A method for synthesizing aryl phosphine compounds based on a novel phosphorus-carbon bond coupling reaction

Abstract

This invention discloses a method for synthesizing arylphosphine compounds based on a novel phosphorus-carbon bond coupling reaction. The chemical formula of the arylphosphine compounds of this invention is: R 1 3‑n PAr n The aryl phosphorus compound is derived from phosphorus halide reagent R. 1 3‑n PX n Aryltrialkyltin reagent ArSnR 2 3. Synthesis is carried out through a cross-coupling reaction catalyzed by a transition metal catalyst; wherein, R 1 It is a phenyl, alkyl, or alkylamine group, where X is a chlorine or bromine atom, and R is a phenyl, alkyl, or alkylamine group. 2 The methyl group is methyl or n-butyl, and Ar is phenyl, substituted phenyl, aromatic heteroyl, or substituted heteroaryl. The method of this invention can synthesize arylphosphide compounds in good yields, and the synthesis method of this invention has the advantages of good substrate compatibility, mild reaction conditions, few byproducts, and easy separation and purification.

Description

Technical Field

[0001] This invention relates to a method for synthesizing aryl phosphorus compounds based on a novel phosphorus-carbon bond coupling reaction, belonging to the field of organic synthesis technology. Background Technology

[0002] Arylphosphides are an important class of organophosphorus compounds that play a vital role in pharmaceutical synthesis, organic synthesis, and materials science. [1-4] Currently, the common method for synthesizing triarylphosphine compounds involves the direct reaction of phosphorus halides with reactive organometallic reagents such as organolithium, organozinc, organomagnesium, or organomercury. These organomercury reagents generally exhibit high reactivity, are extremely sensitive to water and oxygen, making them unsuitable for long-term storage, and require very cumbersome and rigorous procedures in experiments. Furthermore, these organomercury reagents generally possess strong nucleophilicity, thus placing high demands on the substituents of the reaction substrate. For example, these organomercury reagents are incompatible with fluorine (F), nitrile (CN), and aldehyde / carbonyl substituents. In addition, organomercury reagents are highly toxic; improper experimental handling can cause significant harm to the health of the experimenter.

[0003] To address the limitations in the synthesis of the aforementioned triarylphosphine compounds, researchers have recently begun to utilize transition metal catalysis to construct phosphorus-carbon bonds. [6,7] This method provides greater support for the development of fields such as pharmaceutical synthesis, organic synthesis, and materials. Compared to transition metal-catalyzed carbon-carbon coupling reactions, transition metal-catalyzed phosphorus-carbon coupling methods are relatively simple. Phosphorus reagents (such as dialkyl phosphites, phosphonates, primary phosphine, secondary phosphine, and triarylphosphine) typically participate in phosphorus-carbon coupling reactions as nucleophiles. Figure 1 While the formation of a single phosphorus-carbon bond from a phosphorus center has achieved high selectivity and yield, the formation of multiple phosphorus-carbon bonds from a single phosphorus center remains very challenging. To date, only a few studies have reported reactions involving the formation of three phosphorus-carbon bonds from a single phosphorus center. [8,9] However, this reaction is limited to alkyne-carbon substrates.

[0004] References:

[0005] [1]Xie C,Smaligo AJ,Song XR,et al.Phosphorus-Based Catalysis[J].ACSCentral Science,2021,7(4):536-558.

[0006] [2]Guo H C,Fan Y C,Sun Z H,et al.Phosphine Organocatalysis[J].Chemical Reviews,2018,118(20):10049-10293.

[0007] [3]Hirai M,Tanaka N,Sakai M,et al.Structurally Constrained Boron-,Nitrogen-,Silicon-,and Phosphorus-Centered Polycyclic pi-Conjugated Systems[J].Chemical Reviews,2019,119(14):8291-8331.

[0008] [4]Orton G R F,Pilgrim B S,Champness N R.The chemistry of phosphinesin constrained,well-defined microenvironments[J].Chemical Society Reviews,2021.

[0009] [5]Baumgartner T,Reau R.Organophosphorus pi-conjugated materials[J].Chemical Reviews,2006,106(11):4681-4727.

[0010] [6]Oestreich M,Tappe F,Trepohl V.Transition-Metal-Catalyzed C-PCross-Coupling Reactions[J].Synthesis,2010,2010(18):3037-3062.

[0011] [7]Schwan AL.Palladium catalyzed cross-coupling reactions forphosphorus-carbon bond formation[J].Chemical Society Reviews,2004,33(4):218-224.

[0012] [8]Afanasiev VV,Beletskaya IP,Kazankova MA,et al.A convenient and direct route to phosphinoalkynes via copper-catalyzed cross-coupling ofterminal alkynes with chlorophosphanes[J].Synthesis-Stuttgart,2003,(18):2835-2838.

[0013] [9]Beletskaya IP,Afanasiev VV,Kazankova MA,et al.New approach tophosphinoalkynes based on Pd-and Ni-catalyzed cross-coupling of terminalalkynes with chlorophosphanes[J].Organic Letters,2003,5(23):4309-4311. Summary of the Invention

[0014] The technical problem to be solved by this invention is: how to use commercially available phosphorus reagents containing phosphorus-halogen bonds to cross-couple with organotin reagents to form one or more phosphorus-carbon bonds in order to synthesize aryl phosphorus compounds.

[0015] To address the aforementioned technical problems, this invention provides a method for synthesizing aryl phosphorus compounds based on a novel phosphorus-carbon bond coupling reaction, wherein the chemical formula of the aryl phosphorus compound is: R 1 3-n PAr n The aryl phosphorus compound is derived from phosphorus halide reagent R. 1 3-n PX n Aryltrialkyltin reagent ArSnR 2 3. Dissolve in a solvent, and then synthesize by heating under the catalysis of a transition metal catalyst to undergo a cross-coupling reaction;

[0016] Where n is 1, 2, or 3, R 1 It is a phenyl, alkyl, or alkylamine group, and the halogen atom X is a chlorine or bromine atom, R 2 It is methyl or n-butyl, and Ar is any one of the following structural formulas:

[0017]

[0018] In the above structural formula, FG can be H, alkyl, alkoxy, F atom, F-substituted alkyl, phenyl, or trimethylsilyl.

[0019] Preferably, the alkylamine group is diethylamino, the alkyl group is methyl or tert-butyl, and the alkyl group substituted by the F atom is trifluoromethyl.

[0020] Preferably, the transition metal catalyst is selected from palladium catalysts and / or nickel catalysts, and the amount of the transition metal catalyst is 5 to 20% of the molar amount of the phosphorus halide reagent.

[0021] More preferably, the palladium catalyst is selected from at least one of palladium acetate, palladium dichlorobis(triphenylphosphine), palladium tridibenzylacetone, and palladium tetra(triphenylphosphine); the nickel catalyst is selected from one or two of nickel diacetylacetonate and nickel 1,3-bis(diphenylphosphine)dichloride.

[0022] Most preferably, the transition metal catalyst is selected from palladium catalysts, and the palladium catalyst is selected from palladium acetate and / or tetra(triphenylphosphine)palladium.

[0023] Preferably, the solvent is selected from at least one of benzene, toluene, xylene, chlorobenzene, dichlorobenzene, tetrahydrofuran, and dioxane.

[0024] Preferably, the amounts of the phosphorus halide reagent and the aryltrialkyltin reagent are calculated according to a molar ratio of halogen atom X to aryltrialkyltin of 1:2 to 3 in the phosphorus halide reagent.

[0025] Preferably, the temperature of the cross-coupling reaction is 20–150°C, and the time is 8–72 h.

[0026] More preferably, the reaction time is 20 to 30 hours.

[0027] Preferably, the aryltrialkyltin reagent ArSnR 2 3 is prepared by the following reaction:

[0028]

[0029] The above-mentioned aryltrialkyltin reagents can be synthesized by common methods, such as the substitution of aryl halide compounds with hexamethyldistin under palladium catalysis as reported in the literature.

[0030] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0031] (1) This invention provides a novel method for synthesizing aryl phosphorus compounds by cross-coupling of commercial phosphorus reagents containing phosphorus-halogen bonds with organotin reagents under the catalysis of a transition metal catalyst to form phosphorus-carbon bonds. This method can synthesize aryl phosphorus compounds in good yield.

[0032] (2) The synthesis method of the present invention has the advantages of good substrate compatibility, mild reaction conditions, few by-products, and easy separation and purification. Attached Figure Description

[0033] Figure 1 This is a schematic diagram of the traditional phosphorus-carbon bond coupling mechanism;

[0034] Figure 2 The present invention provides a synthetic route for aryl phosphorus compounds. Detailed Implementation

[0035] To make the present invention more apparent and understandable, preferred embodiments are described in detail below.

[0036] Unless otherwise specified, all reagents, materials and instruments used in the following embodiments are commercially available.

[0037] This invention provides a method for synthesizing arylphosphine compounds, and the synthetic route is as follows:

[0038]

[0039] This invention synthesizes arylphosphine compounds by cross-coupling of phosphorus halide reagents with aryltrialkyltin reagents to form phosphorus-carbon bonds. The table below lists some of the organophosphorus compounds synthesized using this method:

[0040]

[0041] The aryltrialkyltin reagent is synthesized by the following method:

[0042]

[0043] Compound 1 (1 eq.) was dissolved in dry THF (0.1 M) under anhydrous and oxygen-free conditions. A hexane solution of n-BuLi (1.05–1.1 eq., 1–2.5 M) was added dropwise at -78 °C. The mixture was then slowly brought back to room temperature and stirred for 3 h. After the reaction was complete, the reaction solution was poured into water, extracted with dichloromethane, and the organic phase was collected. The organic phase was dried over anhydrous Na₂SO₄, filtered, and the low-boiling solvent was removed by rotary evaporation. Finally, the target organotin compound was obtained by vacuum distillation.

[0044] Example 1

[0045] Synthesis of compounds a-h: Dry Shrek tubes were used to synthesize palladium acetate (5 mmol%), PCl3 (0.5 mmol), and ArSnR under anhydrous and oxygen-free conditions. 2 3 (3.75 mmol) was dissolved in 1 mL of toluene solvent, heated at 100 °C for 24 h, and then separated by silica gel column chromatography to obtain the product.

[0046] Compound a, isolated in 97% yield. 1 H NMR (400MHz, CDCl3): δ7.58 (dd, J=1.1, 5.0Hz, 1H), 7.36 (ddd, J=1.1, 3.5, 6.3Hz, 1H), 7.09 (ddd, J=1.4, 3.5, 4.9Hz, 1H); 13 C{ 1 H} NMR (101MHz, CDCl3): δ135.51 (d, J=27.6Hz), 132.02, 128.05 (d, J=8.3Hz); 31 P{ 1 H} NMR (162MHz, CDCl3): δ-46.25.

[0047] Compound b, isolated yield 73%. 1 H NMR (400MHz, CDCl3): δ7.87-7.74 (m, 6H), 7.70 (dd, J=7.3, 0.8Hz, 3H), 7.42-7.30 (m, 6H); 13 C{ 1 H} NMR (101MHz, CDCl3): δ144.02, 140.08 (d, J=9.4Hz), 138.80 (d, J=23.7Hz), 133.31 (d, J=28.2Hz), 125.38, 124.66, 124.27, 122.48; 31 P{ 1 H} NMR (162MHz, CDCl3): δ-38.66.

[0048] Compound c, isolated in 61% yield. 1 H NMR (400MHz, CDCl3): δ7.66 (d, J=1.7Hz, 3H), 6.80 (ddd, J=0.7, 1.9, 3.1Hz, 3H), 6.41 (dt, J=1.8, 3.4Hz, 3H); 13 C{ 1 H} NMR (101MHz, CDCl3): δ98.04, 97.65, 89.99 (d, J=7.5Hz), 86.97 (d, J=1.9Hz); 31 P{ 1 H}NMR (162MHz, CDCl3): δ-77.75.

[0049] Compound d, isolated yield 52%. 1H NMR (500MHz, CDCl3): δ7.58 (dd, J=1.2, 7.7Hz, 3H), 7.54 (d, J=8.3Hz, 3H), 7.33 (ddd, J=1.3, 7.1, 8.4Hz, 3H), 7.28-7.26 (m, 3H), 7.24 (t, J=7.4Hz, 3H); 13 C{ 1 H} NMR (126MHz, CDCl3): δ158.27 (d, J=3.2Hz), 150.99 (d, J=4.8Hz), 127.97 (d, J=6.5Hz), 125.73, 123.17, 121.60, 118.53 (d, J=22.6Hz), 111.90; 31 P{ 1 H} NMR (202MHz, CDCl3): δ-67.72.

[0050] Compound e, isolated yield 56%. 1 H NMR (400MHz, CDCl3): δ8.72 (dt, J=1.4, 4.8Hz, 3H), 7.62 (tt, J=2.0, 7.7Hz, 3H), 7.41 (ddt, J=1.1, 2.1, 7.8Hz, 3H), 7.22 (ddt, J=1.2, 4.8, 7.5Hz, 3H); 13 C{ 1 H} NMR (101MHz, CDCl3): δ161.97, 150.60 (d, J=11.9Hz), 136.07, 129.43 (d, J=20.0Hz), 122.98; 31 P{ 1 H}NMR (162MHz, CDCl3): δ-0.72.

[0051] Compound f, isolated in 31% yield. 1 H NMR (400MHz, CDCl3): δ6.82 (q, J=2.4Hz, 3H), 6.14 (ddd, J=1.0, 2.6, 3.6Hz, 3H), 5.98 (ddd, J=0.9, 1.8, 3.6Hz, 3H), 3.62 (s, 9H); 13 C{ 1 H} NMR (101MHz, CDCl3): δ126.60 (d, J=3.0Hz), 125.58 (d, J=10.2Hz), 118.27 (d, J=5.0Hz), 108.49 (d, J=3.7Hz), 35.24 (d, J=12.3Hz); 31 P{1 H}NMR (162MHz, CDCl3): δ-73.07.

[0052] Compound g, isolated yield 10%. 1 H NMR (400MHz, CDCl3): δ7.23 (dd, J=8.7, 1.4Hz, 6H), 6.88 (dd, J=8.7, 1.0Hz, 6H), 3.80 (s, 9H); 13 C{ 1 H} NMR (101MHz, CDCl3): δ160.24, 135.08 (d, J=20.8Hz), 128.94, 114.27 (d, J=7.7Hz), 55.32; 31 P{ 1 H} NMR (162MHz, CDCl3): δ-10.16.

[0053] Compound h, isolated in 62% yield. 1 H NMR (400MHz, CDCl3): δ7.59-7.53(m, 6H), 7.40-7.30(m, 9H); 13 C{ 1 H} NMR (101MHz, CDCl3): δ132.26 (d, J=2.0Hz), 129.55, 128.45, 122.18, 105.80 (d, J=11.4Hz), 79.53 (d, J=6.7Hz); 31 P{ 1 H} NMR (162MHz, CDCl3): δ-88.30.

[0054] Example 2

[0055] Synthesis of compound i: A dry Shrek tube was prepared by reacting tetrakis(triphenylphosphine)palladium (5 mmol%), PhPCl2 (0.5 mmol), and ArSnR under anhydrous and oxygen-free conditions. 2 3 (2.5 mmol) was dissolved in 1 mL of toluene solvent, heated at 100 °C for 24 h, and then separated by silica gel column chromatography to obtain the product.

[0056] Compound i, isolated in 88% yield. 1 H NMR (400MHz, CDCl3): δ7.60 (dd, J=4.9, 1.1Hz, 2H), 7.42-7.29 (m, 7H), 7.12 (ddd, J=4.8, 3.5, 1.3Hz, 2H); 13 C{ 1H} NMR (101MHz, CDCl3): δ138.90, 138.48 (d, J=24.3Hz), 136.30 (d, J=27.4Hz), 132.24, 132.06, 128.93, 128.48 (d, J=6.8Hz), 128.09 (d, J=8.3Hz); 31 P{ 1 H} NMR (162MHz, CDCl3): δ-34.11.

[0057] Example 3

[0058] Synthesis of compound j: A dry Shrek tube was prepared by reacting palladium acetate (5 mmol%), Ph₂PCl (0.5 mmol), and ArSnR under anhydrous and anaerobic conditions. 2 3 (1.25 mmol) was dissolved in 1 mL of toluene solvent, heated at 100 °C for 24 h, and then separated by silica gel column chromatography (petroleum ether as eluent) to obtain the product.

[0059] Compound j, isolated yield 76%. 1 H NMR (400MHz, CDCl3): δ7.59 (dd, J=4.9, 1.0Hz, 1H), 7.44-7.27 (m, 11H), 7.13 (td, J=4.1, 1.2Hz, 1H); 13 C NMR (101MHz, CDCl3): δ138.12, 138.03, 136.48 (d, J=26.4Hz), 133.23 (d, J=19.7Hz), 132.16, 128.99, 128.58 (d, J=7.0Hz), 128.18 (d, J=7.9Hz); 31 P NMR (162MHz, CDCl3): δ-19.94.

[0060] The above embodiments are merely preferred embodiments of the present invention and are not intended to limit the present invention in any form or substance. It should be noted that those skilled in the art can make several improvements and additions without departing from the present invention, and these improvements and additions should also be considered within the scope of protection of the present invention.

Claims

1. A method for synthesizing aryl phosphorus compounds based on a novel phosphorus-carbon bond coupling reaction, characterized in that, The chemical formula of the arylphosphine compound is: R 1 3-n PAr n The aryl phosphorus compound is derived from phosphorus halide reagent R. 1 3-n PX n Aryltrialkyltin reagent ArSnR 2 3. Dissolve in a solvent, and then synthesize by heating under the catalysis of a transition metal catalyst to undergo a cross-coupling reaction; Where n is 3, halogen atom X is a chlorine atom or a bromine atom, and R 2 It is methyl or n-butyl, and Ar is any one of the following structural formulas: In the above structural formula, FG represents H, alkyl, alkoxy, F atom, phenyl, trimethylsilyl, or F-substituted alkyl. The transition metal catalyst is selected from palladium catalysts and / or nickel catalysts.

2. The method for synthesizing aryl phosphorus compounds based on a novel phosphorus-carbon bond coupling reaction as described in claim 1, characterized in that, The amount of the transition metal catalyst is 5-20% of the molar amount of the phosphorus halide reagent.

3. The method for synthesizing aryl phosphorus compounds based on a novel phosphorus-carbon bond coupling reaction as described in claim 2, characterized in that, The palladium catalyst is selected from at least one of palladium acetate, palladium dichlorobis(triphenylphosphine), palladium tridibenzylacetone, and palladium tetra(triphenylphosphine); the nickel catalyst is selected from one or two of nickel diacetylacetonate and nickel 1,3-bis(diphenylphosphine)dichloride.

4. The method for synthesizing aryl phosphorus compounds based on a novel phosphorus-carbon bond coupling reaction as described in claim 1, characterized in that, The solvent is selected from at least one of benzene, toluene, xylene, chlorobenzene, dichlorobenzene, tetrahydrofuran, and dioxane.

5. The method for synthesizing aryl phosphorus compounds based on a novel phosphorus-carbon bond coupling reaction as described in claim 1, characterized in that, The amounts of phosphorus halide reagent and aryltrialkyltin reagent added are calculated based on a molar ratio of halogen atom X to aryltrialkyltin of 1:2 to 3 in the phosphorus halide reagent.

6. The method for synthesizing aryl phosphorus compounds based on a novel phosphorus-carbon bond coupling reaction as described in claim 1, characterized in that, The cross-coupling reaction is carried out at a temperature of 20~150℃ for a time of 8~72 h.

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