Method for preparing chiral alkynyl phosphine oxide through palladium-catalyzed asymmetric cross-coupling reaction

Abstract

The invention discloses a method for preparing chiral alkynyl phosphine oxide through palladium-catalyzed asymmetric cross-coupling reaction, which is characterized in that racemization secondary phosphine oxide and chloro alkyne are used as raw materials, and asymmetric construction of a C (sp)-P bond is realized in a kinetic resolution mode. The reaction conditions are mild, the yield is up to 90% or above, and the ee value can also reach 90% or above. The chiral alkynyl phosphine is prepared through the asymmetric palladium catalysis reaction, raw materials are cheap and easy to obtain, reaction conditions are mild, experimental operation is simple, the yield is high, the chiral maintaining effect is good, the method is an economical and efficient synthesis route, a new route is provided for synthesis of chiral alkynyl phosphine oxide, and the method can be suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of organic chemical synthesis, and more particularly to a method for preparing chiral alkynylphosphine oxides by a palladium-catalyzed asymmetric cross-coupling reaction. Background Technology

[0002] Pentavalent chiral alkynylphosphine oxides, phosphorus-centered chiral compounds, have broad application prospects in industrial production and daily life. They are important structural units in many natural products, drugs, and chiral ligands, serving not only as multifunctional building blocks for complex molecules but also as high-performance chiral ligands in catalytic reactions. For example, they exhibit high catalytic activity and stereoselectivity as chiral phosphine ligands in asymmetric hydrogenation reactions. Chiral alkynylphosphides also show great promise in immunosuppression and antitumor applications. Developing novel and efficient asymmetric synthetic methods for chiral alkynylphosphine oxides is of great significance.

[0003] The preparation of chiral alkynylphosphine oxides is achieved through transition metal-catalyzed desymmetry reactions of chiral dialkynylphosphine precursors. For example, desymmetry cycloaddition reactions of dialkynylphosphine oxides can occur under the catalysis of transition metals (such as copper, gold, rhodium, ruthenium, and thulium) to construct phosphine-centered chiral centers. However, the starting materials for this method are often difficult to obtain, and it can only construct chiral organophosphine molecules with specific structures, limiting its application. Summary of the Invention

[0004] The purpose of this invention is to provide a palladium-catalyzed asymmetric cross-coupling reaction for the preparation of chiral alkynylphosphine oxides, addressing the problems of harsh reaction conditions, difficult raw material preparation, and poor functional group tolerance in existing methods. Specifically, it provides a more direct alternative to palladium-catalyzed C(sp)-P asymmetric bonding and offers a new perspective on the reactivity and transformation of the PH bond in secondary phosphine oxides.

[0005] This invention relates to a palladium-catalyzed asymmetric cross-coupling reaction for the preparation of chiral alkynylphosphine oxides, wherein the chiral alkynylphosphine oxides are... ;

[0006] Wherein, Ar1 is any one of phenyl, 4-methylphenyl, 4-ethylphenyl, 4-isopropylphenyl, 4-n-butylphenyl, 4-tert-butylphenyl, 4-phenylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-trifluoromethylphenyl, 2-methylphenyl, 2-fluorophenyl, 2-bromophenyl, 3-methylphenyl, 3-methoxyphenyl, naphth-2-yl, phenanthrene-9-yl, quinolin-3-yl, and thiophene-3-yl;

[0007] Ar2 is any one of phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, and 2-methylphenyl.

[0008] This invention provides a method for preparing chiral alkynylphosphine oxides via a palladium-catalyzed asymmetric cross-coupling reaction, comprising:

[0009] The step involves preparing chiral alkynylphosphine oxides via an asymmetric cross-coupling reaction of chloroalkynes with aryl-tert-butylphosphine oxides in the presence of a palladium catalyst, ferrocene chiral bisphosphine ligands, and a Lewis base.

[0010] ;

[0011] Ar1 is any one of phenyl, 4-methylphenyl, 4-ethylphenyl, 4-isopropylphenyl, 4-n-butylphenyl, 4-tert-butylphenyl, 4-phenylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-trifluoromethylphenyl, 2-methylphenyl, 2-fluorophenyl, 2-bromophenyl, 3-methylphenyl, 3-methoxyphenyl, naphth-2-yl, phenanthrene-9-yl, quinoline-3-yl, and thiophene-3-yl.

[0012] Preferably, the reaction is carried out in the presence of a chiral bisphosphine ligand of ferrocene, which is any one of 1,1'-bis[(2S,4S)-2,5-dimethyl-1-phosphacyclobutyl]ferrocene, 1,1'-bis[(2S,5S)-2,5-dimethyl-1-phosphacyclopentyl]ferrocene, 1,1'-bis[(2S,5S)-2,5-diethyl-1-phosphacyclopentyl]ferrocene, and 1,1'-bis[(2S,5S)-2,5-diisopropyl-1-phosphacyclopentyl]ferrocene.

[0013] Preferably, the molar ratio of chloroalkyne: aryl tert-butylphosphine oxide: palladium catalyst: ferrocene chiral bisphosphine compound: Lewis base is 1:4:0.15:0.2:2.

[0014] The preferred structure of aryl-tert-butylphosphine oxide is as follows:

[0015] ;

[0016] Ar2 is any one of phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, and 2-methylphenyl.

[0017] Preferably, the Lewis base is any one of potassium phosphate, potassium hydrogen phosphate, sodium carbonate, sodium bicarbonate, triethylamine, triethylenediamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, and 4-dimethylaminopyridine.

[0018] Preferably, the palladium catalyst is any one of bis(dibenzylacetone)palladium, tri(dibenzylacetone)palladium, palladium acetate, palladium neopentanoate, palladium chloride, palladium iodide, palladium trifluoroacetate, tetra(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, bis(triphenylphosphine)diacetate, and bis(2,2,6,6-methyl-3,5-heptadecanoic acid)palladium.

[0019] Preferably, the reaction is carried out in an oil bath at 45°C for a reaction time of more than 18 hours.

[0020] Specifically, a method for preparing chiral alkynylphosphine oxides via a palladium-catalyzed asymmetric cross-coupling reaction is provided, comprising the following steps:

[0021] The raw material components are obtained, including chloroalkyne, aryl-tert-butylphosphine oxide, palladium catalyst, ferrocene chiral bisphosphine compound, Lewis base, and acetonitrile solvent, wherein the molar ratio of chloroalkyne, tert-butylphenylphosphine oxide, palladium catalyst, ferrocene chiral bisphosphine compound, Lewis base, and acetonitrile solvent is 1:4:0.15:0.2:2:10;

[0022] Under an argon gas flow, palladium catalyst, ferrocene chiral bisphosphine, and acetonitrile solvent were added to a Shrek tube to obtain mixed solution A, which was then stirred.

[0023] Under an argon gas flow, Lewis base, chloroalkyne and aryl-tert-butylphosphine oxide were added to mixed solution A to obtain mixed solution B;

[0024] After the reaction of mixed solution B was complete, it was concentrated by rotary evaporation and separated by silica gel column chromatography to obtain chiral alkynylphosphine oxide.

[0025] Compared with the prior art, the technical advantages of the present invention are as follows:

[0026] This invention uses readily available tert-butylarylphosphine oxides and chloroalkynes as starting materials to synthesize chiral alkynylphosphine oxides through a direct asymmetric cross-coupling reaction catalyzed by transition metals under the action of palladium catalyst, ferrocene chiral bisphosphine ligands, and Lewis bases. The cross-coupling reaction of chloroalkynes with different substituents and various substituted arylphosphine oxides achieves yields of up to 90% or more, with ee values ​​reaching up to approximately 95%. The reaction conditions are mild, the operation is simple, the starting materials are readily available, the reaction is highly efficient, and the production cost is low, making it suitable for industrial production. Detailed Implementation

[0027] The present invention will be further described in detail below through specific embodiments. The following embodiments will help those skilled in the art to further understand the present invention, but do not limit the present invention in any way. It should be noted that the following embodiments are only for further illustration of the present invention and should not be construed as limiting the scope of protection of the present invention. Some non-essential improvements and adjustments made by those skilled in the art based on the above-described invention are still within the scope of protection of the present invention.

[0028] It should be noted that terms such as "upper", "lower", "left", "right", and "middle" used in this specification are only for clarity of description and are not intended to limit the scope of implementation. Changes or adjustments to their relative relationships, without substantially altering the technical content, should also be considered as within the scope of this application.

[0029] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application pertains; the term “and / or” as used herein includes any and all combinations of one or more of the associated listed items.

[0030] Unless otherwise specified in the examples, the procedures should be performed under standard conditions or conditions recommended by the manufacturer. Reagents or instruments whose manufacturers are not specified are all commercially available products.

[0031] As used herein, the term “about” is used to provide for the flexibility and imprecision associated with a given term, measure, or value. Those skilled in the art can readily determine the degree of flexibility for a particular variable.

[0032] As used herein, the term “at least one of…” is intended to be synonymous with “one or more of…”. For example, “at least one of A, B, and C” explicitly includes only A, only B, only C, and combinations thereof.

[0033] This application provides a method for preparing chiral alkynylphosphine oxides via a palladium-catalyzed asymmetric cross-coupling reaction. Detailed descriptions follow. It should be noted that the order of description in the following embodiments is not intended to limit the preferred order of the embodiments. Furthermore, in the description of this application, various embodiments of the invention may be presented in the form of a range; it should be understood that the description in the form of a range is merely for convenience and brevity and should not be construed as a rigid limitation on the scope of the invention; therefore, it should be considered that the range description specifically discloses all possible sub-ranges and single numerical values ​​within that range. For example, it should be considered that the range description from 1 to 6 specifically discloses sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 5, from 2 to 6, from 3 to 6, etc., and single numbers within the range, such as 1, 2, 3, 4, 5, and 6, regardless of the range. Additionally, whenever a numerical range is indicated herein, it means including any referenced number (fraction or integer) within the indicated range.

[0034] Example 1

[0035] Under an argon atmosphere, 25.5 mg (0.044 mmol) of bis(benzylacetone)palladium, 24.9 mg (0.06 mmol) of 1,1'-bis[(2S,5S)-2,5-dimethyl-1-phosphacyclopentyl]ferrocene, and 4.5 mL of acetonitrile were added to a 10 mL Shrek tube. After stirring the mixture for a few minutes, 60.7 mg (0.6 mmol) of triethylamine, 41 mg (0.3 mmol) of phenylchloroacetylene, and 218.6 mg (1.2 mmol) of phenyl(tert-butyl)phosphine oxide were added to the 10 mL Shrek tube. The mixture was stirred in an oil bath at 45 °C for 18 hours to allow for complete reaction. After the reaction was complete, the mixture was purified by silica gel column chromatography to obtain 77 mg of chiral alkynylphosphine oxide, namely tert-butyl(phenylacetyl)phenylphosphine oxide, with a yield of 91%. The target product, tert-butyl(phenylethynyl)phenylphosphine oxide, has extremely high purity, and no other organic impurities are generated during its preparation.

[0036] Figure 1 The structural diagram and nuclear magnetic resonance (NMR) spectrum data of tert-butyl(phenylethynyl)phenylphosphine oxide in this embodiment are as follows:

[0037] 1 H NMR (500 MHz, Chloroform-d) δ = 7.97 – 7.89 (m, 2H), 7.64 – 7.53(m, 3H), 7.54 – 7.42 (m,3H), 7.42 – 7.36 (m, 2H), 1.37 – 1.12 (d, J=16.9 Hz,9H).

[0038] 13 C NMR (126 MHz, Chloroform-d) δ = 132.52 (d, J=2.0 Hz), 132.10,132.04 (d, J=9.3 Hz), 130.55, 129.53 (d, J=109.2 Hz), 128.62, 128.19 (d, J=12.4 Hz), 120.19, 104.38 (d, J=24.1 Hz), 81.37 (d, J=149.1 Hz), 34.13 (d, J=83.4 Hz), 23.91.

[0039] 31 P NMR (202 MHz, Chloroform-d) δ = 31.22;

[0040] Example 2

[0041] The rest is the same as in Example 1, except that the chloroacetylene is (4-methylphenyl)chloroacetylene, yielding tert-butyl(4-methylphenylacetyl)phenylphosphine oxide in 86% yield. Its structural formula is as follows: Figure 2 As shown, the target product, tert-butyl(4-methylphenylethynyl)phenylphosphine oxide, has extremely high purity, and no other organic impurities are generated during the preparation process.

[0042] Figure 2 The structural diagram and nuclear magnetic resonance (NMR) spectrum data of tert-butyl(4-methylphenylethynyl)phenylphosphine oxide in this embodiment are as follows:

[0043] 1 H NMR (500 MHz, Chloroform-d) δ = 7.97 – 7.89 (m, 2H), 7.58 – 7.53(m, 1H), 7.53 – 7.45 (m, 4H), 7.22 – 7.16 (d, J=8.0 Hz, 2H), 2.49 – 2.23 (s,3H), 1.28 – 1.20 (d, J=16.8 Hz, 9H).

[0044] 13C NMR (126 MHz, Chloroform-d) δ = 141.13, 132.45 (d, J Hz =1.8), 132.06 (d, J Hz =9.1), 130.17 (d, J=110.1 Hz), 129.36, 128.20, 128.10, 117.11(d, J=4.0 Hz), 104.87 (d, J=24.6 Hz), 80.72 (d, J=150.9 Hz), 34.11 (d, J=83.3Hz), 23.93, 21.73.

[0045] 31 P NMR (202 MHz, Chloroform-d) δ = 31.13.

[0046] Example 3

[0047] The rest is the same as in Example 1, except that the chloroalkyne is (4-ethylphenyl)chloroacetylene, yielding tert-butyl(4-ethylphenylacetyl)phenylphosphine oxide in 85% yield. Its structural formula is as follows: Figure 3 As shown, the target product, tert-butyl(4-ethylphenylethynyl)phenylphosphine oxide, has extremely high purity, and no other organic impurities are generated during the preparation process.

[0048] Figure 3 The structural diagram and nuclear magnetic resonance (NMR) spectrum data of tert-butyl(4-ethylphenylethynyl)phenylphosphine oxide in this embodiment are as follows:

[0049] 1 H NMR (500 MHz, Chloroform-d) δ = 7.98 – 7.87 (m, 2H), 7.61 – 7.42(m, 5H), 7.25 – 7.18 (d, J=8.0 Hz, 2H), 2.72 – 2.64 (q, J=7.6 Hz, 2H), 1.28 –1.19 (m, 12H).

[0050] 13C NMR (126 MHz, Chloroform-d) δ = 147.38, 132.57 (d, J=1.8 Hz), 132.06 (d, J=9.5 Hz), 130.15 (d, J=109.1 Hz), 129.28, 128.20, 128.11, 117.31(d, J=3.8 Hz), 104.90 (d, J=24.5 Hz), 80.67 (d, J=151.4 Hz), 34.11 (d, J=83.5Hz), 29.01, 23.92, 15.24.

[0051] 31 P NMR (202 MHz, Chloroform-d) δ = 31.19.

[0052] Example 4

[0053] The rest is the same as in Example 1, except that the chloroalkyne is (4-n-butylphenyl)chloroacetylene, yielding tert-butyl(4-n-butylphenylacetyl)phenylphosphine oxide in 74% yield. Its structural formula is as follows: Figure 4 As shown, the target product, tert-butyl(4-n-butylphenylethynyl)phenylphosphine oxide, has extremely high purity, and no other organic impurities are generated during its preparation.

[0054] Figure 4 The structural diagram and nuclear magnetic resonance (NMR) spectrum data for tert-butyl(4-n-butylphenylethynyl)phenylphosphine oxide in this embodiment are as follows:

[0055] 1 H NMR (500 MHz, Chloroform-d) δ = 7.96 – 7.87 (m, 2H), 7.59 – 7.53(m, 1H), 7.53 – 7.46 (m, 4H), 7.22 – 7.16 (d, J=7.8 Hz, 2H), 2.68 – 2.57 (t,J=7.7 Hz, 2H), 1.64 – 1.52 (m, 2H), 1.40 – 1.30 (m, 2H), 1.27 – 1.19 (d, J=16.9 Hz, 9H), 0.95 – 0.89 (t, J=7.3 Hz, 3H).

[0056] 13C NMR (126 MHz, Chloroform-d) δ = 146.10, 132.47 (d, J=1.9 Hz), 132.09, 132.02, 129.73 (d, J=109.2 Hz), 128.73, 128.15 (d, J=12.2 Hz), 117.26(d, J=3.7 Hz), 104.91 (d, J=24.7 Hz), 80.68 (d, J=151.2 Hz), 35.74, 34.11 (d,J=83.5 Hz), 33.26, 23.92, 22.27, 13.90.

[0057] 31 P NMR (202 MHz, Chloroform-d) δ = 31.12.

[0058] Example 5

[0059] The rest is the same as in Example 1, except that the chloroalkyne is (4-tert-butylphenyl)chloroacetylene, yielding tert-butyl(4-tert-butylphenylacetylene)phenylphosphine oxide in 82% yield. Its structural formula is as follows: Figure 5 As shown, the target product, tert-butyl(4-tert-butylphenylethynyl)phenylphosphine oxide, has extremely high purity, and no other organic impurities are generated during the preparation process.

[0060] Figure 5 The structural diagram and nuclear magnetic resonance (NMR) spectrum data for tert-butyl(4-tert-butylphenylethynyl)phenylphosphine oxide in this embodiment are as follows:

[0061] 1 H NMR (500 MHz, Chloroform-d) δ = 8.03 – 7.85 (m, 2H), 7.60 – 7.51(m, 3H), 7.53 – 7.45 (m, 2H), 7.44 – 7.38 (m, 2H), 1.38 – 1.30 (s, 9H), 1.28– 1.19 (d, J=16.8 Hz, 9H).

[0062] 13C NMR (126 MHz, Chloroform-d) δ = 154.21, 132.34 (d, J=1.8 Hz), 132.11, 132.03, 130.18 (d, J=109.2 Hz), 128.15 (d, J=12.2 Hz), 125.66, 117.11(d, J=3.9 Hz), 104.91 (d, J=24.6 Hz), 80.72 (d, J=151.3 Hz), 35.07, 34.12 (d,J=83.3 Hz), 31.07, 23.93.

[0063] 31 P NMR (Chloroform-d) δ: 31.15.

[0064] Example 6

[0065] The rest is the same as in Example 1, except that the chloroalkyne is (4-isopropylphenyl)chloroacetylene, yielding tert-butyl(4-isopropylphenylacetylene)phenylphosphine oxide in 83% yield. Its structural formula is as follows: Figure 6 As shown, the target product, tert-butyl(4-isopropylphenylethynyl)phenylphosphine oxide, has extremely high purity, and no other organic impurities are generated during its preparation.

[0066] Figure 6 The structural diagram and nuclear magnetic resonance (NMR) spectrum data for tert-butyl(4-isopropylphenylethynyl)phenylphosphine oxide in this embodiment are as follows:

[0067] 1 H NMR (500 MHz, Chloroform-d) δ = 7.96 – 7.89 (m, 2H), 7.59 – 7.46(m, 5H), 7.29 – 7.23 (m, 2H), 2.94 (pent, J=6.9 Hz, 1H), 1.28 – 1.24 (m,12H), 1.22 (s, 3H).

[0068] 13C NMR (126 MHz, Chloroform-d) δ = 152.0, 132.6 (d, J=1.8), 132.1,132.0, 129.7 (d, J=108.9 Hz), 128.2 (d, J=12.3 Hz), 126.8, 117.4 (d, J=3.7Hz), 104.9 (d, J=24.4 Hz), 80.6 (d, J=151.2 Hz), 34.4, 34.3, 33.8, 23.8 (d, J=30.6 Hz).

[0069] 31 P NMR (202 MHz, Chloroform-d) δ = 31.12.

[0070] Example 7

[0071] The rest is the same as in Example 1, except that the chloroalkyne is (4-phenylphenyl)chloroacetylene, yielding tert-butyl(4-phenylphenylacetyl)phenylphosphine oxide in 80% yield. Its structural formula is as follows: Figure 7 As shown, the target product, tert-butyl(4-phenylphenylethynyl)phenylphosphine oxide, has extremely high purity, and no other organic impurities are generated during its preparation.

[0072] Figure 7 The structural diagram and nuclear magnetic resonance (NMR) spectrum data of tert-butyl(4-phenylphenylethynyl)phenylphosphine oxide in this embodiment are as follows:

[0073] 1 H NMR (500 MHz, Chloroform-d) δ = 7.99 – 7.91 (m, 2H), 7.71 – 7.66(m, 2H), 7.64 – 7.55 (m, 5H), 7.54 – 7.44 (m, 4H), 7.42 – 7.37 (m, 1H), 1.26(d, J=16.8, 9H).

[0074] 13C NMR (126 MHz, Chloroform-d) δ = 143.37, 139.80, 132.99 (d, J=1.9Hz), 132.14, 132.10, 132.02, 129.62 (d, J=109.5 Hz), 129.00, 128.27, 128.17,127.21 (d, J=16.8 Hz), 118.88 (d, J=3.8 Hz), 104.40 (d, J=24.0 Hz), 81.98 (d, J=149.1 Hz), 34.17 (d, J=83.4 Hz), 23.95.

[0075] 31 P NMR (202 MHz, Chloroform-d) δ = 31.26.

[0076] Example 8

[0077] The rest is the same as in Example 1, except that the chloroalkyne is (4-methoxyphenyl)chloroacetylene, yielding tert-butyl(4-methoxyphenylacetyl)phenylphosphine oxide in 52% yield. Its structural formula is as follows: Figure 8 As shown, the target product, tert-butyl(4-methoxyphenylethynyl)phenylphosphine oxide, has extremely high purity, and no other organic impurities are generated during its preparation.

[0078] Figure 8 The structural diagram and nuclear magnetic resonance (NMR) spectrum data for tert-butyl(4-methoxyphenylethynyl)phenylphosphine oxide in this embodiment are as follows:

[0079] 1 H NMR (500 MHz, Chloroform-d) δ = 7.98 – 7.86 (m, 2H), 7.58 – 7.52(m, 3H), 7.51 – 7.46 (m, 2H), 6.89 (d, J=8.8 Hz, 2H), 3.84 (s, 3H), 1.23 (d,J=16.7 Hz, 9H).

[0080] 13C NMR (126 MHz, Chloroform-d) δ = 161.30, 134.20, 131.99 (d, J=9.5Hz), 131.98, 129.79 (d, J=109.0 Hz), 128.10 (d, J=12.3 Hz), 114.26, 111.92 (d, J=3.7 Hz), 104.97 (d, J=25.1 Hz), 80.09 (d, J=152.2 Hz), 55.39, 34.03 (d, J=83.6 Hz), 23.89.

[0081] 31 P NMR (202 MHz, Chloroform-d) δ = 31.12.

[0082] Example 9

[0083] The rest is the same as in Example 1, except that the chloroalkyne is (4-fluorophenyl)chloroacetylene, yielding tert-butyl(4-fluorophenylacetylene)phenylphosphine oxide in 88% yield. Its structural formula is as follows: Figure 9 As shown, the target product, tert-butyl(4-fluorophenylethynyl)phenylphosphine oxide, has extremely high purity, and no other organic impurities are generated during the preparation process.

[0084] Figure 9 The structural diagram and nuclear magnetic resonance (NMR) spectrum data of tert-butyl(4-fluorophenylethynyl)phenylphosphine oxide in this embodiment are as follows:

[0085] 1 H NMR (500 MHz, Chloroform-d) δ = 7.95 – 7.86 (m, 2H), 7.62 – 7.54(m, 3H), 7.53 – 7.47 (m, 2H), 7.08 (t, J=8.6 Hz, 2H), 1.23 (d, J=16.8 Hz,9H).

[0086] 13C NMR (126 MHz, Chloroform-d) δ 163.80 (d, J = 253.6 Hz), 134.74(dd, J = 8.8, 1.8 Hz), 132.17 (d, J = 2.9 Hz), 132.00 (d, J = 9.6 Hz), 129.47(d, J = 109.2 Hz), 128.22 (d, J = 12.4 Hz), 116.14 (d, J = 22.5 Hz), 103.28(d, J = 24.2 Hz), 81.33 (d, J = 149.6 Hz), 34.12 (d, J = 83.2 Hz), 23.89.

[0087] 19 F NMR (471 MHz, Chloroform-d) δ = -106.46.

[0088] 31 P NMR (202 MHz, Chloroform-d) δ = 31.31.

[0089] Example 10

[0090] The rest is the same as in Example 1, except that the chloroalkyne is 4-chlorophenylchloroacetylene, yielding tert-butyl(4-chlorophenylacetyl)phenylphosphine oxide in 91% yield. Its structural formula is as follows: Figure 10 As shown, the target product, tert-butyl(4-chlorophenylethynyl)phenylphosphine oxide, has extremely high purity, and no other organic impurities are generated during its preparation.

[0091] Figure 10 The structural diagram and nuclear magnetic resonance (NMR) spectrum data of tert-butyl(4-chlorophenylethynyl)phenylphosphine oxide in this embodiment are as follows:

[0092] 1 H NMR (500 MHz, Chloroform-d) δ = 7.95 – 7.86 (m, 2H), 7.61 – 7.46 (m, 5H), 7.39 – 7.34 (m, 2H), 1.23 (d, J=16.9 Hz, 9H).

[0093] 13C NMR (126 MHz, Chloroform-d) δ = 136.92, 133.72, 132.23 (d, J=2.9Hz), 131.98 (d, J=9.4 Hz), 129.77 (d, J=110.1 Hz), 129.08, 128.25 (d, J=12.3Hz), 118.61 (d, J=3.7 Hz), 103.07 (d, J=23.9 Hz), 82.47 (d, J=147.0 Hz), 34.14 (d, J=83.2 Hz), 23.88.

[0094] 31 P NMR (202 MHz, Chloroform-d) δ = 31.42.;

[0095] Example 11

[0096] The rest is the same as in Example 1, except that the chloroalkyne is 4-bromophenylchloroacetylene, yielding tert-butyl(4-bromophenylacetyl)phenylphosphine oxide in 88% yield. Its structural formula is as follows: Figure 11 As shown, the target product, tert-butyl(4-bromophenylethynyl)phenylphosphine oxide, has extremely high purity, and no other organic impurities are generated during its preparation.

[0097] Figure 11 The structural diagram and nuclear magnetic resonance (NMR) spectrum data of tert-butyl(4-bromophenylethynyl)phenylphosphine oxide in this embodiment are as follows:

[0098] 1 H NMR (500 MHz, Chloroform-d) δ = 7.96 – 7.86 (m, 2H), 7.60 – 7.47(m, 5H), 7.47 – 7.44 (m, 2H), 1.23 (d, J=16.8 Hz, 9H).

[0099] 13C NMR (126 MHz, Chloroform-d) δ = 133.83 (d, J=1.7 Hz), 132.23 (d, J=2.7 Hz), 132.01, 131.95, 129.34 (d, J=108.1 Hz), 128.25 (d, J=12.3 Hz),125.28, 119.08 (d, J=3.4 Hz), 103.00 (d, J=23.7 Hz), 83.24 (d, J=146.5 Hz), 34.15 (d, J=83.4 Hz), 23.88.

[0100] 31 P NMR (202 MHz, Chloroform-d) δ = 31.49.

[0101] Example 12

[0102] The rest is the same as in Example 1, except that the chloroalkyne is 4-trifluoromethylphenylchloroacetylene, yielding tert-butyl(4-trifluoromethylphenylacetylene)phenylphosphine oxide in 48% yield. Its structural formula is as follows: Figure 12 As shown, the target product, tert-butyl(4-trifluoromethylphenylethynyl)phenylphosphine oxide, has extremely high purity, and no other organic impurities are generated during its preparation.

[0103] Figure 12 The structural diagram and nuclear magnetic resonance (NMR) spectrum data of tert-butyl(4-trifluoromethylphenylethynyl)phenylphosphine oxide in this embodiment are as follows:

[0104] 1 H NMR (500 MHz, Chloroform-d) δ = 7.97 – 7.86 (m, 2H), 7.71 (d, J=8.2, 2H), 7.65 (d, J=8.2 Hz, 2H), 7.62 – 7.54 (m, 1H), 7.55 – 7.47 (m, 2H),1.25 (d, J=16.9 Hz, 9H).

[0105] 13C NMR (126 MHz, Chloroform-d) δ 132.83 (d, J = 1.8 Hz), 132.34 (q, J= 2.8 Hz), 131.95 (d, J = 9.6 Hz), 129.13 (d, J = 109.4 Hz), 128.31 (d, J =12.3 Hz), 125.59 (q, J = 3.6 Hz), 123.92, 123.54 (q, J = 268.2 Hz), 102.13,83.88 (d, J = 143.1 Hz), 34.19 (d, J = 82.9 Hz), 23.86.

[0106] 19 F NMR (471 MHz, Chloroform-d) δ = -63.14.

[0107] 31 P NMR (202 MHz, Chloroform-d) δ = 31.55.

[0108] Example 13

[0109] The rest is the same as in Example 1, except that the chloroalkyne is 2-methylphenylchloroacetylene, yielding tert-butyl(2-methylphenylacetyl)phenylphosphine oxide in 83% yield. Its structural formula is as follows: Figure 13 As shown, the target product, tert-butyl(2-methylphenylethynyl)phenylphosphine oxide, has extremely high purity, and no other organic impurities are generated during the preparation process.

[0110] Figure 13 The structural diagram and nuclear magnetic resonance (NMR) spectrum data of tert-butyl(2-methylphenylethynyl)phenylphosphine oxide in this embodiment are as follows:

[0111] 1 H NMR (500 MHz, Chloroform-d) δ = 8.00 – 7.90 (m, 2H), 7.60 – 7.53(m, 2H), 7.54 – 7.47 (m, 2H), 7.35 (td, J=7.6 Hz, 1.4, 1H), 7.29 – 7.24 (m,1H), 7.21 (t, J=7.5 Hz, 1.2, 1H), 2.53 (s, 3H), 1.26 (d, J=16.8 Hz, 9H).

[0112] 13C NMR (126 MHz, Chloroform-d) δ = 141.57, 133.12 (d, J=2.0 Hz), 132.07, 132.00, 130.53, 129.80, 129.71 (d, J=109.0 Hz), 128.17 (d, J=12.1Hz), 125.87, 120.05 (d, J=3.6 Hz), 103.44 (d, J=24.3 Hz), 85.06 (d, J=149.7Hz), 34.04 (d, J=83.5 Hz), 23.93, 20.88.

[0113] 31 P NMR (202 MHz, Chloroform-d) δ = 31.11.

[0114] Example 14

[0115] The rest is the same as in Example 1, except that the chloroalkyne is 2-fluorophenylchloroacetylene, yielding tert-butyl(2-fluorophenylacetylene)phenylphosphine oxide in 72% yield. Its structural formula is as follows: Figure 14 As shown, the target product, tert-butyl(2-fluorophenylethynyl)phenylphosphine oxide, has extremely high purity, and no other organic impurities are generated during the preparation process.

[0116] Figure 14 The structural diagram and nuclear magnetic resonance (NMR) spectrum data of tert-butyl(2-fluorophenylethynyl)phenylphosphine oxide in this embodiment are as follows:

[0117] 1 H NMR (500 MHz, Chloroform-d) δ = 7.97 – 7.89 (m, 2H), 7.60 – 7.53(m, 2H), 7.54 – 7.46 (m, 2H), 7.48 – 7.40 (m, 1H), 7.21 – 7.09 (m, 2H), 1.25(d, J=16.8 Hz, 9H).

[0118] 13C NMR (126 MHz, Chloroform-d) δ 163.60 (d, J = 253.1 Hz), 134.07 (d,J = 1.9 Hz), 132.47 (d, J = 8.2 Hz), 132.19, 132.02 (d, J = 9.6 Hz), 97.46 (d, J = 23.7 Hz),86.73 (d, J = 149.4 Hz), 34.15 (d, J = 83.1 Hz), 23.79.

[0119] 19 F NMR (471 MHz, Chloroform-d) δ = -107.68.

[0120] 31 P NMR (202 MHz, Chloroform-d) δ = 31.63.

[0121] Example 15

[0122] The rest is the same as in Example 1, except that the chloroalkyne is 2-bromophenylchloroacetylene, yielding tert-butyl(2-bromophenylacetyl)phenylphosphine oxide in 66% yield. Its structural formula is as follows: Figure 15 As shown, the target product, tert-butyl(2-bromophenylethynyl)phenylphosphine oxide, has extremely high purity, and no other organic impurities are generated during its preparation.

[0123] Figure 15 The structural diagram and nuclear magnetic resonance (NMR) spectrum data of tert-butyl(2-bromophenylethynyl)phenylphosphine oxide in this embodiment are as follows:

[0124] 1 H NMR (500 MHz, Chloroform-d) δ = 8.03 – 7.95 (m, 2H), 7.68 – 7.61(m, 2H), 7.60 – 7.55 (m, 1H), 7.54 – 7.48 (m, 2H), 7.39 – 7.28 (m, 2H), 1.28(d, J=17.0 Hz, 9H).

[0125] 13C NMR (126 MHz, Chloroform-d) δ = 134.70, 132.70, 132.18, 132.10,131.59, 129.27 (d, J=109.1 Hz), 128.19 (d, J=12.4 Hz), 127.34, 126.07 (d, J=2.2 Hz), 122.75 (d, J=3.7 Hz), 101.69 (d, J=23.7 Hz), 85.83 (d, J=145.6 Hz), 34.26 (d, J=83.1 Hz), 23.86.

[0126] 31 P NMR (202 MHz, Chloroform-d) δ = 31.78.

[0127] Example 16

[0128] The rest is the same as in Example 1, except that the chloroalkyne is 3-methylphenylchloroacetylene, yielding tert-butyl(3-methylphenylacetyl)phenylphosphine oxide in 88% yield. Its structural formula is as follows: Figure 16 As shown, the target product, tert-butyl(3-methylphenylethynyl)phenylphosphine oxide, has extremely high purity, and no other organic impurities are generated during its preparation.

[0129] Figure 16 The structural diagram and nuclear magnetic resonance (NMR) spectrum data of tert-butyl(3-methylphenylethynyl)phenylphosphine oxide in this embodiment are as follows:

[0130] 1 H NMR (500 MHz, Chloroform-d) δ = 7.99 – 7.88 (m, 2H), 7.61 – 7.54(m, 1H), 7.53 – 7.48 (m, 2H), 7.43 – 7.40 (m, 2H), 7.31 – 7.23 (m, 2H), 2.37(s, 3H), 1.24 (d, J=16.7 Hz, 9H).

[0131] 13C NMR (126 MHz, Chloroform-d) δ = 138.43, 132.89, 132.08, 132.01 (d,J=9.3 Hz), 131.48, 129.63, 129.60 (d, J=109.1 Hz), 128.51, 128.16 (d, J=12.3Hz), 119.92 (d, J=3.7 Hz), 104.70 (d, J=24.2 Hz), 80.92 (d, J=150.0 Hz), 34.10 (d, J=83.2 Hz), 23.90, 21.18.

[0132] 31 P NMR (202 MHz, Chloroform-d) δ = 31.19.

[0133] Example 17

[0134] The rest is the same as in Example 1, except that the chloroalkyne is 3-methoxyphenylchloroacetylene, yielding tert-butyl(3-methoxyphenylacetylene)phenylphosphine oxide in 82% yield. Its structural formula is as follows: Figure 17 As shown, the target product, tert-butyl(3-methoxyphenylethynyl)phenylphosphine oxide, has extremely high purity, and no other organic impurities are generated during its preparation.

[0135] Figure 17 The structural diagram and nuclear magnetic resonance (NMR) spectrum data for tert-butyl(3-methoxyphenylethynyl)phenylphosphine oxide in this embodiment are as follows:

[0136] 1 H NMR (500 MHz, Chloroform-d) δ = 7.99 – 7.88 (m, 2H), 7.66 – 7.54(m, 1H), 7.54 – 7.47 (m, 2H), 7.37 – 7.25 (m, 1H), 7.20 (d, J=7.6 Hz, 1.2,1H), 3.82 (s, 3H), 1.25 (d, J=16.8 Hz, 9H).

[0137] 13C NMR (126 MHz, Chloroform-d) δ = 159.38, 132.15, 132.13, 132.00 (d,J=9.5 Hz), 129.75, 129.50 (d, J=109.2 Hz), 128.20 (d, J=12.3 Hz), 124.95,121.04 (d, J=3.6 Hz), 117.18, 104.30 (d, J=24.0 Hz), 81.05 (d, J=148.9 Hz), 55.42, 34.12 (d, J=83.2 Hz), 23.88.

[0138] 31 P NMR (202 MHz, Chloroform-d) δ = 31.33.

[0139] Example 18

[0140] The rest is the same as in Example 1, except that the chloroalkyne is naphth-2-ylphenylchloroacetylene, yielding tert-butyl(naphth-2-ylphenylacetyl)phenylphosphine oxide with a yield of 94%. Its structural formula is as follows: Figure 18 As shown, the target product, tert-butyl(naphthyl-2-phenylethynyl)phenylphosphine oxide, has extremely high purity, and no other organic impurities are generated during its preparation.

[0141] Figure 18 The structural diagram and nuclear magnetic resonance (NMR) spectrum data for tert-butyl(naphthyl-2-phenylethynyl)phenylphosphine oxide in this embodiment are as follows:

[0142] 1 H NMR (500 MHz, Chloroform-d) δ = 8.16 (s, 1H), 8.01 – 7.93 (m, 2H), 7.87 – 7.82 (m, 3H), 7.65 – 7.48 (m, 6H), 1.28 (d, J=16.8 Hz, 9H).

[0143] 13C NMR (126 MHz, Chloroform-d) δ = 133.75, 133.52, 133.50, 132.57,132.16, 132.14, 132.06 (d, J=9.5 Hz), 129.64 (d, J=109.0 Hz), 128.46, 128.23(d, J=12.3 Hz), 128.07, 127.91, 127.10, 117.29 (d, J=3.7 Hz), 104.83 (d, J=24.0 Hz), 81.60 (d, J=148.9 Hz), 34.18 (d, J=83.3 Hz), 23.97.

[0144] 31 P NMR (202 MHz, Chloroform-d) δ = 31.27.

[0145] Example 19

[0146] The rest is the same as in Example 1, except that the chloroalkyne is phenanthrene-9-ylphenylchloroacetylene, yielding tert-butyl(phenanthrene-9-ylphenylacetyl)phenylphosphine oxide in 82% yield. Its structural formula is as follows: Figure 19 As shown, the target product, tert-butyl(phenanthrene-9-ylphenylethynyl)phenylphosphine oxide, has extremely high purity, and no other organic impurities are generated during the preparation process.

[0147] Figure 19 The structural diagram and nuclear magnetic resonance (NMR) spectrum data for tert-butyl(phenanthrene-9-ylphenylethynyl)phenylphosphine oxide in this embodiment are as follows:

[0148] 1 H NMR (500 MHz, Chloroform-d) δ = 8.77 – 8.64 (m, 2H), 8.41 (dd, J=7.9, 1.5 Hz, 1H), 8.21 (s, 1H), 8.10 – 7.98 (m, 2H), 7.90 (dd, J=7.9, 1.4 Hz,1H), 7.76 – 7.67 (m, 3H), 7.66 – 7.57 (m, 2H), 7.57 – 7.50 (m, 2H), 1.34 (d,J=16.8 Hz, 9H).

[0149] 13C NMR (126 MHz, Chloroform-d) δ = 134.96 (d, J=2.3 Hz), 132.21 (d, J=2.9 Hz), 132.18, 132.10, 131.12, 130.56, 130.04, 129.28 (d, J=109.1 Hz),129.04, 128.76, 128.35, 128.25, 127.61, 127.32, 126.55, 123.02, 122.77,116.70 (d, J=3.7 Hz), 103.01 (d, J=23.9 Hz), 85.72 (d, J=147.5 Hz), 34.26 (d, J=83.3 Hz), 24.07.

[0150] 31 P NMR (202 MHz, Chloroform-d) δ = 31.37.

[0151] Example 20

[0152] The rest is the same as in Example 1, except that the chloroalkyne is quinoline-3-ylphenylchloroacetylene, yielding tert-butyl(quinoline-3-ylphenylacetyl)phenylphosphine oxide in 55% yield. Its structural formula is as follows: Figure 20 As shown, the target product, tert-butyl(quinoline-3-ylphenylethynyl)phenylphosphine oxide, has extremely high purity, and no other organic impurities are generated during its preparation.

[0153] Figure 20 The structural diagram and nuclear magnetic resonance (NMR) spectrum data of tert-butyl(quinoline-3-ylphenylethynyl)phenylphosphine oxide in this embodiment are as follows:

[0154] 1 H NMR (500 MHz, Chloroform-d) δ = 9.01 (d, J=2.1 Hz, 1H), 8.43 (d, J=2.1 Hz, 1H), 8.13 (d, J=8.5 Hz, 1H), 8.00 – 7.92 (m, 2H), 7.86 – 7.76 (m,2H), 7.67 – 7.57 (m, 2H), 7.56 – 7.50 (m, 2H), 1.28 (d, J=16.9 Hz, 9H).

[0155] 13C NMR (126 MHz, Chloroform-d) δ = 151.47, 147.74, 140.59 (d, J=1.9Hz), 132.35 (d, J=2.8 Hz), 132.04, 131.96, 131.44, 128.74 (d, J=109.3 Hz),128.39, 128.29, 127.94, 127.88, 114.35 (d, J=23.9 Hz), 101.44 (d, J=23.3 Hz), 84.94 (d, J=143.2 Hz), 34.22 (d, J=83.0 Hz), 23.92.

[0156] 31 P NMR (202 MHz, Chloroform-d) δ = 31.68.

[0157] Example 21

[0158] The rest is the same as in Example 1, except that the chloroalkyne is thiophene-3-ylphenylchloroacetylene, yielding tert-butyl(thiophene-3-ylphenylacetyl)phenylphosphine oxide in 85% yield. Its structural formula is as follows: Figure 21 As shown, the target product, tert-butyl(thiophene-3-ylphenylethynyl)phenylphosphine oxide, has extremely high purity, and no other organic impurities are generated during its preparation.

[0159] Figure 21 The structural diagram and nuclear magnetic resonance (NMR) spectrum data of tert-butyl(thiophene-3-ylphenylethynyl)phenylphosphine oxide in this embodiment are as follows:

[0160] 1 H NMR (500 MHz, Chloroform-d) δ = 7.96 – 7.88 (m, 2H), 7.74 (d, J=3.0 Hz, 1.2, 1H), 7.62 – 7.53 (m, 1H), 7.54 – 7.47 (m, 2H), 7.34 (dd, J=5.0 ,3.0 Hz, 1H), 7.27 – 7.22 (m, 1H), 1.24 (d, J=16.9 Hz, 9H).

[0161] 13C NMR (126 MHz, Chloroform-d) δ = 132.86, 132.11, 131.99 (d, J=9.6Hz), 129.88, 129.56 (d, J=109.0 Hz), 128.17 (d, J=12.1 Hz), 126.19, 119.38 (d, J=3.9 Hz), 99.61 (d, J=24.8 Hz), 81.25 (d, J=149.4 Hz), 34.07 (d, J=83.5Hz), 23.88.

[0162] 31 P NMR (202 MHz, Chloroform-d) δ = 31.36.

[0163] Example 22

[0164] The rest is the same as in Example 1, except that: aryl-tert-butylphosphine oxide is 4-methylphenyl(tert-butyl)phosphine oxide, yielding tert-butyl(phenylethynyl)(4-methylphenyl)phosphine oxide with a yield of 93%, and its structural formula is as follows. Figure 22 As shown, the target product, tert-butyl(phenylethynyl)(4-methylphenyl)phosphine oxide, has extremely high purity, and no other organic impurities are generated during its preparation.

[0165] Figure 22 The structural diagram and nuclear magnetic resonance (NMR) spectrum data for tert-butyl(phenylethynyl)(4-methylphenyl)phosphine oxide in this embodiment are as follows:

[0166] 1 H NMR (500 MHz, Chloroform-d) δ = 7.79 (dd, J=11.9 , 8.1 Hz, 2H),7.63 – 7.56 (m, 2H), 7.48 – 7.42 (m, 1H), 7.40 – 7.34 (m, 2H), 7.32 – 7.28(m, 2H), 2.41 (s, 3H), 1.22 (d, J=16.8 Hz, 10H).

[0167] 13C NMR (126 MHz, Chloroform-d) δ = 142.63 (d, J=2.8 Hz), 132.48,132.04 (d, J=9.8 Hz), 130.47, 128.96 (d, J=12.7 Hz), 128.59, 126.22 (d, J=111.7 Hz), 120.28, 104.12 (d, J=23.9 Hz), 81.59 (d, J=148.3 Hz), 34.12 (d, J=83.6 Hz), 23.91, 21.63.

[0168] 31 P NMR (202 MHz, Chloroform-d) δ = 31.41.

[0169] Example 23

[0170] The rest is the same as in Example 1, except that: aryl-tert-butylphosphine oxide is 4-methoxyphenyl(tert-butyl)phosphine oxide, yielding tert-butyl(phenylethynyl)(4-methoxyphenyl)phosphine oxide with a yield of 90%, and its structural formula is as follows. Figure 23 As shown, the target product, tert-butyl(phenylethynyl)(4-methoxyphenyl)phosphine oxide, has extremely high purity, and no other organic impurities are generated during its preparation.

[0171] Figure 23 The structural diagram and nuclear magnetic resonance (NMR) spectrum data for tert-butyl(phenylethynyl)(4-methoxyphenyl)phosphine oxide in this embodiment are as follows:

[0172] 1 H NMR (500 MHz, Chloroform-d) δ = 7.84 (dd, J=11.5 , 8.7 Hz, 2H),7.64 – 7.56 (m, 2H), 7.49 – 7.41 (m, 1H), 7.40 – 7.34 (m, 2H), 7.03 – 6.98(m, 2H), 3.86 (s, 3H), 1.22 (d, J=16.8 Hz, 9H).

[0173] 13C NMR (126 MHz, Chloroform-d) δ = 162.71 (d, J=3.0 Hz), 133.83 (d, J=10.9 Hz), 132.49 (d, J=1.9 Hz), 130.47, 128.59, 121.01 (d, J=116.2 Hz), 120.27 (d, J=3.8 Hz), 113.81 (d, J=13.3 Hz), 104.09 (d, J=23.9 Hz), 81.05 (d, J=147.9 Hz), 55.36, 34.22 (d, J=84.5 Hz), 23.90.

[0174] 31 P NMR (202 MHz, Chloroform-d) δ = 31.20.

[0175] Example 24

[0176] The rest is the same as in Example 1, except that: aryl-tert-butylphosphine oxide is 4-fluorophenyl (tert-butyl)phosphine oxide, yielding tert-butyl (phenylethynyl) (4-fluorophenyl)phosphine oxide with a yield of 90%, and its structural formula is as follows. Figure 24 As shown, the target product, tert-butyl(phenylethynyl)(4-fluorophenyl)phosphine oxide, has extremely high purity, and no other organic impurities are generated during its preparation.

[0177] Figure 24 The structural diagram and nuclear magnetic resonance (NMR) spectrum data for tert-butyl(phenylethynyl)(4-fluorophenyl)phosphine oxide in this embodiment are as follows:

[0178] 1 H NMR (500 MHz, Chloroform-d) δ = 7.97 – 7.90 (m, 2H), 7.65 – 7.57(m, 2H), 7.50 – 7.44 (m, 1H), 7.44 – 7.35 (m, 2H), 7.20 (td, J=8.8 Hz, 2.2,2H), 1.24 (d, J=16.9 Hz, 9H).

[0179] 13C NMR (126 MHz, Chloroform-d) δ 165.26 (dd, J = 253.4, 3.3 Hz), 134.77 – 133.99 (m), 132.49 (d, J = 2.0 Hz), 130.67, 128.64, 125.51 (dd, J =111.7, 3.4 Hz), 119.93, 115.60 (dd, J = 21.3, 13.3 Hz), 104.65 (d, J = 24.6Hz), 81.09 (d, J = 150.3 Hz), 34.16 (d, J = 84.1 Hz), 23.82.

[0180] 19 F NMR (471 MHz, Chloroform-d) δ = -106.61.

[0181] 31 P NMR (202 MHz, Chloroform-d) δ = 30.21.

[0182] Example 25

[0183] The rest is the same as in Example 1, except that: aryl-tert-butylphosphine oxide is 4-chlorophenyl(tert-butyl)phosphine oxide, yielding tert-butyl(phenylethynyl)(4-chlorophenyl)phosphine oxide with a yield of 93%, and its structural formula is as follows. Figure 25 As shown, the target product, tert-butyl(phenylethynyl)(4-chlorophenyl)phosphine oxide, has extremely high purity, and no other organic impurities are generated during its preparation.

[0184] Figure 25 The structural diagram and nuclear magnetic resonance (NMR) spectrum data of tert-butyl(phenylethynyl)(4-chlorophenyl)phosphine oxide in this embodiment are as follows:

[0185] 1 H NMR (500 MHz, Chloroform-d) δ = 7.85 (dd, J=11.5, 8.4 Hz, 2H), 7.63 – 7.56 (m, 2H), 7.53 – 7.44 (m, 3H), 7.43 – 7.36 (m, 2H), 1.23 (d, J=17.0 Hz, 9H).

[0186] 13C NMR (126 MHz, Chloroform-d) δ = 138.76, 133.41 (d, J=10.4 Hz), 132.52 (d, J=1.8 Hz), 130.72, 128.66, 128.54, 128.20 (d, J=109.3 Hz), 119.90 (d, J=3.7 Hz), 104.81 (d, J=24.5 Hz), 80.91 (d, J=151.1 Hz), 34.18 (d, J=84.0Hz), 23.82.

[0187] 31 P NMR (202 MHz, Chloroform-d) δ = 30.22.

[0188] Example 26

[0189] The rest is the same as in Example 1, except that: aryl-tert-butylphosphine oxide is replaced with 2-methylphenyl(tert-butyl)phosphine oxide, yielding tert-butyl(phenylethynyl)(2-methylphenyl)phosphine oxide in 90% yield. Its structural formula is as follows: Figure 26 As shown, the target product, tert-butyl(phenylethynyl)(2-methylphenyl)phosphine oxide, has extremely high purity, and no other organic impurities are generated during its preparation.

[0190] Figure 26 The structural diagram and nuclear magnetic resonance (NMR) spectrum data of tert-butyl(phenylethynyl)(2-methylphenyl)phosphine oxide in this embodiment are as follows:

[0191] 1 H NMR (500 MHz, Chloroform-d) δ = 7.95 – 7.85 (m, 1H), 7.71 – 7.56(m, 2H), 7.49 – 7.35 (m, 4H), 7.32 – 7.22 (m, 2H), 2.79 (d, J=1.5 Hz, 3H),1.27 (d, J=16.7 Hz, 9H).

[0192] 13C NMR (126 MHz, Chloroform-d) δ = 143.91 (d, J=9.7 Hz), 133.95 (d, J=11.7 Hz), 132.42 (d, J=2.1 Hz), 132.24 (d, J=12.0 Hz), 131.80 (d, J=2.8 Hz),130.40, 128.58, 126.62 (d, J=106.2 Hz), 124.89 (d, J=12.7 Hz), 120.46 (d, J=3.8 Hz), 104.02 (d, J=23.7 Hz), 82.78 (d, J=148.7 Hz), 35.70 (d, J=82.1 Hz), 24.29, 21.96 (d, J=2.7 Hz).

[0193] 31 P NMR (202 MHz, Chloroform-d) δ = 36.41.

[0194] Example 27

[0195] The rest is the same as in Example 1, except that: aryl-tert-butylphosphine oxide is 2-methylphenyl(tert-butyl)phosphine oxide, and the chloroalkyne is 4-ethylphenylchloroacetylene, yielding tert-butyl(4-ethylphenylacetyl)(2-methylphenyl)phosphine oxide with a yield of 90%. Its structural formula is as follows: Figure 27 As shown, the target product, tert-butyl(4-ethylphenylethynyl)(2-methylphenyl)phosphine oxide, has extremely high purity, and no other organic impurities are generated during its preparation.

[0196] Figure 27 The structural diagram and nuclear magnetic resonance (NMR) spectrum data of tert-butyl(4-ethylphenylethynyl)(2-methylphenyl)phosphine oxide in this embodiment are as follows:

[0197] 1 H NMR (500 MHz, Chloroform-d) δ = 7.90 (dd, J=14.8, 7.5 Hz, 1H), 7.52 (d, J=8.0 Hz, 2H), 7.46 – 7.36 (m, 1H), 7.33 – 7.24 (m, 2H), 7.22 (d, J=8.0 Hz, 2H), 2.79 (s, 3H), 2.68 (q, J=7.6 Hz, 2H), 1.30 – 1.22 (m, 12H).

[0198] 13C NMR (126 MHz, Chloroform-d) δ = 147.20, 143.78 (d, J=9. Hz 7), 133.97 (d, J=11.9 Hz), 132.42, 132.19 (d, J=11.9 Hz), 131.76, 128.16, 126.66(d, J=106.2 Hz), 124.88 (d, J=12.8 Hz), 117.49 (d, J=3.7 Hz), 104.53 (d, J=24.2 Hz), 82.06 (d, J=150.7 Hz), 35.65 (d, J=82.0 Hz), 28.96, 24.26, 21.94(d, J=2.6 Hz), 15.24.

[0199] 31 P NMR (202 MHz, Chloroform-d) δ = 36.29.

[0200] Example 28

[0201] The rest is the same as in Example 1, except that: aryl-tert-butylphosphine oxide is 2-methylphenyl(tert-butyl)phosphine oxide, and the chloroalkyne is 4-n-butylphenylchloroacetylene, yielding tert-butyl(4-n-butylphenylacetylene)(2-methylphenyl)phosphine oxide with a yield of 80%. Its structural formula is as follows: Figure 28 As shown, the target product, tert-butyl(4-n-butylphenylethynyl)(2-methylphenyl)phosphine oxide, has extremely high purity, and no other organic impurities are generated during its preparation.

[0202] Figure 28 The structural diagram and nuclear magnetic resonance (NMR) spectrum data of tert-butyl(4-n-butylphenylethynyl)(2-methylphenyl)phosphine oxide in this embodiment are as follows:

[0203] 1H NMR (500 MHz, Chloroform-d) δ = 7.94 – 7.86 (m, 1H), 7.51 (d, J=8.1 Hz, 2H), 7.46 – 7.37 (m, 1H), 7.33 – 7.23 (m, 2H), 7.20 (d, J=8.1 Hz,2H), 2.79 (s, 3H), 2.68 – 2.61 (m, 2H), 1.71 – 1.53 (m, 2H), 1.35 (h, J=7.4Hz, 2H), 1.26 (d, J=16.7 Hz, 9H), 0.93 (t, J=7.4 Hz, 3H).

[0204] 13 C NMR (126 MHz, Chloroform-d) δ = 145.89, 143.76 (d, J=9.9 Hz), 133.96 (d, J=11.8 Hz), 132.33, 132.17 (d, J=11.9 Hz), 131.74, 128.69, 126.67(d, J=106.2 Hz), 124.87 (d, J=12.6 Hz), 117.45 (d, J=3.7 Hz), 104.53 (d, J=24.1 Hz), 82.08 (d, J=150.6 Hz), 35.69, 35.64 (d, J=82.1 Hz), 33.23, 24.25,22.23, 21.93 (d, J=2.5 Hz), 13.89.

[0205] 31 P NMR (202 MHz, Chloroform-d) δ = 36.29.

[0206] Example 29

[0207] The rest is the same as in Example 1, except that: aryl-tert-butylphosphine oxide is 2-methylphenyl(tert-butyl)phosphine oxide, and the chloroalkyne is 4-tert-butylphenylchloroacetylene, yielding tert-butyl(4-tert-butylphenylacetylene)(2-methylphenyl)phosphine oxide with a yield of 91%, and its structural formula is as follows: Figure 29 As shown, the target product, tert-butyl(4-tert-butylphenylethynyl)(2-methylphenyl)phosphine oxide, has extremely high purity, and no other organic impurities are generated during its preparation.

[0208] Figure 29The structural diagram and nuclear magnetic resonance (NMR) spectrum data of tert-butyl(4-tert-butylphenylethynyl)(2-methylphenyl)phosphine oxide in this embodiment are as follows:

[0209] 1 H NMR (500 MHz, Chloroform-d) δ = 7.90 (dd, J=14.7, 6.9 Hz, 1H), 7.54 (d, J=8.5 Hz, 2H), 7.44 – 7.38 (m, 3H), 7.33 – 7.21 (m, 2H), 2.79 (s,3H), 1.33 (s, 9H), 1.26 (d, J=16.6 Hz, 9H).

[0210] 13 C NMR (126 MHz, Chloroform-d) δ = 154.00, 143.77 (d, J Hz =9.7), 133.97 (d, J=11.9 Hz), 132.21, 132.13, 131.76 (d, J=2.8 Hz), 126.70 (d, J=106.2 Hz), 125.60, 124.88 (d, J=12.6 Hz), 117.32 (d, J=3.7 Hz), 104.41 (d, J=24.0 Hz), 82.13 (d, J=150.5 Hz), 35.66 (d, J=82.2 Hz), 35.00, 31.06, 24.28,21.95 (d, J=2.4 Hz).

[0211] 31 P NMR (202 MHz, Chloroform-d) δ = 36.26.

[0212] Example 30

[0213] The rest is the same as in Example 1, except that: aryl-tert-butylphosphine oxide is 2-methylphenyl(tert-butyl)phosphine oxide, and the chloroalkyne is 4-phenylphenylchloroacetylene, yielding tert-butyl(4-phenylphenylacetyl)(2-methylphenyl)phosphine oxide with a yield of 72%. Its structural formula is as follows: Figure 30 As shown, the target product, tert-butyl(4-phenylphenylethynyl)(2-methylphenyl)phosphine oxide, has extremely high purity, and no other organic impurities are generated during its preparation.

[0214] Figure 30 The structural diagram and nuclear magnetic resonance (NMR) spectrum data of tert-butyl(4-phenylphenylethynyl)(2-methylphenyl)phosphine oxide in this embodiment are as follows:

[0215] 1 H NMR (500 MHz, Chloroform-d) δ = 7.92 (dd, J=14.7, 8.0 Hz, 1H), 7.67 (d, J=8.3 Hz, 2H), 7.64 – 7.56 (m, 4H), 7.47 (t, J=7.7 Hz, 2H), 7.45 –7.36 (m, 2H), 7.31 – 7.24 (m, 2H), 2.80 (s, 3H), 1.28 (d, J=16.7 Hz, 9H).

[0216] 13 C NMR (126 MHz, Chloroform-d) δ = 143.90 (d, J=9.8 Hz), 143.21,139.85, 133.97 (d, J=11.7 Hz), 132.89, 132.26 (d, J=11.9 Hz), 131.84, 83.40 (d, J=148.5 Hz), 35.74 (d, J=82.1Hz), 24.31, 21.99 (d, J=2.4 Hz).

[0217] 31 P NMR (202 MHz, Chloroform-d) δ = 36.43.

[0218] The yields and ee values ​​of the target products prepared in the above embodiments are listed in Table 1.

[0219] Example Yield of chiral alkynylphosphine oxide ee value of chiral alkynylphosphine oxide 1 91% 93% 2 86% 96% 3 85% 93% 4 74% 94% 5 82% 94% 6 83% 94% 7 80% 94% 8 52% 93% 9 88% 93% 10 91% 91% 11 88% 92% 12 48% 88% 13 83% 93% 14 72% 93% 15 66% 92% 16 88% 92% 17 82% 94% 18 94% 91% 19 82% 92% 20 55% 89% 21 85% 92% 22 93% 91% 23 90% 90% 24 90% 91% 25 93% 90% 26 90% 90% 27 90% 90% 28 80% 90% 29 91% 90% 30 72% 88%

[0220] Table (1)

[0221] The above embodiments provide a method for preparing chiral alkynylphosphine oxides via a palladium-catalyzed asymmetric cross-coupling reaction. Using readily available chloroalkynes and aryl-tert-butylphosphine oxide as starting materials, acetonitrile as solvent, ferrocene chiral bisphosphine as chiral ligand, and triethylamine as Lewis base, the chloroalkynes and aryl-tert-butylphosphine oxides undergo a cross-coupling reaction under palladium catalysis to synthesize chiral alkynylphosphine oxides. This method can prepare a wide range of substrates. As shown in Table (1), the phosphine oxide substrate for chiral alkynylphosphine oxides can be tert-butylarylphosphine oxides, such as phenyl(tert-butyl)phosphine oxide, and the chloroalkyne substrate for chiral alkynylphosphine oxides can be any of phenylchloroacetylene, 4-chlorophenylchloroacetylene, 4-methylphenylchloroacetylene, and arylchloroacetylene with different substituted groups.

[0222] This invention provides a method for preparing chiral alkynylphosphine oxides via a palladium-catalyzed asymmetric cross-coupling reaction. The method uses readily available chloroalkynes and aryl-tert-butylphosphine oxides as starting materials, acetonitrile as solvent, palladium as a transition metal catalyst, ferrocene chiral bisphosphine ligands as chiral ligands, and triethylamine as a Lewis base. The chiral alkynylphosphine oxides are synthesized directly via palladium catalysis through an asymmetric cross-coupling reaction, achieving a yield of over 90%. Furthermore, the reaction conditions are simple and mild, the starting materials are readily available, the reaction is highly efficient, and the production cost is low, making it suitable for industrial production.

[0223] In the above embodiments, the descriptions of each embodiment have different focuses. For parts not described in detail in a certain embodiment, please refer to the relevant descriptions in other embodiments.

[0224] The foregoing provides a detailed description of a palladium-catalyzed asymmetric cross-coupling reaction method for preparing chiral alkynylphosphine oxides. Specific examples have been used to illustrate the principles and implementation methods of this application. The descriptions of the above embodiments are only for the purpose of helping to understand the technical solutions and core ideas of this application. Those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of this application.

Claims

1. A palladium-catalyzed asymmetric cross-coupling reaction for the preparation of chiral alkynylphosphine oxides, characterized in that, The chiral alkynylphosphine oxide is ; Wherein, Ar1 is any one of phenyl, 4-methylphenyl, 4-ethylphenyl, 4-isopropylphenyl, 4-n-butylphenyl, 4-tert-butylphenyl, 4-phenylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-trifluoromethylphenyl, 2-methylphenyl, 2-fluorophenyl, 2-bromophenyl, 3-methylphenyl, 3-methoxyphenyl, naphth-2-yl, phenanthrene-9-yl, quinolin-3-yl, and thiophene-3-yl; Ar2 is any one of phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, and 2-methylphenyl.

2. A method for preparing chiral alkynylphosphine oxides via a palladium-catalyzed asymmetric cross-coupling reaction, characterized in that, Includes the following steps: The raw material components are obtained, including chloroalkyne, aryl-tert-butylphosphine oxide, palladium catalyst, ferrocene chiral bisphosphine compound, Lewis base, and acetonitrile solvent, wherein the molar ratio of chloroalkyne, tert-butylphenylphosphine oxide, palladium catalyst, ferrocene chiral bisphosphine compound, Lewis base, and acetonitrile solvent is 1:4:0.15:0.2:2:10; Under an argon gas flow, palladium catalyst, ferrocene chiral bisphosphine, and acetonitrile solvent were added to a Shrek tube to obtain mixed solution A, which was then stirred. Lewis base, chloroalkyne and aryl tert-butylphosphine oxide were added to mixed solution A under an argon gas flow to obtain mixed solution B; After the reaction of mixed solution B was complete, it was concentrated by rotary evaporation and separated by silica gel column chromatography to obtain chiral alkynylphosphine oxide.

3. The method for producing chiral alkynylphosphine oxides as described in claim 2, characterized in that, The molecular structural formula of the chlorinated alkyne is: ； Ar1 is any one of phenyl, 4-methylphenyl, 4-ethylphenyl, 4-isopropylphenyl, 4-n-butylphenyl, 4-tert-butylphenyl, 4-phenylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-trifluoromethylphenyl, 2-methylphenyl, 2-fluorophenyl, 2-bromophenyl, 3-methylphenyl, 3-methoxyphenyl, naphth-2-yl, phenanthrene-9-yl, quinoline-3-yl, and thiophene-3-yl.

4. The method for producing chiral alkynylphosphine oxides as described in claim 2, characterized in that, The molecular structural formula of the aryl-tert-butylphosphine oxide is: ； Ar2 is any one of phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, and 2-methylphenyl.

5. The method for producing chiral alkynylphosphine oxides as described in claim 2, characterized in that, The palladium catalyst is one of bis(dibenzylacetone)palladium, tri(dibenzylacetone)palladium, palladium acetate, palladium neopentanoate, palladium chloride, palladium iodide, palladium trifluoroacetate, tetra(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, bis(triphenylphosphine)diacetate, and bis(2,2,6,6-methyl-3,5-heptadecanoic acid)palladium.

6. The method for producing chiral alkynylphosphine oxides as described in claim 2, characterized in that, The ferrocene chiral bisphosphine compound is one of 1,1'-bis[(2S,4S)-2,5-dimethyl-1-phosphacyclobutyl]ferrocene, 1,1'-bis[(2S,5S)-2,5-dimethyl-1-phosphacyclopentyl]ferrocene, 1,1'-bis[(2S,5S)-2,5-diethyl-1-phosphacyclopentyl]ferrocene, and 1,1'-bis[(2S,5S)-2,5-diisopropyl-1-phosphacyclopentyl]ferrocene.

7. The method for producing chiral alkynylphosphine oxides as described in claim 2, characterized in that, The Lewis base is one of potassium phosphate, potassium hydrogen phosphate, sodium carbonate, sodium bicarbonate, triethylamine, triethylenediamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, and 4-dimethylaminopyridine.

8. The method for producing chiral alkynylphosphine oxides as described in claim 2, characterized in that, In the step of adding a Lewis base, a chloroalkyne, and an aryl-tert-butylphosphine oxide to mixed solution A under an argon gas flow to obtain mixed solution B,... Mixed solution B was stirred in an oil bath at 45°C for 18 hours to allow it to react fully.

9. The chiral alkynylphosphine oxide obtained by the method according to any one of claims 2-8.

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