CN119978004A

CN119978004A - A water-stable 2-pyridine inner salt boron reagent and its preparation method and application in coupling reaction

Info

Publication number: CN119978004A
Application number: CN202510067461.9A
Authority: CN
Inventors: 张力; 陈雨; 李伟
Original assignee: Suzhou University
Current assignee: Suzhou University
Priority date: 2025-01-16
Filing date: 2025-01-16
Publication date: 2025-05-13

Abstract

The invention discloses a water-stable 2-pyridine inner salt boron reagent, a preparation method thereof and application thereof in coupling reaction, wherein the 2-pyridine inner salt boron reagent has a structure shown in a formula (I) and can be prepared by reacting 2-pyridine boric acid, 2-pyridine boric acid ester or 2-pyridine boron anion complex salt with a fluoride anion source and a proton source in the presence of a solvent. The preparation method of the 2-pyridine inner salt boron reagent provided by the invention is simple, mild in reaction condition and high in yield, is suitable for industrial production, and is more critical in that the 2-pyridine inner salt boron reagent has good stability in a water phase, can be used as an aryl nucleophilic reagent to carry out a coupling reaction with aryl halide fast and efficiently, synthesizes 2-aryl pyridine derivatives with various structures, has wide substrates and high yield, and has good application prospects in the fields of chemical synthesis, drug development, material science and the like.

Description

Water-stable 2-pyridine inner salt boron reagent, preparation method thereof and application thereof in coupling reaction

Technical Field

The invention relates to the field of organic synthesis, in particular to a water-stable 2-pyridine inner salt boron reagent, a preparation method thereof and application thereof in coupling reaction.

Background

Pyridine is a widely occurring building block in natural products, functional materials and drugs, and among small molecule drugs approved by the FDA, pyridine is the most frequently occurring nitrogen heterocycle in the past decade. In the preparation of medicaments comprising pyridine building blocks, it is generally necessary to introduce the pyridine structure into the intermediate or end product by means of a cross-coupling reaction using nucleophiles containing the pyridine structure, however, the use of 2-pyridine derivatives as nucleophiles in cross-coupling reactions still faces stability challenges. In order to overcome the problem of 2-pyridine, researchers are continuously advancing the development of 2-pyridine nucleophiles by combining the innovations of modern transition metal catalytic cross-coupling reactions.

Compared with organotin, grignard and organozinc reagents, organoboron reagents have become the most widely used aryl nucleophiles in cross-coupling chemistry due to their low toxicity, high stability and ease of handling. However, 2-pyridineboronic acids readily form a zwitterionic intermediate that has a half-life of only a few seconds in the pH range of 4-10, resulting in rapid degradation of the 2-pyridineboron reagent. This rapid decomposition mechanism significantly limits the use of 2-pyridineboronic acid for 2-pyridineization reactions under aqueous conditions. Therefore, the 2-pyridine boron reagent which can exist in water stably and has high reactivity is developed, and has important research and application values.

Disclosure of Invention

In order to solve the problems, the invention provides a water-stable 2-pyridine inner salt boron reagent, a preparation method thereof and application thereof in coupling reaction, wherein the 2-pyridine inner salt boron reagent can be prepared by reacting 2-pyridine boric acid, 2-pyridine boric acid ester or 2-pyridine boron anion complex salt with a fluoride anion source and a proton source in the presence of a solvent, the preparation method is simple, the reaction condition is mild, the yield is high, and the method is suitable for industrial production, and more importantly, the 2-pyridine inner salt boron reagent provided by the invention has good stability in a water phase, can be used as an aryl nucleophilic reagent and aryl halide to carry out coupling reaction rapidly and efficiently, and has good application prospect in the fields of chemical synthesis, drug development and the like.

Specifically, the invention provides the following technical scheme:

The first aspect of the invention provides a 2-pyridine inner salt boron reagent, and the structure of the 2-pyridine inner salt boron reagent is shown as a formula (I):

Wherein R ¹ is a substituent at any position on the pyridine ring, selected from hydrogen, halogen, dimethylamino, halogen substituted or unsubstituted C1-C6 alkyl, halogen substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted phenyl, wherein the substituent of the substituted phenyl is selected from one or more of halogen, C1-C6 alkyl, C1-C6 alkoxy, halogen substituted C1-C6 alkyl, halogen substituted C1-C6 alkoxy.

Halogen herein refers to iodine, bromine, chlorine or fluorine.

Further, R ¹ is hydrogen, F, cl, methyl, t-butyl, trifluoromethyl, methoxy, benzyloxy, or dimethylamino.

The second aspect of the invention provides a preparation method of the 2-pyridine inner salt boron reagent according to the first aspect, which comprises the following steps of reacting a compound shown in a formula (1) or a formula (2) with a fluoride anion source in the presence of a solvent to obtain the 2-pyridine inner salt boron reagent;

the structures of the formula (1) and the formula (2) are as follows:

Wherein R ¹ is as defined above for formula (I);

R ² is hydrogen OR C1-C6 alkyl, OR-B in formula (1) (OR ²)₂ is

R ³ is hydrogen OR C1-C6 alkyl, OR-B in formula (2) (OR ³)₃ is

M is Li, na or K.

Further, the fluoride ion source and proton source are preferably a mixture of inorganic acid and tetrafluoroborate or an ether tetrafluoroborate solution, and more preferably, when the fluoride ion source and proton source are ether tetrafluoroborate solutions, the molar ratio of the compound represented by formula (1) or formula (2) to the fluoride ion source is 1 (1-3), such as 1:1, 1:2, 1:3, etc., including but not limited to the molar ratios listed above.

Further, the solvent is one or more of alcohol solvent ether solvents, amide solvents, acetonitrile and water.

Further, the ratio of the molar amount of the compound represented by the formula (1) or the formula (2) to the volume of the solvent is preferably (0.2 to 0.4) mol to 1L.

Further, the temperature of the reaction is preferably 25-50 ℃, and the time of the reaction is preferably 5min-12h.

In a third aspect the present invention provides the use of a 2-pyridinium inner salt boron reagent according to the first aspect as an aryl nucleophile in a coupling reaction.

Further, the 2-pyridine inner salt boron reagent is adopted as an aryl nucleophilic reagent to prepare the 2-aryl pyridine derivative through a coupling reaction with aryl halide, and the method specifically comprises the following steps of carrying out the coupling reaction of the 2-pyridine inner salt boron reagent and the aryl halide shown in the formula (3) in the presence of a palladium catalyst, an organic phosphine ligand, a zinc salt and a solvent under an inert atmosphere to obtain the 2-aryl pyridine derivative shown in the formula (II);

The structure of the formula (3) is as follows:

R⁴-X

(3),

The structure of formula (II) is as follows:

Wherein R ¹ is as defined above for formula (I);

R ⁴ is a substituted or unsubstituted aryl group, the substituents of the substituted aryl group being selected from one or more of halogen, cyano, heterocycle, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkenyl, C1-C6 alkenyloxy, C1-C6 alkynyl, C1-C6 alkynyloxy, C1-C6 ester, C1-C6 alkoxycarbonyl, benzyloxy, halogen substituted C1-C6 alkyl, halogen substituted C1-C6 alkoxy, halogen substituted C1-C6 carbonyl, Phenylcarbonyl group,

X is iodine, bromine or chlorine.

Further, the molar ratio of the 2-pyridinium inner salt boron reagent to the aryl halide of formula (3) is (2-3): 1, e.g., 2:1, 2.5:1, 3:1, etc., including but not limited to the molar ratios listed above.

Further, the palladium catalyst may be selected from palladium (II) acetate, palladium (II) chloride, tetrakis (triphenylphosphine) palladium (0), tris (dibenzylideneacetone) dipalladium (0), bis (dibenzylideneacetone) palladium (0), bis (acetonitrile) palladium (II) dichloride, bis (tri-tert-butylphosphine) palladium (0), allylpalladium (II) chloride dimer (II), bis (acetylacetonato) palladium (II), chloro (2-dicyclohexylphosphino-2, 6-di-I-propoxy-1, 1-biphenyl) [2- (2-aminoethylphenyl) ] palladium (II), chloro [ (n-butylbis (1-adamantyl) phosphine) -2- (2-aminobiphenyl) ] palladium (II), (1, 5-cyclooctadiene) palladium (II) dichloride, dichloro [1, 4-bis (diphenylphosphine) butane ] palladium (II), bis (di-tert-butylphenylphosphine) dichloride (II), bis (tricyclohexylphosphine) palladium (II) dichloride, dicyclohexyl (2 ',4' -tris-isopropyl-3, 6-dimethoxy-2- (2-aminophenyl) phosphine) bis (2-methylphenyl) 2- (2-aminophenyl) phosphine), hexafluoroacetylacetonate palladium (II), bis [ di-tert-butyl- (4-dimethylaminophenyl) phosphine ] dichloropalladium (II), allyl [1, 3-bis (2, 6-diisopropylphenyl) imidazol-2-ylidene ] palladium (II), [1, 3-bis (2, 6-di-isopropylphenyl) -4, 5-dihydroimidazol-2-ylidene ] chloro [ 3-phenylallyl ] palladium (II), 1, 3-bis (diisopropylphenyl) -2-imidazolinylidene palladium (II) dimer, [1, 3-bis (diphenylphosphino) propane ] palladium (II), azacyclo-carbene-palladium (II) -1-phenylimidazole complex, methanesulfonic acid [ N-butyldi (1-adamantyl) phosphine ] (2-amino-1, 1' -biphenyl-2-yl) palladium (II), methanesulfonic acid (2-dicyclohexylphosphino-N, N-dimethylamino-1, 1' -biphenyl) (2 ' -amino-1, 1' -biphenyl-2 ' -palladium), bis (2 ' -methoxy) palladium (1, 3-bis (diphenylphosphino) 2-3 ', 4-dimethylamino) phosphine (2, 6' -3 ' -isobutylphosphino) phosphine, one or more of [1, 3-bis (2, 6-diisopropylphenyl) imidazol-2-yl-isoquinolin-2-yl ] palladium (II) dichloride, (2 '-amino-1, 1' -biphenyl-2-yl) methanesulfonyl palladium (II), dimer, bis (di-tert-butyl-4-dimethylaminophenyl phosphine) palladium (0), other palladium catalysts commonly used in the art, may also be employed.

Further, the organophosphine ligand may be selected from [ (4- (N, N-dimethylamino) phenyl ] di-tert-butylphosphine, tri-tert-butylphosphine, triadamantane-based phosphine, 2- (di-tert-butylphosphine) biphenyl, tricyclohexylphosphine, N-butylbis (1-adamantyl) phosphine, 2-dicyclohexylphosphine-2 ',6' -diisopropyloxy-1, 1 '-biphenyl, 2-dicyclohexylphosphine-2', 4',6' -triisopropylbiphenyl, 2- (dicyclohexylphosphine) 3, 6-dimethoxy-2 ',4',6 '-triisopropyl-1, 1' -biphenyl, tris (o-methylphenyl) phosphine, tris (4-methoxyphenyl) phosphine, tris (2-furyl) phosphine, 1,2,3,4, 5-pentylphenyl-1 '- (di-tert-butylphosphino) ferrocene, dicyclohexyl (3-isopropoxy-2', 4',6' -triisopropyl- [1,1 '-biphenyl ] -2-yl) phosphine alkane, tris (pentafluorophenyl) phosphine, 2- (di-tert-butylphosphine) -1,1' -binaphthyl, di-1-adamantyl (4 '-butyl-2', 3', 5', 6 '-tetrafluoro-2', 4',6' -triisopropyl-2-methoxy-m-terphenyl) phosphine, tert-butyldiphenylphosphine, 1, 4-bis (dicyclohexylphosphine) butane, triphenylphosphine, and, one or more of 1,1' -ferrocenediyl-bis (diphenylphosphine) may also be employed with other phosphine ligands commonly used in the art.

Further, the zinc salt is selected from one or more of zinc oxide, zinc sulfide, zinc acetate, zinc triflate, zinc methanesulfonate, zinc tetrafluoroborate, zinc nitrate, zinc phosphate, zinc carbonate and zinc sulfate.

Further, the solvent is one or more of alcohol solvents, ether solvents, amide solvents, acetonitrile and water.

Further, the ratio of the molar amount of the aryl halide represented by the formula (3) to the volume of the solvent is (0.2-0.4): 1L.

Further, the temperature of the coupling reaction is 70-100 ℃, and the time of the coupling reaction is 3-12 h.

The invention has the beneficial effects that:

1. The invention provides a 2-pyridine inner salt boron reagent which has good stability in a water phase, can be used as an aryl nucleophilic reagent to carry out a coupling reaction with aryl halide fast and efficiently, synthesizes 2-aryl pyridine derivatives with various structures, adapts to different substrates and reaction conditions, overcomes the problem that the existing 2-pyridine boron reagent (such as 2-pyridine boric acid) cannot carry out 2-pyridine reaction in the water phase, provides an efficient, reliable and simple strategy for complex molecular construction, is favorable for expanding the structural diversity of pyridine compounds, and has good application prospect in the aspects of chemical synthesis, drug development and the like.

2. The invention also provides a method for preparing the 2-pyridine inner salt boron reagent, which takes 2-pyridine boric acid, 2-pyridine boric acid ester or 2-pyridine boron anion complex salt as a starting material, and directly reacts with a fluoride anion source at normal temperature to prepare the 2-pyridine inner salt boron reagent. The preparation method is simple, the reaction condition is mild, the yield is high, the preparation cost by taking the 2-pyridine boron anion complex salt as the starting material is low (the 2-pyridine boron anion complex salt can be prepared by taking a cheap and easily available 2-pyridine halide as the starting material), the preparation method is suitable for industrialized mass production, and the promotion of the practical application of the 2-pyridine inner salt boron reagent is facilitated.

Drawings

FIG. 1 is a ¹ H NMR chart of the 2-pyridinium inner salt boron reagent prepared in example 1 after 5min, 3 hours, and 3 days of storage in D ₂ O, respectively.

Detailed Description

Unless defined otherwise, 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 invention belongs. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. The term "and/or" as used herein includes any and all combinations of one or more of the associated listed items.

The present invention will be further described with reference to specific examples, which are not intended to be limiting, so that those skilled in the art will better understand the present invention and practice it.

In the following examples, 2-pyridineboronic acid, 5-chloro-2-pyridineboronic acid was purchased from Shanghai Honghai biological medicine technologies Co., ltd, the purity was >95%, 5-chloro-2-pyridineboronic acid contained 50% LiOH, the other substituent 2-pyridineboronic acid was purchased from Piobtained medicine technologies, the purity was >95%, the ether tetrafluoroborate solution was purchased from Shanghai Michelin Biochemical technologies Co., ltd, the purity was >95%, and anhydrous methanol was purchased from Shanghai Taitan technologies Co., ltd, the purity was >99.5%. 2-bromo-4-fluoro-pyridine, 2-bromo-4-chloro-pyridine, 2-bromo-4-tert-butyl-pyridine, 2-bromo-4 (dimethylamino) -pyridine were all purchased from Pickle pharmaceutical technology with purity >95%, 2-bromo-4-methoxy-pyridine, 2-bromo-4-trifluoromethyl-pyridine, 2-bromo-5-methoxy-pyridine, 2-bromo-4-benzyloxy-pyridine were all purchased from Shanghai-Tai Tech Co., ltd., purity >95%, triisopropyl borate were all purchased from Shanghai-Meilin Biochemical Co., purity >98%, n-butyllithium were all purchased from Shanghai-Allatin Biochemical Co., and were 2.2 mol/liter in hexane solution, and other aryl-halogenated hydrocarbon substrates were all purchased from Tachyle pharmaceutical, shanghai-Meilin Biochemical Co., shanghai-Tech Co., and other reagent companies with purity >95%.

In the following examples, me represents methyl, ^t Bu represents tert-butyl, OMe represents methoxy, CF ₃ represents trifluoromethyl, OBn represents benzyloxy, and NMR represents nuclear magnetic resonance.

Example 1

The example relates to the preparation of a 2-pyridine inner salt boron reagent, the reaction formula is as follows:

To a 20mL sample bottle was added a magnetic stirrer, 2-pyridineboronic acid (49.2 mg,0.400 mmol), 2mL methanol (0.2 mol/L) and then tetrafluoroboric acid diethyl ether solution (71.2 mg,0.440 mmol) were added dropwise. The sample bottle was sealed with a cap with a septum, placed on a room temperature stirrer, and stirred for 12 hours. After the reaction, the mixture was concentrated, washed 2-3 times with methyl t-butyl ether, and then recrystallized by adding 0.2mL of methanol and 4mL of methyl t-butyl ether to precipitate a large amount of white solid, thereby obtaining 2-pyridine inner salt boron reagent (52.9 mg, yield 90%). The results of the nuclear magnetic characterization of the product are as follows:

¹H NMR(400MHz,CD₃CN,25℃,δ):12.97–12.39(m,1H),8.44(t,J＝6.3Hz,1H),8.34(t,J＝7.8Hz,1H),7.98(d,J＝7.8Hz,1H),7.76(t,J＝6.9Hz,1H);

¹³C NMR(101MHz,CD₃ CN,25 ℃, δ) 145.59,140.19,130.75,125.78, (carbon directly attached to the boron atom cannot be detected due to the nucleation quadrupole moment. )

¹⁹F NMR(376MHz,CD₃CN,25°C,δ):-147.41(q,J=40.3Hz);

¹¹B NMR(128MHz,CD₃CN,25°C,δ):0.64(q,J=40.3Hz)。

Amplification test A50 mL round bottom flask was charged with magnetic stirrer, 2-pyridineboronic acid (1.23 g,10.0 mmol) and 25mL methanol (0.4 mol/L) in sequence, and stirred well. Subsequently, an ether tetrafluoroborate solution (1.36 mL,1.78g,11 mmol) was slowly added dropwise. After the addition was completed, the mixture was placed in an ultrasonic water bath for treatment until all solids were completely dissolved as a transparent solution. The round bottom flask was sealed with a flip top stopper and stirred at ambient temperature for 12h. After the reaction was completed, the reaction mixture was concentrated directly, and the product was washed with methyl t-butyl ether 2-3 times. Subsequently, 5mL of methanol and 95mL of methyl t-butyl ether were added for recrystallization to give 1.20g of 2-pyridinetrifluoroborate in 82% yield.

Stability test in aqueous phase 30mg of the 2-Pyridinium inner salt boron reagent prepared in this example was placed in a nuclear magnetic tube, 0.5mL of D ₂ O was added, and ¹ H NMR detection was performed (storage time of 2-Pyridinium inner salt boron reagent in D ₂ O was about 5 min). In addition, the sample after 3 hours of storage was subjected to nuclear magnetic resonance monitoring, and as a result, as shown in FIG. 1, it was found that the sample did not decompose. To further examine the stability of the 2-pyridinium inner salt boron reagent in the aqueous phase, the storage time was prolonged to 3 days, and nuclear magnetic monitoring was performed, which revealed that the structure of the 2-pyridinium inner salt boron reagent remained unchanged. Therefore, the 2-pyridine inner salt boron reagent is not easy to degrade in the water phase and has good stability.

Example 2

The embodiment relates to a preparation method of a 2-pyridine inner salt boron reagent, which takes 5-chloro-2-pyridine boric acid as a reaction raw material to prepare the following 2-pyridine inner salt boron reagent:

The specific operation is as follows:

To a 20mL sample bottle was added a magnetic stirrer, 5-chloro-2-pyridineboronic acid (62.8 mg,0.400 mmol), 2mL methanol (0.2 mol/L) and then an ether tetrafluoroborate solution (0.800 mmol) was added dropwise. The sample bottle was sealed with a cap with a septum, placed on a normal temperature stirrer, and stirred for 5min. After completion of the reaction, the mixture was concentrated, washed 2 to 3 times with methyl t-butyl ether, and then 0.2mL of methanol and 4mL of methyl t-butyl ether were added for recrystallization, whereby a large amount of white solid (72.5 mg, equivalent) was precipitated. The results of the nuclear magnetic characterization of the product are as follows:

¹H NMR(400MHz,CD₃CN,25℃,δ):13.09–12.63(m,1H),8.56(dd,J＝6.9,2.2Hz,1H),8.35(dd,J＝8.5,2.2Hz,1H),7.97(d,J＝8.5Hz,1H);

¹³C{¹H}NMR(101MHz,CD₃ CN,25 ℃, δ) 145.52,139.42,133.31,131.73, (carbon directly attached to the boron atom cannot be detected due to the nucleation quadrupole moment. )

¹⁹F NMR(376MHz,CD₃CN,25°C,δ):–147.20(q,J=39.7Hz);

¹¹B NMR(128MHz,CD₃CN,25°C,δ):0.50(q,J=39.7Hz)。

Examples 3 to 6

The corresponding 2-pyridine inner salt boron reagent is prepared by taking 2-pyridine boric acid substituted by different substituents or 2-pyridine boric acid ester substituted by different substituents as reaction raw materials, and the concrete is shown in the following table 1:

TABLE 1

^a Reaction conditions 0.400mmol starting material, 0.440mmol tetrafluoroborate diethyl ether, 2mL methanol, c=0.2M;

the reaction conditions for examples 4-6 were all identical to those for example 3.

Example 7

The embodiment relates to a preparation method of a 2-pyridine inner salt boron reagent, which takes 4-dimethylamino-2-pyridine boron anion complex salt as a reaction raw material to prepare the 2-pyridine inner salt boron reagent shown as follows:

The specific operation is as follows:

To a20 mL sample bottle was added a magnetic stirrer, 2-pyridineboron anion complex salt (126.4 mg,0.400 mmol), 2mL methanol (0.2 mol/L), and then an ether tetrafluoroborate solution (0.800 mmol) was added dropwise. The sample bottle was sealed with a cap with a septum, placed on a room temperature stirrer, and stirred for 30min. After completion of the reaction, it was concentrated and then purified by column chromatography (DCM: CH ₃ oh=50:1) (59.2 mg, 78%). The results of the nuclear magnetic characterization of the product are as follows:

¹H NMR(400MHz,CD₃CN,25℃,δ):10.59(brs,1H),7.85(d,J＝7.5Hz,1H),7.07(d,J＝2.8Hz,1H),6.83(dd,J＝7.5,2.8Hz,1H),3.17(s,6H);

¹³C{¹H}NMR(101MHz,CD₃CN,25°C,δ):157.02,150.01,143.68,109.78,107.44,39.48;

¹⁹F NMR(376MHz,CD₃CN,25°C,δ):–147.29(q,J=44.9Hz);

¹¹B NMR(128MHz,CD₃CN,25°C,δ):0.78(q,J=44.9Hz)。

Examples 8 to 15

The corresponding 2-pyridine inner salt boron reagent is prepared by taking the 2-pyridine boron anion complexes substituted by different substituents as reaction raw materials, and other operations are consistent with example 7, and the specific operations are shown in the following table 2:

TABLE 2

Application example

The 2-pyridine inner salt boron reagent prepared in the embodiment is taken as an aryl nucleophilic reagent, and is respectively subjected to coupling reaction with different aryl halides to prepare different 2-aryl pyridine derivatives, wherein the preparation method comprises the following steps:

Pd (Amphos) ₂ (5-20 mol%) and ZnO (0.600 mmol) were added to a 10mL Schlenk tube containing a magnetic stirrer. Subsequently, 2-pyridine inner salt boron reagent (0.600 mmol) was added to the schlenk tube, followed by aryl halide (0.300 mmol) and methanol (1.5 ml, c=0.2 mol/L), closed with a rubber stopper, and connected to a nitrogen balloon, and the reaction mixture was stirred in an oil bath at 70 ℃ for 3 hours. And after the reaction is finished, purifying the crude product through column chromatography to finally obtain a 2-pyridine product.

The aryl nucleophiles, substrates, reaction products, yields, etc. employed are shown in table 3 below:

TABLE 3 Table 3

In summary, 2-pyridine boric acid ester or 2-pyridine boron anion complex salt are taken as raw materials to synthesize the 2-pyridine inner salt boron reagent, the substituent on the pyridine ring of the raw materials does not influence the synthesis of the 2-pyridine inner salt boron reagent, and the 2-pyridine inner salt boron reagent with various structures can be prepared by adopting the raw materials substituted by different substituents.

The above-described embodiments are merely preferred embodiments for fully explaining the present invention, and the scope of the present invention is not limited thereto. Equivalent substitutions and modifications will occur to those skilled in the art based on the present invention, and are intended to be within the scope of the present invention. The protection scope of the invention is subject to the claims.

Claims

1. A 2-pyridine inner salt boron reagent, characterized in that the structure of the 2-pyridine inner salt boron reagent is as shown in formula (I):

Wherein, ^R1 is a substituent at any position on the pyridine ring, selected from hydrogen, halogen, dimethylamino, halogen substituted or unsubstituted C1-C6 alkyl, halogen substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted phenyl, and the substituent of the substituted phenyl is selected from one or more of the following groups: halogen, C1-C6 alkyl, C1-C6 alkoxy, halogen substituted C1-C6 alkyl, halogen substituted C1-C6 alkoxy.

2. The 2-pyridine ylid boron reagent according to claim 1, wherein ^R1 is hydrogen, F, Cl, methyl, tert-butyl, trifluoromethyl, methoxy, benzyloxy or dimethylamino.

3. A method for preparing the 2-pyridine inner salt boron reagent according to claim 1 or 2, characterized in that it comprises the following steps: reacting the compound represented by formula (1) or formula (2) with a fluorine anion source and a proton source in the presence of a solvent to obtain the 2-pyridine inner salt boron reagent;

The structures of formula (1) and formula (2) are as follows:

Wherein, R ¹ is as defined in claim 1 or claim 2;

R ² is hydrogen or C1-C6 alkyl, or -B(OR ² ) ₂ in formula (1) is

R ³ is hydrogen or C1-C6 alkyl, or -B(OR ³ ) ₃ in formula (2) is

M is Li, Na or K.

4. The preparation method according to claim 3, characterized in that the fluorine anion source and the proton source are a mixture of an inorganic acid and tetrafluoroborate or a tetrafluoroborate ether solution;

When the fluorine anion source and the proton source are tetrafluoroborate ether solution, the molar ratio of the compound represented by formula (1) or formula (2) to the fluorine anion source is 1:(1-3).

5. The preparation method according to claim 3, characterized in that the solvent is one or more of an alcohol solvent, an ether solvent, an amide solvent, acetonitrile, and water;

The ratio of the molar amount of the compound represented by the formula (1) or formula (2) to the volume of the solvent is (0.2-0.4) mol:1L.

6. The preparation method according to claim 3, characterized in that the reaction temperature is 25-50°C and the reaction time is 5min-12h.

7. Use of the 2-pyridine inner salt boron reagent according to claim 1 or 2 as an aromatic nucleophilic reagent in a coupling reaction.

8. The use according to claim 7, characterized in that, under an inert atmosphere, the 2-pyridine inner salt boron reagent is subjected to a coupling reaction with the aryl halide represented by formula (3) in the presence of a palladium catalyst, an organic phosphine ligand, a zinc salt and a solvent to obtain a 2-aryl pyridine derivative represented by formula (II);

The structure of formula (3) is as follows:

R ⁴ ·X

(3)

The structure of formula (II) is shown below:

Wherein, R ¹ is as defined in claim 1 or claim 2;

^R4 is a substituted or unsubstituted aryl group, and the substituent of the substituted aryl group is selected from one or more of the following groups: halogen, cyano, heterocycle, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkenyl, C1-C6 alkenyloxy, C1-C6 alkynyl, C1-C6 alkynyloxy, C1-C6 ester, C1-C6 alkoxycarbonyl, benzyloxy, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy, halogen-substituted C1-C6 carbonyl, Phenylcarbonyl,

X is iodine, bromine or chlorine.

9. The use according to claim 8, characterized in that the molar ratio of the 2-pyridine inner salt boron reagent to the aryl halide represented by formula (3) is (2-3):1;

The ratio of the molar amount of the aryl halide represented by the formula (3) to the volume of the solvent is (0.2-0.4): 1L;

The coupling reaction temperature is 70-100° C., and the coupling reaction time is 3 h-12 h.

10. The use according to claim 8, characterized in that the palladium catalyst is selected from palladium acetate (II), palladium chloride (II), tetrakis (triphenylphosphine) palladium (0), tris (dibenzylideneacetone) dipalladium (0), bis (dibenzylideneacetone) palladium (0), bis (acetonitrile) dichloropalladium (II), di (tri-tert-butylphosphine) palladium (0), allyl palladium (II) chloride dimer (II), bis (acetylacetonate) palladium (II), chloro (2-dicyclohexylphosphino-2,6-di-I-propoxy-1,1-biphenyl) [2-(2-aminoethylphenyl)] palladium (II), chloro [(n-butyldi (1-adamantyl) phosphine)-2- [(2-aminobiphenyl)] palladium (II), (1,5-cyclooctadiene) dichloropalladium (II), dichloro[1,4-bis(diphenylphosphino)butane] palladium (II), bis(di-tert-butylphenylphosphine) dichloropalladium (II), bis(tricyclohexylphosphine) dichloropalladium (II), dicyclohexyl(2',4',6'-triisopropyl-3,6-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine-(2-(2-aminoethyl)phenyl)palladium (II) chloride, hexafluoroacetylacetonate palladium (II), bis[di-tert-butyl-(4-dimethylaminophenyl)phosphine] dichloropalladium (II), allyl[1,3-bis(2 ,6-diisopropylphenyl)imidazol-2-ylidene]palladium(II) chloride, [1,3-bis(2,6-di-isopropylphenyl)-4,5-dihydroimidazol-2-ylidene]chloro[3-phenylallyl]palladium(II), 1,3-bis(diisopropylphenyl)-2-imidazolinylidenepalladium(II) chloride dimer, [1,3-bis(diphenylphosphino)propane]palladium(II) chloride, azacyclic carbene-palladium(II) chloride-1-phenylimidazole complex, methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II), methanesulfonic acid (2-dicyclohexylphosphino-N, One or more of (N-dimethylamino-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II), methanesulfonic acid (2-di-tert-butylphosphine-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II), [1,3-bis(2,6-diisopropylphenyl)imidazol-2-yl-isoquinolin-2-yl]dichloropalladium(II), (2'-amino-1,1'-biphenyl-2-yl)methanesulfonylpalladium(II) dimer, and bis(di-tert-butyl-4-dimethylaminophenylphosphine)palladium(0);

The organic phosphine ligand is selected from [(4-(N,N-dimethylamino)phenyl]di-tert-butylphosphine, tri-tert-butylphosphine, triadamantylphosphine, 2-(di-tert-butylphosphine)biphenyl, tricyclohexylphosphine, n-butyldi(1-adamantyl)phosphine, 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl, 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl, 2-(dicyclohexylphosphine)3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl, tri(o-methylphenyl)phosphine, tri(4-methoxyphenyl)phosphine, tri(2-furyl)phosphine, 1,2, One or more of 3,4,5-pentylphenyl-1′-(di-tert-butylphosphino)ferrocene, dicyclohexyl(3-isopropoxy-2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine, tri(pentafluorophenyl)phosphine, 2-(di-tert-butylphosphino)-1,1′-binaphthyl, di-1-adamantyl(4″-butyl-2″,3″,5″,6″-tetrafluoro-2′,4′,6′-triisopropyl-2-methoxy-m-terphenyl)phosphine, tert-butyldiphenylphosphine, 1,4-bis(dicyclohexylphosphino)butane, triphenylphosphine, and 1,1′-ferrocenediyl-bis(diphenylphosphine);

The zinc salt is selected from one or more of zinc oxide, zinc sulfide, zinc acetate, zinc trifluoromethanesulfonate, zinc methanesulfonate, zinc tetrafluoroborate, zinc nitrate, zinc phosphate, zinc carbonate, and zinc sulfate;

The solvent is one or more of alcohol solvents, ether solvents, amide solvents, acetonitrile and water.