[0037] The mixture was quickly filtered through silica gel using dichloromethane as the eluent. After the solvent was concentrated, the mixture was separated and purified by silica gel column chromatography using dichloromethane / methanol (30 / 1) as the eluent to obtain (S)-vinylphosphine dole oxide (S)-2a (31.7 mg, 0.18 mmol). The structure of the compound is shown below:

[0038]

[0039] According to the experimental steps, the yield of compound (S)-2a was 92%, and it was a white solid.

[0040] The ee value of 81% was determined by HPLC. Separation conditions: chiral IG column, flow rate: 1.0 mL / min, n-hexane / isopropanol: 80 / 20, 230 nm, 17.4 min (R), 18.8 min (S). 1 H NMR(600MHz, CDCl3)δ7.66(t,J=8.2Hz,1H),7.48(t,J=7.5Hz,1H),7.30-7.40(m,3H),6.55(ddd,J= 23.3Hz, 18.5Hz, 1.6Hz, 1H), 6.36 (dd, J=25.7Hz, 8.5Hz, 1H), 6.22-6.25 (m, 1H), 6.01-6.11 (m, 1H); 13 C NMR (150MHz, CDCl3) δ145.1 (d, J = 13.3Hz), 141.7 (d, J = 31.3Hz), 135.7, 132.9, 131.1 (d, J = 107.9Hz), 12 9.4(d,J=10.5Hz), 128.8(d,J=10.3Hz), 128.6(d,J=93.5Hz), 125.5(d,J=96.8Hz), 124.8(d,J=9.8Hz).

[0041] Example 2

[0042] Synthesis of Compound (S)-5-Methyl-1-vinylphosphine Indole Oxide (S)-2b

[0043] Under argon protection, (2-bromo-4-methylphenyl)divinylphosphine oxide (54.0 mg, 0.20 mmol), Pd2(Alyl)Cl2 (4.39 mg, 12 μmol, 6.0 mol% Pd), ligand (12.2 mg, 24 μmol), NEt3 (80.8 mg, 0.80 mmol) and chloroform (1.0 mL) were added to a dry reaction tube and stirred in an oil bath at 50°C for 12 h.

[0044] The mixture was quickly filtered through silica gel using dichloromethane as the eluent. After the solvent was concentrated, the mixture was separated and purified by silica gel column chromatography using dichloromethane / methanol (30 / 1) as the eluent to obtain (S)-5-methyl-1-vinylphosphine dole oxide (S)-2b (36.1 mg, 0.19 mmol). The structure of the compound is shown below:

[0045]

[0046] According to the experimental steps, the yield of compound (S)-2b was 95%, and it was a white solid.

[0047] The ee value of 85% was determined by HPLC. Separation conditions: chiral IG column, flow rate: 1.0 mL / min, n-hexane / isopropanol: 80 / 20, 230 nm, t major =25.6min(s), t minor =21.2min(R). 1 H NMR (600MHz, CDCl3) δ7.54(t,J=8.2Hz,1H),7.29(dd,J=38.8Hz,8.5Hz,1H),7.19(dd,J=6.7Hz,2.9Hz,1H),7.12(s,1H),6.52( ddt,J=23.2Hz,18.5Hz,1.5Hz,1H),6.34(ddd,J=25.6Hz,8.5Hz,1.3Hz,1H),6.19-6.30(m,1H),5.99-6.12(m,1H),2.39(s,3H); 13 C NMR (150MHz, CDCl3) δ145.2 (d, J = 12.9Hz), 143.7 (d, J = 1.6Hz), 142.2 (d, J = 31.7Hz), 135.4, 130.0 (d, J = 10.7Hz), 128.9(d,J=93.7Hz), 128.7(d,J=10.6Hz), 127.8(d,J=110.6Hz), 125.8(d,J=10.3Hz), 125.7(d,J=96.8Hz), 21.7; 31 P NMR (243 MHz, CDCl3) δ 37.3.

[0048] Example 3

[0049] Synthesis of Compound (S)-6-Methyl-1-vinylphosphine Indole Oxide (S)-2c

[0050] Under argon, (2-bromo-5-methylphenyl)divinylphosphine oxide (54.0 mg, 0.20 mmol), Pd2(Alyl)Cl2 (4.39 mg, 12 μmol, 6.0 mol% Pd), ligand (12.2 mg, 24 μmol), NEt3 (80.8 mg, 0.80 mmol), and chloroform (1.0 mL) were added to a dry reaction tube and stirred in a 50°C oil bath for 12 h. The mixture was quickly filtered through silica gel using dichloromethane as the eluent. After solvent concentration, the mixture was isolated and purified by silica gel column chromatography using dichloromethane / methanol (30 / 1) as the eluent to obtain (S)-6-methyl-1-vinylphosphine dole oxide (S)-2c (34.2 mg, 0.18 mmol). Its structure is shown below:

[0051]

[0052] According to the experimental steps, the yield of compound (S)-2c was 89%, and it was a white solid.

[0053] The ee value of 85% was determined by HPLC. Separation conditions: chiral IG column, flow rate: 1.0 mL / min, n-hexane / isopropanol: 80 / 20, 230 nm, t major =18.3min(s), t minor =16.3min(R). 1 H NMR (600MHz, CDCl3) δ7.48 (d, J=9.6Hz, 1H), 7.27-7.35 (m, 2H), 7.19 (dd, J=38.8Hz, 8.5Hz, 1H), 7.19 (dd, J=7.6Hz, 3.2Hz, 1H),6.55(ddd,J=23.2Hz,18.5Hz,1.7Hz,1H),6.22-6.31(m,2H),6.06(ddd,J=28.8Hz,18.5Hz,12.5Hz,1H),2.38(s,3H); 13C NMR (150MHz, CDCl3) δ145.2 (d, J = 13.2Hz), 139.8 (d, J = 10.2Hz), 139.2 (d, J = 31.3Hz), 135.5, 133.3 (d, J = 2.1Hz), 131.3(d,J=107.6Hz), 129.7(d,J=10.3Hz), 128.9(d,J=93.3Hz), 124.6(d,J=10.4Hz), 124.4(d,J=97.1Hz), 21.3; 31 P NMR (243 MHz, CDCl3) δ 37.5.

[0054] Example 4

[0055] Synthesis of Compound (S)-6-Methoxy-1-vinylphosphine Indole Oxide (S)-2d

[0056] Under argon protection, (2-bromo-5-methoxyphenyl)divinylphosphine oxide (57.0 mg, 0.20 mmol), Pd2(Alyl)Cl2 (4.39 mg, 12 μmol, 6.0 mol% Pd), ligand (12.2 mg, 24 μmol), NEt3 (80.8 mg, 0.80 mmol) and chloroform (1.0 mL) were added to a dry reaction tube and stirred in an oil bath at 50°C for 12 h.

[0057] The mixture was quickly filtered through silica gel using dichloromethane as the eluent. After the solvent was concentrated, the mixture was separated and purified by silica gel column chromatography using dichloromethane / methanol (30 / 1) as the eluent to obtain (S)-6-methyl-1-vinylphosphine dole oxide (S)-2d (34.2 mg, 0.18 mmol). The structure of the compound is shown below:

[0058]

[0059] According to the experimental steps, the yield of compound (S)-2d was 91%, and it was a white solid.

[0060] The ee value of 83% was determined by HPLC. Separation conditions: chiral IG column, flow rate: 1.0 mL / min, n-hexane / isopropanol: 80 / 20, 230 nm, t major =28.2min(S), t minor =24.6min(R). 1H NMR (600MHz, CDCl3) δ7.35-7.26(m,1H),7.25-7.19(m,2H),6.96(dd,J=8.2Hz,1.5Hz,1H),6.55(ddd,J= 23.2Hz, 18.5Hz, 1.6Hz, 1H), 6.33-6.17 (m, 2H), 6.06 (ddd, J=28.7Hz, 18.5Hz, 12.5Hz, 1H), 3.84 (s, 3H); 13 C NMR (150MHz, CDCl3) δ161.1 (d, J = 13.2Hz), 145.1 (d, J = 13.1Hz), 135.5, 134.3 (d, J = 32.4Hz), 129.0 (d, J=91.8Hz), 125.8 (d, J=11.7Hz), 123.0 (d, J=98.2Hz), 117.9 (d, J=1.7Hz), 114.9 (d, J=11.7Hz), 55.7; 31 P NMR (243 MHz, CDCl3) δ 37.8.

[0061] Parts not described in the present invention are the same as those in the prior art or can be implemented using the prior art. Although the embodiments of the present invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and variations may be made to these embodiments without departing from the principles and spirit of the present invention. The scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A method for preparing a P-chiral benzo five-membered cyclic phosphine compound, characterized in that: The following steps are involved: Under an argon atmosphere, a substrate (2-bromophenyl) divinylphosphine oxide (Formula 1) with different substituents, a catalyst, a ligand, and a base are placed in a solvent and reacted at 50° C. for 12 h. The product (S)-vinylphosphine dole oxide (Formula 2) with different substituents is obtained by heating. The reaction formula is as follows: Wherein, R is an alkyl, alkoxy, fluorine, chlorine, or trifluoromethyl substituent.

2. The method for preparing a P-chiral benzo five-membered cyclic phosphine compound according to claim 1, wherein: The catalyst is allylpalladium (II) chloride dimer (Pd2(Alyl)Cl2), and the amount used is 6.0% equivalent based on the (2-bromophenyl)divinylphosphine oxide (Formula 1).

3. The method for preparing a P-chiral benzo five-membered cyclic phosphine compound according to claim 1, wherein: The ligand structural formula is The amount used was 12.0% equivalent based on the (2-bromophenyl)divinylphosphine oxide (Formula 1).

4. The method for preparing a P-chiral benzo five-membered cyclic phosphine compound according to claim 1, wherein: The base is triethylamine, and the amount used is 4.0 equivalents based on the (2-bromophenyl)divinylphosphine oxide (Formula 1).

5. The method for preparing a P-chiral benzo five-membered cyclic phosphine compound according to claim 1, wherein: The solvent is chloroform, and the amount of the solvent used is measured at 5.0 mL of solvent per millimole of (2-bromophenyl)divinylphosphine oxide (Formula 1).

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