CN115894560A - A Ni-Catalyzed Hirao Reaction Method for Constructing C-P Bonds - Google Patents

Abstract

其中，X为F、Cl、Br、I、OTf、B(OH)₂、OCF₃中的任意一种；Ar为芳香基。本发明方法具有底物具有普适性，操作简单，条件温和，无需贵金属催化剂和膦配体成本低，收率高的效果。The present invention provides a kind of method that the Hirao reaction of nickel catalysis constructs C-P bond, comprises the following steps: in the presence of nickel catalyst, additive, alkali, the aryl compound 1 that replaces and diphenylphosphine oxide 2 are in organic solvent Carry out coupling reaction in, generate aryl phosphine oxide compound 3, reaction formula is:

Wherein, X is any one of F, Cl, Br, I, OTf, B(OH) ₂ , OCF ₃ ; Ar is an aromatic group. The method of the invention has the effects of universal substrate, simple operation, mild condition, no need of noble metal catalyst and phosphine ligand, low cost and high yield.

Description

A Ni-Catalyzed Hirao Reaction Method for Constructing C-P Bonds

technical field

The invention relates to the technical field of organophosphine synthesis, in particular to a method for constructing a C-P bond through a nickel-catalyzed Hirao reaction.

Background technique

Phosphine-containing compounds are widely used in synthetic chemistry, medicinal chemistry, agriculture and material chemistry (L.D.Quin, AGuide to Organophosphorus Chemistry; John Wiley & Sons: New York, 2000.), according to the type of C-P bond in the organophosphine compound, the organophosphine compound It can be divided into aryl (en) phosphine compounds, alkynyl phosphine compounds and alkyl phosphine compounds. Among them, a series of compounds including aryl phosphine, aryl phosphate, phospholene and its derivatives are widely used in organic synthesis, polymer flame retardant materials, functional materials, pharmaceuticals and biochemistry. There are applications in traditional Chinese medicine, such as various arylphosphonanes that play an important role as ligands and catalysts in many organic reactions catalyzed by transition metals and small molecules. Therefore, the research on the synthesis method of arylphosphine compounds is of great significance.

At present, the most commonly used and most effective method for constructing CP in organophosphine compounds is the Hirao reaction, which often requires the use of noble metal palladium as a catalyst. This reaction uses zero-valent palladium (the specific Pd catalyst is Pd(PPh ₃ ) ₄ ) to catalyze the coupling of halogenated aromatic hydrocarbons or halogenated alkenes (halogenated atoms are generally bromine or iodine atoms) and phosphite diesters in the presence of organic bases. The advantage of this method is that the reaction conditions are relatively mild.

With the in-depth research on the construction of CP bonds by the Hirao reaction, people have successively proposed different degrees of improvement and expansion in the scope of substrates and reaction conditions such as catalysts, solvents and heating methods, and developed a series of efficient methods for the construction of CP bonds. In recent years, the CP bond formation reaction involving cheap metals has been widely developed, especially the reaction with nickel as the catalyst is more common. However, the current nickel-catalyzed CP bond reactions are mostly limited to active Ar-X (X=Cl, Br, I, OTf, ONf, B(OH) ₂ , etc.) substrates, and the reaction conditions are complex (such as Org.Chem .2021, 86, 17036-17049. Org. CCSChem. 2020, 2, 179–190.). Although the reaction of nickel-catalyzed Ar-F substrates has been reported (Chem.Rev.2015,115,931-972.J.Org.Chem.2021,86,8987-8996.joc.2022,87,9969-9976.), However, metal (including palladium, nickel, etc.) catalyzed Ar-F substrates involved in the formation of CP bond reaction has not been reported.

Recently (2021), Germany Yinghua reported the method of constructing C-P bond in the reaction mode of cooperative SNAr involving inactive Ar-F substrate and phosphine oxide compound through potassium ion (Angew.Chem.Int.Ed.2021,58,283 -287), but electron-rich Ar-F, Ph-F and ArBr/I do not react. In this document, two equivalents of strong water-absorbing strong alkali reagent (KHMDS) are required. This kind of strong water-absorbing strong alkali reagent is generally difficult to store in the air, and the laboratory is usually kept in a glove box. Although this report also mentions that KHMDS can also be replaced by weaker bases such as potassium tert-butoxide, potassium methylate, and potassium carbonate in the template reaction, but the effect is not good (low yield or no activity at all). In the same year, Professor Li Chaojun’s research group reported that under the conditions of ultraviolet light (254nm) and three equivalents of strong alkali NaH, Ar-F and phosphine oxide compounds can be freely coupled to construct C-P bonds (Fundamental Research 2021, 742–746) . Yet this kind of method that allows Ar-F to generate free radical by ultraviolet light (254nm) irradiation, shortcoming is also obvious, as only having the substrate of electron-donating group on Ar-F, yield just can be good, Ar-Br/ I, etc. do not react, and the use of ultraviolet light limits the wide application of the reaction. Among several commonly used coupling substrates, the reactivity of aryl p-toluenesulfonate and aryl methanesulfonate is far less than that of iodo or bromoarene and aryl trifluoromethanesulfonate.

Therefore, it is of great significance to develop a kind of CP construction method with a wide range of mild reaction conditions and high yield using Ar-F/Cl/Br/I/OTf/B(OH) ₂ /OCF ₃ as substrates.

Contents of the invention

Aiming at the deficiencies in the prior art, the invention provides a method for constructing a C-P bond through a nickel-catalyzed Hirao reaction, which solves the problems in the prior art that the substrates are not extensive, the reaction conditions are complicated, and the yield is not high. question.

The invention 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 diphenylphosphine oxide 2 in an organic solvent in the presence of a nickel catalyst, an additive, and a base Link reaction, generate aryl phosphine oxide compound 3, the reaction formula is as follows:

Wherein, X is any one of F, Cl, Br, I, OTf, B(OH) ₂ , OCF ₃ , and Ar is an aromatic group.

Preferably, in addition to X substitution, the aromatic ring of Ar includes one or more substituents selected from the group consisting of alkyl, alkoxy, cycloalkyl, ester, amide, amino, aromatic any of the bases.

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

It can be understood that when the aromatic ring of Ar has one substituent or multiple substituents, the substituents are in the para-position, ortho-position or meta-position relative to X.

It can be understood that when the aromatic ring of Ar has multiple substituents, the multiple substituents may be the same or different.

As used herein, the alkyl group is preferably an alkyl group having 1-10 carbon atoms, including but not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl , pentyl, isopentyl, neopentyl, etc.; more preferably, an alkyl group having 1 to 4 carbon atoms.

As used herein, alkoxy is preferably an alkoxy group having 1-10 carbon atoms, including but not limited to methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy , tert-butoxy, sec-butoxy, etc.; more preferably, an alkoxy group having 1 to 4 carbon atoms.

As used herein, cycloalkyl preferably has 3-15 ring-forming carbon atoms, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, Cyclopentenyl, cyclohexenyl, cyclohexadienyl, etc.; more preferably, cycloalkyl having 3 to 6 carbon atoms.

As used herein, aryl can be non-heterocyclic aryl or heterocyclic aryl, including but not limited to phenyl, substituted phenyl, naphthyl, substituted naphthyl, pyridyl, substituted pyridyl, furyl, substituted furyl and the like; more preferably, any of phenyl, naphthyl, and pyridyl.

As used herein, ester groups include, but are not limited to, carbomethoxy, carboethyl, carbopropyl, and carbomethoxy.

Further, the nickel catalyst is ethylene glycol dimethyl ether nickel bromide.

Further, the additive is zinc.

Further, the base is potassium tert-butoxide.

Further, the organic solvent is dimethylacetamide.

Further, the molar equivalent ratio of the substituted aryl compound and diphenylphosphine oxide is 1:2; the molar equivalent ratio of the base and the substituted aryl compound is 1:3; On a molar equivalent basis, the volume of the organic solvent is 10V.

Further, in terms of molar equivalent percentage, the nickel catalyst is used in an amount of 20% of the substituted aromatic compound; the additive is used in an amount of 30% of the substituted aromatic compound.

Further, the reaction temperature is 130° C., and the reaction time is 16-24 hours.

As used herein, the term "OTf" means triflate and " _OCF3 " means trifluoromethoxy.

In this paper, the term "equiv." is the molar equivalent, and "V" is the volume of the solvent. For example, 10V means that the volume of the solvent is 10 times the molar equivalent of the solute, and each mole corresponds to each liter. Specifically, the solute molar equivalent is 1 equiv., the solvent dosage is 10 V, and the concentration is 0.1 mol/L.

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

(1) The substrate of the present invention has good universality, expands the substrate scope of Hirao reaction to generate C-P bond, and is especially suitable for the Ar-F substrate that is difficult to activate for electron donation, and participates in the reaction of constructing C-P bond. breakthrough;

(2) The method of the present invention does not need the addition of ligand and precious metal palladium, only with cheap nickel catalyst, and the cost is low;

(3) The method of the present invention participates in the method for activating Ar-F/Ar-OCF ₃ substrates and constructing CP bonds through nickel for the first time;

(4) The reaction involved in the method of the present invention does not require a superbasic reagent, and the reaction conditions are relatively mild; no irradiation of ultraviolet light is required, the application is more extensive, and the operation is simple;

(5) The method of the present invention has a high yield, especially for Ar-F/Ar-OTf substrates, up to 99%.

Detailed ways

The technical solution in the present invention will be further described below in conjunction with the embodiments.

的合成Example 1

Synthesis

Under the condition of _N2 protection, in the round-bottomed flask that has placed stirring bar, add organic base potassium tert-butoxide 2.0equiv., catalyst ethylene glycol dimethyl ether nickel bromide 20mol%, additive Zn powder 30mol%, react The substance p-fluoroanisole 1.0equiv. and the reactant diphenylphosphine oxide 2.0equiv. Then add the solvent DMA (10V) and react at 130° C. for 16 h. Then cool to room temperature, add water to quench the reaction, and extract with ethyl acetate, collect the organic phase, dry with anhydrous sodium sulfate, spin dry and pass through a silica gel column (eluent: ethyl acetate/n-hexane=10/1-4/ 1), the pure product was obtained with a yield of 65%.

的合成Example 2

Synthesis

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

Under the condition of _N2 protection, in the round-bottomed flask that has placed stirring bar, add organic base potassium tert-butoxide 2.0equiv., catalyst ethylene glycol dimethyl ether nickel bromide 20mol%, additive Zn powder 30mol%, react The substance p-fluorobiphenyl 1.0equiv. and the reactant diphenylphosphine oxide 2.0equiv. Then add the solvent DMA (10V) and react at 130° C. for 16 h. Then cool to room temperature, add water to quench the reaction, and extract with ethyl acetate, collect the organic phase, dry with anhydrous sodium sulfate,

Spin-dried and passed through a silica gel column (eluent: ethyl acetate/n-hexane=10/1-4/1) to obtain a pure product with a yield of 99%.

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

Under the condition of _N2 protection, in the round-bottomed flask that has placed stirring bar, add organic base potassium tert-butoxide 2.0equiv., catalyst ethylene glycol dimethyl ether nickel bromide 20mol%, additive Zn powder 30mol%, react P-bromobiphenyl 1.0equiv. and reactant diphenylphosphine oxide 2.0equiv. Then add the solvent DMA (10V) and react at 130° C. for 16 h. Then cool to room temperature, add water to quench the reaction, and extract with ethyl acetate, collect the organic phase, dry with anhydrous sodium sulfate,

Spin-dried and passed through a silica gel column (eluent: ethyl acetate/n-hexane=10/1-4/1) to obtain a pure product with a yield of 64%.

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

Under the condition of _N2 protection, in the round-bottomed flask that has placed stirring bar, add organic base potassium tert-butoxide 2.0equiv., catalyzer ethylene glycol dimethyl ether nickel bromide 20mol%, additive Zn powder 30mol%, react The substance p-iodobiphenyl 1.0equiv. and the reactant diphenylphosphine oxide 2.0equiv. Then add the solvent DMA (10V) and react at 130° C. for 16 h. Then cool to room temperature, add water to quench the reaction, and extract with ethyl acetate, collect the organic phase, dry with anhydrous sodium sulfate, spin dry and pass through a silica gel column (eluent: ethyl acetate/n-hexane=10/1-4/ 1), the pure product was obtained with a yield of 61%.

By examining the influence of different substrates on the product yield, it can be seen that the product yield obtained by fluorine-substituted aromatic groups is the largest, reaching 99%. It can be seen that this reaction is especially suitable for the Hirao reaction of fluorine-substituted aromatic groups.

的合成Example 3

Synthesis

Under the condition of _N2 protection, in the round-bottomed flask that has placed stirring bar, add organic base potassium tert-butoxide 2.0equiv., catalyst ethylene glycol dimethyl ether nickel bromide 20mol%, additive Zn powder 30mol%, react Object 1-chloronaphthalene 1.0equiv. and reactant diphenylphosphine oxide 2.0equiv. Then add the solvent DMA (10V) and react at 130° C. for 16 h. Then cool to room temperature, add water to quench the reaction, and extract with ethyl acetate, collect the organic phase, dry with anhydrous sodium sulfate, spin dry and pass through a silica gel column (eluent: ethyl acetate/n-hexane=10/1-4/ 1), the pure product was obtained with a yield of 63%.

的合成Example 4

Synthesis

Under the condition of _N2 protection, in the round-bottomed flask that has placed stirring bar, add organic base potassium tert-butoxide 2.0equiv., catalyst ethylene glycol dimethyl ether nickel bromide 20mol%, additive Zn powder 30mol%, react P-methyltrifluoromethoxybenzene 1.0equiv. and reactant diphenylphosphine oxide 2.0equiv. Then add the solvent DMA (10V) and react at 130° C. for 16 h. Then cool to room temperature, add water to quench the reaction, and extract with ethyl acetate, collect the organic phase, dry with anhydrous sodium sulfate, spin dry and pass through a silica gel column (eluent: ethyl acetate/n-hexane=10/1-4/ 1), the pure product was obtained with a yield of 70%.

的合成Example 5

Synthesis

1. With 3,5-dimethylphenyl trifluoromethanesulfonate as substrate:

Under the condition of _N2 protection, in the round-bottomed flask that has placed stirring bar, add organic base potassium tert-butoxide 2.0equiv., catalyst ethylene glycol dimethyl ether nickel bromide 20mol%, additive Zn powder 30mol%, react 3,5-dimethylphenyl trifluoromethanesulfonate 1.0equiv. and reactant diphenylphosphine oxide 2.0equiv. Then add the solvent DMA (10V) and react at 130° C. for 16 h. Then cool to room temperature, add water to quench the reaction, and extract with ethyl acetate, collect the organic phase, dry with anhydrous sodium sulfate, spin dry and pass through a silica gel column (eluent: ethyl acetate/n-hexane=10/1-4/ 1), the pure product was obtained with a yield of 90%.

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

Under the condition of _N2 protection, in the round-bottomed flask that has placed stirring bar, add organic base potassium tert-butoxide 2.0equiv., catalyst ethylene glycol dimethyl ether nickel bromide 20mol%, additive Zn powder 30mol%, react 3,5-Dimethylphenylboronic acid 1.0equiv. and reactant diphenylphosphine oxide 2.0equiv. Then add the solvent DMA (10V) and react at 130° C. for 16 h. Then cool to room temperature, add water to quench the reaction, and extract with ethyl acetate, collect the organic phase, dry with anhydrous sodium sulfate, spin dry and pass through a silica gel column (eluent: ethyl acetate/n-hexane=10/1-4/ 1), the pure product was obtained with a yield of 68%.

的合成Example 7

Synthesis

1. With 2-fluoropyridine as substrate:

Under the condition of _N2 protection, in the round-bottomed flask that has placed stirring bar, add organic base potassium tert-butoxide 2.0equiv., catalyst ethylene glycol dimethyl ether nickel bromide 20mol%, additive Zn powder 30mol%, react 2-fluoropyridine 1.0equiv. and reactant diphenylphosphine oxide 2.0equiv. Then add the solvent DMA (10V) and react at 130° C. for 16 h. Then cool to room temperature, add water to quench the reaction, and extract with ethyl acetate, collect the organic phase, dry with anhydrous sodium sulfate, spin dry and pass through a silica gel column (eluent: ethyl acetate/n-hexane=4/1-1/ 1), the pure product was obtained with a yield of 66%.

2. With 3-fluoropyridine as substrate:

Under the condition of _N2 protection, in the round-bottomed flask that has placed stirring bar, add organic base potassium tert-butoxide 2.0equiv., catalyst ethylene glycol dimethyl ether nickel bromide 20mol%, additive Zn powder 30mol%, react Object 3-fluoropyridine 1.0equiv. and reactant diphenylphosphine oxide 2.0equiv. Then add the solvent DMA (10V) and react at 130° C. for 16 h. Then cool to room temperature, add water to quench the reaction, and extract with ethyl acetate, collect the organic phase, dry with anhydrous sodium sulfate, spin dry and pass through a silica gel column (eluent: ethyl acetate/n-hexane=4/1-1/ 1), the pure product was obtained with a yield of 72%.

Comparative example 1

Similar to Example 1, the difference is that Zn is not added as an additive in the reaction, and the product yield is only 12%.

Comparative example 2

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

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

It can be seen that Zn is added to the reaction as an additive, which is beneficial to improve the yield of the product.

Finally, it is noted that the above embodiments are only used to illustrate the technical solutions of the present invention without limitation. Although the present invention has been described in detail with reference to the preferred embodiments, those of ordinary skill in the art should understand that the technical solutions of the present invention can be carried out Modifications or equivalent replacements without departing from the spirit and scope of the technical solution of the present invention shall be covered by the claims of the present invention.

Claims (10)

1. A method for constructing a C-P bond by a nickel-catalyzed Hirao reaction comprises the following steps: in the presence of a nickel catalyst, an additive and alkali, carrying out coupling reaction on a substituted aryl compound 1 and diphenyl phosphine oxide 2 in an organic solvent to generate an aryl phosphine oxide compound 3, wherein the reaction formula is as follows:

wherein X is F, cl, br, I, OTf, B (OH) ₂ 、OCF ₃ Ar is an aromatic group.

2. A method of constructing C-P bonds according to the nickel-catalysed Hirao reaction of claim 1, wherein: besides X substitution, the aromatic ring of Ar also comprises one or more substituents selected from any one of alkyl, alkoxy, cycloalkyl, ester group, amide, amino and aromatic group.

3. A method of constructing C-P bonds according to claim 1, wherein: ar-X is selected from the following compounds:

4. a method of constructing C-P bonds according to the nickel-catalysed Hirao reaction of claim 1, wherein: the nickel catalyst is ethylene glycol dimethyl ether nickel bromide.

5. A method of constructing C-P bonds according to claim 1, wherein: the additive is zinc.

6. A method of constructing C-P bonds according to the nickel-catalysed Hirao reaction of claim 1, wherein: the base is potassium tert-butoxide.

7. A method of constructing C-P bonds according to the nickel-catalysed Hirao reaction of claim 1, wherein: the organic solvent is dimethylacetamide.

8. A method of constructing C-P bonds according to the nickel-catalysed Hirao reaction of claim 1, wherein: the molar equivalent ratio of the substituted aromatic compound to the 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 was 10V based on the molar equivalent of the substituted aromatic compound.

9. A method of constructing C-P bonds according to the nickel-catalysed Hirao reaction of claim 1, wherein: the amount of the nickel catalyst is 20 percent of that of the substituted aryl compound by molar equivalent percentage; the amount of the additive is 30% of the amount of the substituted aromatic compound.

10. A method of constructing C-P bonds according to the nickel-catalysed Hirao reaction of claim 1, wherein: the reaction temperature is 130 ℃, and the reaction time is 16-24h.