A method for constructing a c-p bond by a nickel-catalyzed hirao reaction

Abstract

The application provides a method for constructing a C-P bond through a nickel-catalyzed Hirao reaction, comprising the following steps: coupling a substituted aromatic compound 1 and a diphenyl phosphine oxide 2 in an organic solvent in the presence of a nickel catalyst, an additive and a base to generate an aromatic phosphine oxide compound 3, and the reaction formula is as follows: wherein X is any one of F, Cl, Br, I, OTf, B(OH)2 and OCF3; and Ar is an aromatic group. The method has the effects of universality of substrates, simple operation, mild conditions, low cost of noble metal catalysts and phosphine ligands and high yield.

Description

Technical Field

[0001] This invention relates to the field of organophosphorus synthesis technology, and more particularly to a method for constructing CP bonds via a nickel-catalyzed Hirao reaction. Background Technology

[0002] Phosphine-containing compounds have wide applications in synthetic chemistry, medicinal chemistry, agriculture, and materials chemistry (LD Quin, A Guide to Organophosphorus Chemistry; John Wiley & Sons: New York, 2000). Based on the type of CP bond in organophosphine compounds, they can be classified into arylphosphine compounds, alkynylphosphine compounds, and alkylphosphine compounds. Among these, arylphosphine compounds, including arylphosphine alkanes, aryl phosphates, phosphacyclopentadienes, and their derivatives, have applications in organic synthesis, polymer flame retardants, functional materials, pharmaceuticals, and biochemistry. For example, various arylphosphine alkanes play crucial roles as ligands and catalysts in numerous transition metal and small molecule-catalyzed organic reactions. Therefore, research on the synthetic methods of arylphosphine compounds is of particular importance.

[0003] Currently, the most common and efficient method for constructing CP bonds in organophosphorus compounds is the Hirao reaction, which often requires the noble metal palladium as a catalyst. This reaction utilizes zero-valent palladium (specifically, Pd(PPh3)4 as the Pd catalyst) to catalyze the coupling of halogenated aromatic hydrocarbons or halogenated alkenes (halogenated atoms are generally bromine or iodine atoms) with phosphite diesters in the presence of an organic base to construct CP bonds. The advantage of this method is that the reaction conditions are relatively mild.

[0004]

[0005] With in-depth research on the construction of CP bonds through the Hirao reaction, researchers have successively proposed improvements and expansions in substrate scope and reaction conditions such as catalysts, solvents, and heating methods, and developed a series of efficient methods for constructing CP bonds. In recent years, CP bond construction reactions involving inexpensive metals have been widely developed, especially those using nickel as a catalyst. However, most nickel-catalyzed CP bond construction reactions are currently limited to reactive Ar-X (X = Cl, Br, I, OTf, ONf, B(OH)2, etc.) substrates, and the reaction conditions are complex (e.g., Org. Chem. 2021, 86, 17036-17049; Org. CCSChem. 2020, 2, 179–190). Although nickel-catalyzed reactions of Ar-F substrates have been reported (Chem.Rev.2015,115,931-972.J.Org.Chem.2021,86,8987-8996.joc.2022,87,9969-9976.), metal-catalyzed reactions of Ar-F substrates participating in the construction of CP bonds have not yet been reported.

[0006] Recently (2021), Angewandte Chemie reported a method for constructing CP bonds between inactive Ar-F substrates and phosphine oxy compounds via a potassium-ion-involved synergistic SNAr reaction mode (Angew. Chem. Int. Ed. 2021, 58, 283-287). However, electron-rich Ar-F, Ph-F, and ArBr / I did not react. This paper requires two equivalents of a strongly hygroscopic base reagent (KHMDS), which is generally difficult to store in air and is typically kept in a glove box in the laboratory. Although the report also mentions that the template reaction can be replaced with weaker bases such as potassium tert-butoxide, potassium methoxide, and potassium carbonate, the results are unsatisfactory (low yield or no activity). In the same year, Professor Li Chaojun's research group reported the construction of CP bonds between Ar-F and phosphine oxycarbons via free coupling under ultraviolet light (254 nm) and three equivalents of the strong base NaH (Fundamental Research 2021, 742–746). However, this method of generating free radicals in Ar-F through ultraviolet light (254 nm) irradiation also has obvious drawbacks. For example, the yield is good only when the Ar-F substrate has an electron-donating group; Ar-Br / I and other substrates do not react. Moreover, the use of ultraviolet light limits the wide application of the reaction. Among several commonly used coupling substrates, the reactivity of p-toluenesulfonic acid esters and aryl methanesulfonic acid esters is far less than that of iodo- or bromo-aromatic hydrocarbons and aryl trifluoromethanesulfonic acid esters.

[0007] Therefore, it is of great significance to develop a class of CP construction methods with mild reaction conditions and high yields using Ar-F / Cl / Br / I / OTf / B(OH)2 / OCF3 as substrates. Summary of the Invention

[0008] To address the shortcomings of existing technologies, this invention provides a method for constructing CP bonds via a nickel-catalyzed Hirao reaction, which solves the problems of limited substrate availability, complex reaction conditions, and low yields in existing technologies.

[0009] This invention provides a method for constructing CP bonds via a nickel-catalyzed Hirao reaction, comprising the following steps: in the presence of a nickel catalyst, an additive, and a base, a substituted aromatic compound 1 and a diphenylphosphine oxide 2 are coupled in an organic solvent to generate an aromatic phosphine oxide compound 3, as shown in the following reaction formula:

[0010]

[0011] Where X is any one of F, Cl, Br, I, OTf, B(OH)2, and OCF3, and Ar is an aromatic group.

[0012] Preferably, the aromatic ring of Ar includes one or more substituents in addition to X substitution, wherein the substituents are selected from any one of alkyl, alkoxy, cycloalkyl, ester, amide, amino, and aromatic groups.

[0013] Preferably, the Ar-X is selected from the following compounds:

[0014]

[0015]

[0016] It is understandable that when the aromatic ring of Ar has one or more substituents, the substituents are para, ortho, or meta relative to X.

[0017] It is understandable that when Ar has multiple substituents on its aromatic ring, these substituents can be the same or different.

[0018] As used herein, alkyl groups are preferably alkyl groups having 1 to 10 carbon atoms, including but not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, isopentyl, neopentyl, etc.; more preferably, alkyl groups having 1 to 4 carbon atoms.

[0019] As used herein, alkoxy groups are preferably alkoxy groups having 1 to 10 carbon atoms, including but not limited to methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, sec-butoxy, etc.; more preferably, alkoxy groups having 1 to 4 carbon atoms.

[0020] As used herein, cycloalkyl groups preferably have 3-15 cyclic carbon atoms, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, etc.; more preferably, cycloalkyl groups have 3-6 carbon atoms.

[0021] As used herein, the aromatic group may be a non-heterocyclic aromatic group or a heterocyclic aromatic group, including but not limited to phenyl, substituted phenyl, naphthyl, substituted naphthyl, pyridyl, substituted pyridyl, furanyl, substituted furanyl, etc.; more preferably, it includes any one of phenyl, naphthyl, and pyridyl.

[0022] As used herein, ester groups include, but are not limited to, methyl ester, ethyl ester, propyl ester, and butyl ester.

[0023] Furthermore, the nickel catalyst is nickel bromide in ethylene glycol dimethyl ether.

[0024] Furthermore, the additive is zinc.

[0025] Furthermore, the base is potassium tert-butoxide.

[0026] Furthermore, the organic solvent is dimethylacetamide.

[0027] Further, the molar equivalent ratio of the substituted aromatic compound to diphenylphosphine oxide is 1:2; the molar equivalent ratio of the base to the substituted aromatic compound is 1:3; and the volume of the organic solvent is 10V based on the molar equivalent of the substituted aromatic compound.

[0028] Furthermore, the amount of the nickel catalyst is 20% of the substituted aromatic compound, based on molar equivalent percentage; the amount of the additive is 30% of the substituted aromatic compound.

[0029] Furthermore, the reaction temperature is 130℃ and the reaction time is 16-24h.

[0030] In this article, the term "OTf" stands for trifluoromethanesulfonate group and "OCF3" stands for trifluoromethoxy group.

[0031] In this article, the term "equiv." refers to molar equivalent, and "V" refers to solvent volume. For example, 10V means that the solvent volume is 10 times the molar equivalent of the solute, with each mole corresponding to one liter. Specifically, the molar equivalent of the solute is 1 equiv., the solvent volume is 10V, and the concentration is 0.1 mol / L.

[0032] Compared with the prior art, the present invention has the following beneficial effects:

[0033] (1) The substrates of the present invention have good universality, which expands the range of substrates for the formation of CP bonds in the Hirao reaction. They are especially suitable for electron-donating Ar-F substrates that are difficult to activate. Participating in the reaction to build CP bonds is a breakthrough.

[0034] (2) The method of the present invention does not require the addition of ligands and precious metal palladium, but only uses inexpensive nickel catalyst, which is low in cost;

[0035] (3) The method of the present invention is the first to construct CP bonds by activating Ar-F / Ar-OCF3 substrates with nickel;

[0036] (4) The reaction involved in the method of the present invention does not require a superbase reagent, the reaction conditions are relatively mild, it does not require ultraviolet light irradiation, it has a wider range of applications, and it is simple to operate;

[0037] (5) The method of the present invention has a high yield, especially for Ar-F / Ar-OTf substrates, which can reach up to 99%. Detailed Implementation

[0038] The technical solutions of the present invention will be further described below with reference to the embodiments.

[0039] Example 1 Synthesis

[0040]

[0041] Under N2 protection, 2.0 equiv. of potassium tert-butoxide, 20 mol. of ethylene glycol dimethyl ether nickel bromide catalyst, 30 mol. of Zn powder additive, 1.0 equiv. of p-fluoroanisole, and 2.0 equiv. of diphenylphosphine oxide reactants were added to a round-bottom flask with a stir bar. Then, DMA (10V) solvent was added, and the reaction was carried out at 130°C for 16 h. The mixture was then cooled to room temperature, the reaction was quenched with water, and the mixture was extracted with ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, and evaporated to dryness before being passed through a silica gel column (eluent: ethyl acetate / n-hexane = 10 / 1–4 / 1) to obtain the pure product in 65% yield.

[0042] Example 2 Synthesis

[0043] 1. Using p-fluorobiphenyl and diphenylphosphine oxide as substrates:

[0044]

[0045] Under N2 protection, 2.0 equiv. of potassium tert-butoxide, 20 mol. of nickel bromide catalyst (ethylene glycol dimethyl ether), 30 mol. of zinc powder additive, 1.0 equiv. of p-fluorobiphenyl, and 2.0 equiv. of diphenylphosphine oxide were added to a round-bottom flask with a stir bar. Then, DMA (10V) solvent was added, and the reaction was carried out at 130°C for 16 h. The mixture was then cooled to room temperature, the reaction was quenched with water, and the mixture was extracted with ethyl acetate. The organic phase was collected and dried over anhydrous sodium sulfate.

[0046] The product was evaporated to dryness and then passed through a silica gel column (eluting buffer: ethyl acetate / n-hexane = 10 / 1–4 / 1) to obtain the pure product in 99% yield.

[0047] 2. Using p-bromobiphenyl and diphenylphosphine oxide as substrates:

[0048]

[0049] Under N2 protection, 2.0 equiv. of potassium tert-butoxide (potassium), 20 mol. of nickel bromide (ethylene glycol dimethyl ether), 30 mol. of zinc powder, 1.0 equiv. of p-bromobiphenyl, and 2.0 equiv. of diphenylphosphine oxide were added to a round-bottom flask with a stir bar. Then, DMA (10V) was added as solvent, and the reaction was carried out at 130°C for 16 h. The mixture was then cooled to room temperature, the reaction was quenched with water, and the mixture was extracted with ethyl acetate. The organic phase was collected and dried over anhydrous sodium sulfate.

[0050] The product was evaporated to dryness and then passed through a silica gel column (eluting buffer: ethyl acetate / n-hexane = 10 / 1–4 / 1) to give the pure product in 64% yield.

[0051] 3. Using p-iodobiphenyl and diphenylphosphine oxide as substrates:

[0052]

[0053] Under N2 protection, 2.0 equiv. of potassium tert-butoxide, 20 mol. of ethylene glycol dimethyl ether nickel bromide catalyst, 30 mol. of Zn powder additive, 1.0 equiv. of p-iodobiphenyl reactant, and 2.0 equiv. of diphenylphosphine oxide reactant were added to a round-bottom flask with a stir bar. Then, DMA solvent (10V) was added, and the reaction was carried out at 130°C for 16 h. The mixture was then cooled to room temperature, the reaction was quenched with water, and the mixture was extracted with ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, and evaporated to dryness before being passed through a silica gel column (eluent: ethyl acetate / n-hexane = 10 / 1–4 / 1) to obtain the pure product in 61% yield.

[0054] By examining the effect of different substrates on the product yield, it was found that the product yield was highest with fluorinated aromatic groups, reaching 99%. Therefore, this reaction is particularly suitable for the Hirao reaction with fluorinated aromatic groups.

[0055] Example 3 Synthesis

[0056]

[0057] Under N2 protection, 2.0 equiv. of potassium tert-butoxide, 20 mol. of ethylene glycol dimethyl ether nickel bromide catalyst, 30 mol. of Zn powder additive, 1.0 equiv. of 1-chloronaphthalene, and 2.0 equiv. of diphenylphosphine oxide reactants were added to a round-bottom flask with a stir bar. Then, DMA solvent (10V) was added, and the reaction was carried out at 130°C for 16 h. The mixture was then cooled to room temperature, the reaction was quenched with water, and the mixture was extracted with ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, and evaporated to dryness before being passed through a silica gel column (eluent: ethyl acetate / n-hexane = 10 / 1–4 / 1) to obtain the pure product in 63% yield.

[0058] Example 4 Synthesis

[0059]

[0060] Under N2 protection, 2.0 equiv. of potassium tert-butoxide, 20 mol. of ethylene glycol dimethyl ether nickel bromide catalyst, 30 mol. of Zn powder additive, 1.0 equiv. of p-methyltrifluoromethoxybenzene reactant, and 2.0 equiv. of diphenylphosphine oxide reactant were added to a round-bottom flask with a stir bar. Then, DMA solvent (10V) was added, and the reaction was carried out at 130°C for 16 h. The mixture was then cooled to room temperature, the reaction was quenched with water, and the mixture was extracted with ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, and evaporated to dryness before being passed through a silica gel column (eluent: ethyl acetate / n-hexane = 10 / 1–4 / 1) to obtain the pure product in 70% yield.

[0061] Example 5 Synthesis

[0062] 1. Using 3,5-dimethylphenyltrifluoromethanesulfonate as a substrate:

[0063]

[0064] Under N2 protection, 2.0 equiv. of potassium tert-butoxide, 20 mol. of nickel bromide catalyst (ethylene glycol dimethyl ether), 30 mol. of Zn powder additive, 1.0 equiv. of 3,5-dimethylphenyltrifluoromethanesulfonate, and 2.0 equiv. of diphenylphosphine oxide were added to a round-bottom flask with a stir bar. Then, DMA solvent (10V) was added, and the reaction was carried out at 130°C for 16 h. The mixture was then cooled to room temperature, the reaction was quenched with water, and the product was extracted with ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, and evaporated to dryness before being passed through a silica gel column (eluent: ethyl acetate / n-hexane = 10 / 1–4 / 1) to obtain the pure product in 90% yield.

[0065] 2. Using 3,5-dimethylphenylboronic acid as a substrate:

[0066]

[0067] Under N2 protection, 2.0 equiv. of potassium tert-butoxide, 20 mol. of nickel bromide catalyst (ethylene glycol dimethyl ether), 30 mol. of Zn powder additive, 1.0 equiv. of 3,5-dimethylphenylboronic acid, and 2.0 equiv. of diphenylphosphine oxide were added to a round-bottom flask with a stir bar. Then, DMA solvent (10V) was added, and the reaction was carried out at 130°C for 16 h. The mixture was then cooled to room temperature, the reaction was quenched with water, and the product was extracted with ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, and evaporated to dryness before being passed through a silica gel column (eluent: ethyl acetate / n-hexane = 10 / 1–4 / 1) to obtain the pure product in 68% yield.

[0068] Example 7 Synthesis

[0069] 1. Using 2-fluoropyridine as a substrate:

[0070]

[0071] Under N2 protection, 2.0 equiv. of potassium tert-butoxide, 20 mol. of ethylene glycol dimethyl ether nickel bromide catalyst, 30 mol. of Zn powder additive, 1.0 equiv. of 2-fluoropyridine reactant, and 2.0 equiv. of diphenylphosphine oxide reactant were added to a round-bottom flask with a stir bar. Then, DMA solvent (10V) was added, and the reaction was carried out at 130°C for 16 h. The mixture was then cooled to room temperature, the reaction was quenched with water, and the mixture was extracted with ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, and evaporated to dryness before being passed through a silica gel column (eluent: ethyl acetate / n-hexane = 4 / 1–1 / 1) to obtain the pure product in 66% yield.

[0072] 2. Using 3-fluoropyridine as a substrate:

[0073]

[0074] Under N2 protection, 2.0 equiv. of potassium tert-butoxide, 20 mol. of ethylene glycol dimethyl ether nickel bromide catalyst, 30 mol. of Zn powder additive, 1.0 equiv. of 3-fluoropyridine reactant, and 2.0 equiv. of diphenylphosphine oxide reactant were added to a round-bottom flask with a stir bar. Then, DMA solvent (10V) was added, and the reaction was carried out at 130°C for 16 h. The mixture was then cooled to room temperature, the reaction was quenched with water, and the mixture was extracted with ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, and evaporated to dryness before being passed through a silica gel column (eluent: ethyl acetate / n-hexane = 4 / 1–1 / 1) to obtain the pure product in 72% yield.

[0075] Comparative Example 1

[0076] Similar to Example 1, the difference is that no Zn was added as an additive in the reaction, and the product yield was only 12%.

[0077] Comparative Example 2

[0078] Similar to Scheme 2 in Example 2, the difference is that Zn was not added as an additive in the reaction, and the product yield was only 33%.

[0079] Similar to Scheme 3 in Example 2, the difference is that Zn was not added as an additive in the reaction, and the product yield was only 48%.

[0080] This shows that adding Zn as an additive to the reaction is beneficial to improving the product yield.

[0081] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit it. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, and all such modifications or substitutions should be covered within the scope of the claims of the present invention.

Claims

1. A method for constructing CP bonds via a nickel-catalyzed Hirao reaction, comprising the following steps: in the presence of a nickel catalyst, an additive, and a base, a substituted aromatic compound 1 and a diphenylphosphine oxide 2 are coupled in an organic solvent to generate an aromatic phosphine oxide compound 3, as shown in the following reaction formula: in, The Ar-X is selected from the following compounds: The nickel catalyst is nickel bromide in ethylene glycol dimethyl ether, and the additive is zinc; the base is potassium tert-butoxide; the organic solvent is dimethylacetamide; the molar equivalent ratio of the substituted aromatic compound to diphenylphosphine oxide is 1:2; the molar equivalent ratio of the base to the substituted aromatic compound is 1:3; the volume of the organic solvent is 10V based on the molar equivalent of the substituted aromatic compound; the amount of the nickel catalyst is 20% of the substituted aromatic compound by molar equivalent percentage; the amount of the additive is 30% of the substituted aromatic compound; the reaction temperature is 130℃, and the reaction time is 16-24h.

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