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

Abstract

The invention discloses a water-stable 2-pyridine inner salt boron reagent as well as a preparation method and application thereof in a coupling reaction, and the 2-pyridine inner salt boron reagent has a structure as shown in a formula (I), the compound can be prepared by reacting 2-pyridine boric acid, 2-pyridine boric acid ester or 2-pyridine boron anion complex salt with a fluorine anion source and a proton source in the presence of a solvent. The 2-pyridine inner salt boron reagent provided by the invention is simple in preparation method, mild in reaction condition, high in yield and suitable for industrial production; more importantly, the 2-pyridine inner salt boron reagent is good in stability in a water phase, can be used as an aryl nucleophilic reagent to be quickly and efficiently subjected to a coupling reaction with aryl halide to synthesize 2-aryl pyridine derivatives with various structures, and is wide in substrate, high in yield and suitable for industrial production. Good application prospects are realized in the fields of chemical synthesis, medicine development, material science and the like. # imgabs0 #

Description

Technical Field

[0001] The invention relates to the field of organic synthesis, and in particular to a water-stable 2-pyridine inner salt boron reagent and a preparation method thereof and application thereof in coupling reactions. Background Art

[0002] Pyridine is a widely existing structural unit in natural products, functional materials and drugs. In the past decade, pyridine is the most frequently occurring nitrogen heterocycle in small molecule drugs approved by the FDA. To prepare drugs containing pyridine structural units, it is usually necessary to use pyridine-containing nucleophiles to introduce pyridine structures into intermediates or final products through cross-coupling reactions. However, in cross-coupling reactions, the use of 2-pyridine derivatives as nucleophiles still faces stability challenges. In order to overcome the "2-pyridine problem", researchers have combined the innovation of modern transition metal-catalyzed cross-coupling reactions to continuously advance the development of 2-pyridine nucleophiles.

[0003] Compared with organotin, Grignard and organozinc reagents, organoboron reagents have become the most widely used aromatic nucleophiles in cross-coupling chemistry due to their low toxicity, high stability and ease of operation. However, 2-pyridineboronic acid easily forms a diionic intermediate, which 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-pyridylation reactions under aqueous conditions. Therefore, the development of a 2-pyridineboron reagent that can be stably present in water and has high reactivity is of great research and application value. Summary of the invention

[0004] In order to solve the above problems, the present invention provides a water-stable 2-pyridine inner salt boron reagent and a preparation method thereof and application thereof in a coupling reaction. The 2-pyridine inner salt boron reagent can be prepared by reacting 2-pyridine boronic acid, 2-pyridine boronic acid ester or 2-pyridine boronic anion complex salt with a fluorine anion source and a proton source in the presence of a solvent. The preparation method is simple, the reaction conditions are mild and the yield is high, and the reagent is suitable for industrial production. More importantly, the 2-pyridine inner salt boron reagent provided by the present invention has good stability in an aqueous phase, can be used as an aromatic nucleophilic reagent to quickly and efficiently carry out a coupling reaction with an aromatic halide, and synthesize 2-arylpyridine derivatives with diverse structures, and has good application prospects in the fields of chemical synthesis, drug development, etc.

[0005] Specifically, the present invention provides the following technical solutions:

[0006] The first aspect of the present invention provides a 2-pyridine inner salt boron reagent, the structure of the 2-pyridine inner salt boron reagent is shown in formula (I):

[0007]

[0008] Among them, 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, 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.

[0009] Halogen herein refers to iodine, bromine, chlorine or fluorine.

[0010] Furthermore, R 1 is hydrogen, F, Cl, methyl, tert-butyl, trifluoromethyl, methoxy, benzyloxy or dimethylamino.

[0011] The second aspect of the present invention provides a method for preparing the 2-pyridine inner salt boron reagent of the first aspect, comprising the following steps: reacting a compound represented by formula (1) or formula (2) with a fluorine anion source in the presence of a solvent to obtain the 2-pyridine inner salt boron reagent;

[0012] The structures of formula (1) and formula (2) are as follows:

[0013]

[0014] Among them, R 1 As defined above for formula (I);

[0015] R 2 is hydrogen or C1-C6 alkyl, or -B(OR 2 )2 is

[0016] R 3 is hydrogen or C1-C6 alkyl, or -B(OR 3 )3 is

[0017] M is Li, Na or K.

[0018] Furthermore, the fluorine anion source and the proton source are preferably a mixture of an inorganic acid and tetrafluoroborate or a tetrafluoroborate ether solution; more preferably, when the fluorine anion source and the proton source are a 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), for example 1:1, 1:2, 1:3, etc., including but not limited to the molar ratios listed above.

[0019] Furthermore, the solvent is one or more of alcohol solvents, ether solvents, amide solvents, acetonitrile, and water.

[0020] Furthermore, the ratio of the molar amount of the compound represented by formula (1) or formula (2) to the volume of the solvent is preferably (0.2-0.4) mol:1L.

[0021] Furthermore, the reaction temperature is preferably 25-50° C., and the reaction time is preferably 5 min-12 h.

[0022] In a third aspect, the present invention provides a use of the 2-pyridine inner salt boron reagent described in the first aspect as an aromatic nucleophilic reagent in a coupling reaction.

[0023] Furthermore, the 2-pyridine inner salt boron reagent is used as an aromatic nucleophile to couple with an aromatic halide to prepare a 2-arylpyridine derivative, which specifically comprises the following steps: under an inert atmosphere, coupling the 2-pyridine inner salt boron reagent with an aromatic 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-arylpyridine derivative represented by formula (II);

[0024] The structure of formula (3) is as follows:

[0025] R 4 -X

[0026] (3)

[0027] The structure of formula (II) is shown below:

[0028]

[0029] Among them, R 1 As defined above for formula (I);

[0030] R 4 is a substituted or unsubstituted aryl group, wherein 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 group, C1-C6 alkoxycarbonyl, benzyloxy, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy, halogen-substituted C1-C6 carbonyl, Phenylcarbonyl,

[0031] X is iodine, bromine or chlorine.

[0032] Furthermore, the molar ratio of the 2-pyridine inner salt boron reagent to the aryl halide represented by formula (3) is (2-3):1, such as 2:1, 2.5:1, 3:1, etc., including but not limited to the molar ratios listed above.

[0033] Further, the palladium catalyst can be selected from palladium (II) acetate, palladium (II) chloride, 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 (acetylacetone) 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, hexafluoroacetylacetonatepalladium(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, [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate, [2-dicyclohexylphosphino-N,N-dimethylamino-1,1'-biphenyl)(2 The catalyst may be selected from the group consisting of palladium (II), (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) methanesulfonyl palladium (II), dimer, bis(di-tert-butyl-4-dimethylaminophenylphosphine) palladium (0), and other palladium catalysts commonly used in the art may also be used.

[0034] Further, the organic phosphine ligand can be 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, 1,2,3,4,5 -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-termphenyl)phosphine, tert-butyldiphenylphosphine, 1,4-bis(dicyclohexylphosphino)butane, triphenylphosphine, 1,1′-ferrocenediyl-bis(diphenylphosphine), or one or more of the phosphine ligands commonly used in the art.

[0035] Furthermore, 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.

[0036] Furthermore, the solvent is one or more of an alcohol solvent, an ether solvent, an amide solvent, acetonitrile, and water.

[0037] Furthermore, 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.

[0038] Furthermore, the coupling reaction temperature is 70-100° C., and the coupling reaction time is 3 h-12 h.

[0039] Beneficial effects of the present invention:

[0040] 1. The present invention provides a type of 2-pyridine inner salt boron reagent, which has good stability in aqueous phase, can be used as an aromatic nucleophile to quickly and efficiently carry out coupling reaction with aromatic halides, synthesize 2-arylpyridine derivatives with diverse structures, adapt to different substrates and reaction conditions, overcome the problem that existing 2-pyridine boron reagents (such as 2-pyridine boronic acid) cannot carry out 2-pyridylation reaction in aqueous phase, provide an efficient, reliable and simple strategy for complex molecular construction, and is conducive to expanding the structural diversity of pyridine compounds, and has good application prospects in chemical synthesis, drug development and the like.

[0041] 2. The present invention also provides a method for preparing the above-mentioned 2-pyridine inner salt boron reagent, which is prepared by directly reacting 2-pyridine boronic acid, 2-pyridine boronic acid ester or 2-pyridine boronic anion complex salt with a fluorine anion source at room temperature with 2-pyridine boronic acid acid, 2-pyridine boronic acid ester or 2-pyridine boronic anion complex salt as a starting material. The preparation method is simple, the reaction conditions are mild, the yield is high, and the preparation cost of using 2-pyridine boronic anion complex salt as a starting material is low (2-pyridine boronic anion complex salt can be prepared from cheap and readily available 2-pyridine halides as starting materials), which is suitable for industrial mass production and is conducive to promoting the practical application of such 2-pyridine inner salt boron reagents. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] Figure 1 The 2-pyridine inner salt boron reagent prepared in Example 1 was stored in D2O for 5 min, 3 hours, and 3 days. 1 HNMR spectrum. DETAILED DESCRIPTION

[0043] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art of the present invention. The terms used herein in the specification of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention. The term "and / or" used herein includes any and all combinations of one or more related listed items.

[0044] The present invention is further described below in conjunction with specific embodiments so that those skilled in the art can better understand the present invention and implement it, but the embodiments are not intended to limit the present invention.

[0045] In the following examples, 2-pyridineboric acid and 5-chloro-2-pyridineboric acid were purchased from Shanghai Haohong Biomedical Technology Co., Ltd. with a purity of >95%, wherein 5-chloro-2-pyridineboric acid contained 50% LiOH, and other substituted 2-pyridineboric acids were purchased from Bid Pharmaceutical Technology with a purity of >95%; tetrafluoroborate ether solution was purchased from Shanghai MacLean Biochemical Technology Co., Ltd. with a purity of >95%, and anhydrous methanol was purchased from Shanghai Titan Technology Co., Ltd. with a purity of >99.5%. 2-Bromo-4-fluoro-pyridine, 2-bromo-4-chloro-pyridine, 2-bromo-4-tert-butyl-pyridine, and 2-bromo-4 (dimethylamino)-pyridine were all purchased from Bidex Pharmaceutical Technology with a purity of >95%; 2-bromo-4-methoxy-pyridine, 2-bromo-4-trifluoromethyl-pyridine, 2-bromo-5-methoxy-pyridine, and 2-bromo-4-benzyloxy-pyridine were all purchased from Shanghai Titan Technology Co., Ltd. with a purity of >95%; triisopropyl borate was purchased from Shanghai MacLean Biochemical Technology Co., Ltd. with a purity of >98%; n-butyl lithium was purchased from Shanghai Aladdin Biochemical Technology Co., Ltd. as a 2.2 mol / L hexane solution; other aromatic halogenated hydrocarbon substrates were purchased from reagent companies such as Bidex Pharmaceutical Technology, Shanghai MacLean Biochemical Technology Co., Ltd., and Shanghai Titan Technology Co., Ltd. with a purity of >95%.

[0046] In the following examples: Me represents a methyl group, t Bu represents tert-butyl, OMe represents methoxy, CF3 represents trifluoromethyl, OBn represents benzyloxy, and NMR represents nuclear magnetic resonance.

[0047] Example 1

[0048] This embodiment relates to the preparation of a 2-pyridine inner salt boron reagent, and the reaction formula is as follows:

[0049]

[0050] Add a magnetic stirrer, 2-pyridine boronic acid (49.2 mg, 0.400 mmol) to a 20 mL sample bottle, add 2 mL of methanol (0.2 mol / L), and then drop tetrafluoroborate ether solution (71.2 mg, 0.440 mmol). Seal the sample bottle with a lid with a diaphragm, place it on a normal temperature stirrer, and stir for 12 hours. After the reaction is completed, concentrate, wash with methyl tert-butyl ether 2-3 times, then add 0.2 mL of methanol and 4 mL of methyl tert-butyl ether for recrystallization, and a large amount of white solid is precipitated to obtain 2-pyridine inner salt boron reagent (52.9 mg, yield 90%). The NMR characterization results of the product are as follows:

[0051] 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);

[0052] 13 C NMR (101 MHz, CD3CN, 25°C, δ): 145.59, 140.19, 130.75, 125.78; (Due to the nucleation quadrupole moment, the carbon directly connected to the boron atom could not be detected.)

[0053] 19 F NMR (376MHz, CD3CN, 25℃, δ): -147.41 (q, J=40.3Hz);

[0054] 11 B NMR (128MHz, CD3CN, 25°C, δ): 0.64 (q, J=40.3Hz).

[0055] Amplification test: Add a magnetic stirrer to a 50mL round-bottom flask, add 2-pyridine boronic acid (1.23g, 10.0mmol) and 25mL methanol (0.4mol / L) in sequence, and stir evenly. Subsequently, tetrafluoroboric acid ether solution (1.36mL, 1.78g, 11mmol) 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 into a transparent solution. The round-bottom flask was sealed with a turn-down stopper and stirred at room temperature for 12h. After the reaction was completed, the reaction solution was directly concentrated and the product was washed with methyl tert-butyl ether 2-3 times. Subsequently, 5mL methanol and 95mL methyl tert-butyl ether were added for recrystallization to obtain 1.20g of 2-pyridine trifluoroborate with a yield of 82%.

[0056] Stability test in aqueous phase: 30 mg of the 2-pyridine inner salt boron reagent prepared in this example was placed in a nuclear magnetic resonance tube, and 0.5 mL of D2O was added. 1 H NMR detection (the storage time of 2-pyridine inner salt boron reagent in D2O is about 5 minutes). In addition, the sample was monitored by NMR after 3 hours of storage. The results are as follows Figure 1 As shown, it was found that the sample did not decompose. In order to further investigate the stability of the 2-pyridine inner salt boron reagent in the aqueous phase, the storage time was extended to 3 days and NMR monitoring was performed. The results showed that the structure of the 2-pyridine inner salt boron reagent remained unchanged. It can be seen that this type of 2-pyridine inner salt boron reagent is not easily degraded in the aqueous phase and has good stability.

[0057] Example 2

[0058] This embodiment relates to the preparation of a 2-pyridine inner salt boron reagent, and 5-chloro-2-pyridine boronic acid is used as a reaction raw material to prepare the 2-pyridine inner salt boron reagent shown below:

[0059]

[0060] The specific operations are as follows:

[0061] A magnetic stirrer, 5-chloro-2-pyridineboronic acid (62.8 mg, 0.400 mmol) were added to a 20 mL sample bottle, followed by a 2 mL methanol (0.2 mol / L) solution of tetrafluoroborate in ether (0.800 mmol). The sample bottle was sealed with a lid with a diaphragm, placed on a normal temperature stirrer, and stirred for 5 min. After the reaction was completed, the mixture was concentrated, washed with methyl tert-butyl ether 2-3 times, and then 0.2 mL methanol and 4 mL methyl tert-butyl ether were added for recrystallization to precipitate a large amount of white solid (72.5 mg, equivalent). The NMR characterization results of the product are as follows:

[0062] 1 H 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);

[0063] 13 C{ 1 H}NMR (101 MHz, CD3CN, 25°C, δ): 145.52, 139.42, 133.31, 131.73; (Due to the nucleation quadrupole moment, the carbon directly connected to the boron atom could not be detected.)

[0064] 19 F NMR (376MHz, CD3CN, 25℃, δ): –147.20 (q, J=39.7Hz);

[0065] 11 B NMR (128MHz, CD3CN, 25°C, δ): 0.50 (q, J=39.7Hz).

[0066] Embodiment 3-6

[0067] The corresponding 2-pyridine inner salt boron reagents were prepared using 2-pyridine boronic acid substituted with different substituents or 2-pyridine boronic acid esters substituted with different substituents as reaction raw materials, as shown in Table 1 below:

[0068] Table 1

[0069]

[0070] a Reaction conditions: 0.400 mmol of raw material, 0.440 mmol of tetrafluoroborate ether, 2 mL of methanol, c = 0.2 M;

[0071] The reaction conditions of Examples 4-6 are consistent with those of Example 3.

[0072] Example 7

[0073] This embodiment relates to the preparation of a 2-pyridine inner salt boron reagent, and the 2-pyridine inner salt boron reagent shown below is prepared using 4-dimethylamino-2-pyridine boron anion complex salt as a reaction raw material:

[0074]

[0075] The specific operations are as follows:

[0076] Add a magnetic stirrer, 2-pyridine boron anion complex salt (126.4 mg, 0.400 mmol) to a 20 mL sample bottle, add 2 mL of methanol (0.2 mol / L), and then drop tetrafluoroborate ether solution (0.800 mmol). Seal the sample bottle with a lid with a diaphragm, place it on a normal temperature stirrer, and stir for 30 minutes. After the reaction is completed, concentrate and then separate and purify by column chromatography (DCM: CH3OH = 50:1) (59.2 mg, 78%). The NMR characterization results of the product are as follows:

[0077] 1 H 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);

[0078] 13 C{ 1 H}NMR (101MHz, CD3CN, 25℃, δ): 157.02, 150.01, 143.68, 109.78, 107.44, 39.48;

[0079] 19 F NMR (376MHz, CD3CN, 25℃, δ): –147.29 (q, J=44.9Hz);

[0080] 11 B NMR (128MHz, CD3CN, 25°C, δ): 0.78 (q, J=44.9Hz).

[0081] Embodiment 8-15

[0082] The corresponding 2-pyridine inner salt boron reagents were prepared using 2-pyridine boron anion complexes substituted with different substituents as reaction raw materials, and the other operations were consistent with Example 7, as shown in the following Table 2:

[0083] Table 2

[0084]

[0085]

[0086] Application Examples

[0087] The 2-pyridine inner salt boron reagent prepared in the above example is used as an aromatic nucleophilic reagent, and is coupled with different aromatic halides to prepare different 2-arylpyridine derivatives; the preparation method is as follows:

[0088] Pd(Amphos)2 (5mol-20mol%) and ZnO (0.600mmol) were added to a 10mL Shrek tube containing a magnetic stirrer. Subsequently, 2-pyridine inner salt boron reagent (0.600mmol) was added to the Shrek tube, followed by aryl halide (0.300mmol) and methanol (1.5mL, c=0.2mol / L), which was sealed with a rubber stopper and connected to a nitrogen balloon. The reaction mixture was stirred at 70°C in an oil bath for 3 hours. After the reaction was completed, the crude product was purified by column chromatography to obtain a 2-pyridyl product.

[0089] The aromatic nucleophilic reagents, substrates, reaction products, yields, etc. used are shown in Table 3 below:

[0090] Table 3

[0091]

[0092]

[0093]

[0094]

[0095] In summary, 2-pyridine inner salt boron reagents can be synthesized by using 2-pyridine boronic acid, 2-pyridine boronic ester or 2-pyridine boron anion complex salt as raw materials, and the substituents on the raw material pyridine ring will not affect the synthesis of the 2-pyridine inner salt boron reagent. By using raw materials substituted with different substituents, 2-pyridine inner salt boron reagents with diverse structures can be prepared; this type of 2-pyridine inner salt boron reagent has good water stability and can be coupled with different aromatic halides to prepare 2-aryl pyridine derivatives with diverse structures, so that it has broad application prospects in chemical synthesis, drug development and other fields.

[0096] The above-described embodiments are only preferred embodiments for fully illustrating the present invention, and the protection scope of the present invention is not limited thereto. Equivalent substitutions or changes made by those skilled in the art based on the present invention are within the protection scope of the present invention. The protection scope of the present invention shall be 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 shown in formula (I): Among them, 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, 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 inner salt boron reagent according to claim 1, characterized in that R 1 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: The following steps are involved: 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: Among them, R 1 as defined in claim 1 or claim 2; R 2 is hydrogen or C1-C6 alkyl, or -B(OR 2 )2 is R 3 is hydrogen or C1-C6 alkyl, or -B(OR 3 )3 is M is Li, Na or K.

4. The preparation method according to claim 3, characterized in that: The fluorine anion source and 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 5 min-12 h.

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 an 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: Among them, R 1 as defined in claim 1 or claim 2; R 4 is a substituted or unsubstituted aryl group, wherein 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 group, 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 (acetylacetone) 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, hexafluoroacetylacetonatepalladium(II), bis[di-tert-butyl-(4-dimethylaminophenyl)phosphine] dichloropalladium(II), allyl[1,3-bis(2,6-diisopropylphenyl)amidite [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]chloropalladium(II), azacyclic carbene-palladium(II) chloride-1-phenylimidazole complex, [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate, [2-dicyclohexylphosphino-N,N-dimethylamino] one or more of: (1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II), (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.

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