Method for synthesizing fused ring pyridine compound through cycloaddition of alkyne-nitrile compound
By using a catalytic system of inexpensive nickel catalyst and phosphine ligand, the [2+2+2] cycloaddition reaction between alkynium-nitrile compounds is carried out, which solves the problem of slow cycloaddition reaction speed and many side reactions of alkynium-nitrile compounds in the prior art, and achieves efficient, economical and environmentally friendly synthesis of fused pyridine compounds.
Patent Information
- Application Number
- CN202411579576.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-11-07
- Publication Date
- 2025-03-21
AI Technical Summary
In the prior art, the cycloaddition reaction between alkyne-nitrile compounds and alkyne has problems such as slow reaction rates, cyclization of alkynes itself, and carbon-cyanation, and other side reactions. It also uses harsh conditions such as high temperature and radiation, and has a single substrate type, and additional alkynes and additives are required, and precious metal catalysts are used.
Using commercially available cheap nickel catalysts, a catalytic system of nickel catalysts and phosphine ligands is designed. Through the [2+2+2] cycloaddition reaction between alkynium-nitrile compounds, additional alkynes and additives are avoided. The reaction conditions are mild and the application is wide.
It has achieved efficient synthesis of fused ring pyridine compounds, with mild reaction conditions, economical practical, simple operation, high yield and wide substrate applicability, and is suitable for grocery reactions and industrial scale production.
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Abstract
Description
Technical Field
[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for synthesizing condensed ring pyridine compounds through cycloaddition of alkyne-nitrile compounds. Background Art
[0002] As a classic nitrogen-containing heterocyclic compound, pyridine is widely present in many drugs and bioactive molecules, natural products, and pesticide chemicals, and plays a very important role in the pharmaceutical field. At present, there are many methods for synthesizing polysubstituted pyridine compounds, including some classic synthetic reactions, transition metal-catalyzed [2+2+2] cycloaddition reactions, and some processes without metal participation. Due to the advantages of high reaction efficiency, selectivity control, high atom economy and good practicality, the [2+2+2] cycloaddition reaction has become one of the most direct and effective strategies for constructing pyridine compounds.
[0003] At present, the types of [2+2+2] cycloaddition reactions mainly include the following three categories: reactions between diyne compounds and nitrile, two molecules of alkyne and nitrile, and alkyne-nitrile compounds and alkyne. Among these three types of reactions, the transition metal-catalyzed cycloaddition reaction of diyne and nitrile is the most widely studied and mature, representing the most direct strategy for synthesizing pyridine compounds. Although a variety of transition metals such as Co (J. Org. Chem. 2016, 81, 3087-3102.), Ru (Org. Lett. 2012, 14, 4982-4985.), Rh (Org. Lett. 2010, 12, 1312-1315.), Fe (Chem. Commun. 2014, 50, 593-595.) have been successfully developed and used to catalyze such reactions, nickel has obstacles in catalyzing the coupling process of alkyne and nitrile, and its development has been subject to certain restrictions. Until 2005, Louie's team developed the first nickel-catalyzed [2+2+2] cycloaddition reaction of diynes and nitriles (J.Am.Chem.Soc.2005,127,5030-5031.), providing an efficient and mild method for the synthesis of pyridine compounds. Subsequently, Louie's team also developed more nickel-catalyzed cycloaddition reactions of diynes and nitriles, providing new reaction schemes for the synthesis of pyridine compounds.
[0004] However, compared with the cycloaddition reaction of diynes and nitriles, the reaction between alkyne-nitrile compounds and alkynes started relatively late. Before 2016, only two types of catalytic systems, cobalt (Org. Lett. 2007, 9, 393-396.) and iron (Org. Lett., 2011, 13, 2936-2939.), were developed. Moreover, these reactions still have some defects, such as the need for higher reaction temperatures and poor substrate applicability. It was not until 2016 that Liu Yuanhong's team from the Shanghai Institute of Organic Chemistry (Chem-Eur J. 2016, 22, 16765-16769.) reported the first nickel-catalyzed cycloaddition reaction of alkyne-nitrile and alkyne. This reaction can synthesize condensed ring pyridine compounds under mild reaction conditions, which has attracted widespread attention from researchers. In 2023, Professor Liu Wenbo of Wuhan University (Sci. China Chem, 2023, 66, 3148-3153.) also used alkyne-nitrile compounds as reaction substrates, and achieved the [2+2+2] cycloaddition reaction with alkynes through the regulation of chiral ligands, obtaining a series of axial chiral 1-azafluorene compounds. However, this technical solution has some obvious defects, such as the need to operate in a glove box, the nickel catalyst used is sensitive to air, the need to add Lewis acid, and it is not economical and environmentally friendly.
[0005] So far, the development of cycloaddition reactions of alkyne-nitrile compounds with alkynes remains challenging, mainly due to the slow reaction rate of alkyne-nitrile compounds in the heterocyclic coupling process, the cyclization of alkynes themselves, and side reactions such as carbon-cyanation. In addition, the existing technical solutions still have obvious limitations, such as the use of harsh conditions such as radiation and high temperature, a single substrate type, the need to pre-prepare alkyne molecules, the need to add additional Lewis acids or bases, and the use of precious metals such as ruthenium and iridium. Therefore, it is very necessary to develop new transition metal catalytic systems and synthetic strategies, which will not only help to solve the challenges currently faced by research, but also provide new research ideas and possible alternatives for the synthesis of pyridine compounds.
[0006] Based on this, it is urgent to propose a technical solution to solve the above-mentioned problems. Summary of the invention
[0007] Based on the defects of the prior art, the present invention aims to use commercially available and inexpensive nickel catalysts to develop a catalytic system with better applicability, simple reaction operation, simple reaction conditions, and strong substrate universality, so as to solve the deficiencies of the prior art and provide a new synthesis strategy for the synthesis of condensed ring pyridine compounds. The present invention has the following advantages: the reaction conditions are relatively mild and can be carried out in ordinary chemical synthesis laboratories; the use of relatively cheap and readily available nickel catalysts is more economical and applicable; the intermolecular reaction of alkyne-nitrile compounds avoids the additional addition of alkynes, which is more convenient and practical; the catalytic system of nickel catalysts and phosphine ligands is designed, and no additional additives such as Lewis acids and bases are required.
[0008] An object of the present invention is to provide a method for synthesizing fused-ring pyridine compounds by cycloaddition of alkyne-nitrile compounds, comprising the following steps:
[0009] The alkyne-nitrile compound, pinacol diboronate, nickel catalyst, phosphine ligand, organic solvent and inorganic solvent are mixed, heated to react under the protection of inert gas, and after the reaction is completed, quenched, purified, washed and dried to obtain a condensed ring pyridine compound;
[0010] The chemical structural formula of the alkyne-nitrile compound is shown in Formula I, and the chemical structural formula of the fused-ring pyridine compound is shown in Formula II:
[0011]
[0012] in,
[0013] R 1 and R 2 Each of them is independently selected from one or more of hydrogen, C1-C6 alkyl, methoxy, halogen, nitro, cyano, trifluoromethyl, ester, silyl ether, thiophene or C6-C14 aryl.
[0014] Furthermore, the molar ratio of the alkyne-nitrile compound, the bipyraclostrobin, the nickel catalyst and the phosphine ligand is 0.2:(0.24-0.4):(0.01-0.03):(0.01-0.04).
[0015] Furthermore, the alkyne-nitrile compound is selected from one or more of the following compounds:
[0016]
[0017] Furthermore, the nickel catalyst is selected from one or more of nickel acetylacetonate, bis(triphenylphosphine)nickel dichloride, bis(tricyclohexylphosphine)nickel dichloride, nickel tetrafluoroborate hexahydrate, nickel acetate tetrahydrate, nickel iodide, nickel chloride hexahydrate or bis(1,5-cyclooctadiene)nickel.
[0018] Furthermore, the phosphine ligand is selected from one or more of tri-n-butylphosphine tetrafluoroborate, tri-tert-butylphosphine tetrafluoroborate, triisopropylphosphine tetrafluoroborate, di-tert-butyl(methyl)phosphine tetrafluoroborate or tricyclohexylphosphine tetrafluoroborate.
[0019] Furthermore, the organic solvent is selected from one or more of cyclohexane, toluene, trifluorotoluene, acetonitrile, methanol, ethanol, isopropanol or tert-butanol.
[0020] Furthermore, the inorganic solvent is water.
[0021] Furthermore, the heating temperature is 90-150° C., and the reaction time is 16-18 hours.
[0022] Furthermore, the inert gas is selected from one or more of nitrogen, argon or helium.
[0023] The present invention has the following beneficial effects:
[0024] (1) The present invention adopts a relatively low-cost metal nickel catalyst, and designs a catalytic system of a nickel catalyst and a phosphine ligand under an inert gas atmosphere. Under this catalytic system, alkyne-nitrile compounds undergo a [2+2+2] cycloaddition reaction between their own molecules to obtain a series of condensed ring pyridine compounds. The present invention overcomes the defects of the prior art regarding the synthesis method of condensed ring pyridine compounds, such as the use of relatively harsh conditions such as high temperature and radiation, the use of noble metal catalysts, the need to add an additional molecule of alkyne as a reactant, the need to add additional additives, poor regional selectivity, poor substrate universality, and the like, and provides a method for the intermolecular [2+2+2] cycloaddition of condensed ring pyridine compounds with mild reaction conditions, economical and practical, no need to add additional alkynes or additives, high efficiency, low cost, and environmentally friendly.
[0025] (2) The present invention has the advantages of simple operation, high catalytic activity, high regioselectivity, high yield, wide substrate applicability, easy product separation and less environmental pollution, and is not only suitable for gram-scale reactions, but also suitable for industrial-scale production. DETAILED DESCRIPTION
[0026] The following will be combined with the embodiments to clearly and completely describe the concept of the present invention and the technical effects produced, so as to fully understand the purpose, characteristics and effects of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, other embodiments obtained by those skilled in the art without creative work are all within the scope of protection of the present invention.
[0027] Unless otherwise stated, the raw materials, reactions and post-treatment methods mentioned in the examples are common raw materials on the market and technical methods well known to those skilled in the art.
[0028] Example 1
[0029] A method for synthesizing condensed-ring pyridine compounds by cycloaddition of alkyne-nitrile compounds comprises the following steps:
[0030] [2-(phenylethynyl)phenyl]acetonitrile (Ia, 0.2mmol), biboric acid pinacol ester (1.5eq, 0.3mmol), nickel acetylacetonate (0.05eq, 0.01mmol), tricyclohexylphosphine tetrafluoroborate (0.10eq, 0.02mmol), toluene / cyclohexane (v / v=3:1, 2.0mL) and water (2.0eq, 0.4mmol) were added to a 25mL Shrek tube, nitrogen was charged, and the mixture was placed in an oil bath at 120°C for sufficient reaction for 12h. After the reaction was completed, a saturated ammonium chloride solution was used to quench the reaction, and ethyl acetate (15mL×3) was used for extraction. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The mixture was separated by silica gel column chromatography (petroleum ether / ethyl acetate=12 / 1-10 / 1) to obtain a yellow solid fused ring pyridine compound IIa with a yield of 69%;
[0031] in,
[0032] The structural formula of the [2-(phenylethynyl)phenyl]acetonitrile is as follows:
[0033]
[0034] The structural characterization data of the above-mentioned fused ring pyridine compound IIa are as follows:
[0035] 1 H NMR (400MHz, Chloroform-d) δ7.62 (dq, J=4.8, 2.8, 2.4Hz, 3H), 7.57 (d, J=7.5Hz, 1H), 7.47-7. 40(m,1H),7.41-7.34(m,1H),7.25-7.18(m,4H),7.15(d,J=7.7Hz,2H),7.06(t,J=7.6Hz,2H),6 .97(t,J=7.5Hz,1H),6.87(d,J=7.5Hz,1H),6.58(d,J=7.8Hz,1H),6.49(d,J=7.7Hz,1H),4.31( dd,J=9.6,4.3Hz,1H),4.14(s,2H),3.92(dd,J=13.5,4.3Hz,1H),2.88(dd,J=13.5,9.7Hz,1H). 13C NMR(101MHz,Chloroform-d)δ165.67,162.94,145.22,141.73,139.78,139.23,138.91,138.69,137.05,131.81,130.83,129.69,129.65 ,128.62,128.09,128.04,126.92,126.74,126.56,126.24,125.27,125.05,122.98,122.78,49.42,38.79,38.58.HRMS-ESI(m / z):calcd for C 32 H 23 N,[M+H] + :422.1909,found,422.1911.
[0036] According to the above data, the structure of the obtained product is inferred to be:
[0037]
[0038] Example 2
[0039] A method for synthesizing condensed-ring pyridine compounds by cycloaddition of alkyne-nitrile compounds comprises the following steps:
[0040] To a 25 mL Shrek tube, {2-[(4-methylphenyl)ethynyl]phenyl}acetonitrile (Ib, 0.2 mmol), biboronic acid pinacol ester (1.5 eq, 0.3 mmol), nickel acetylacetonate (0.05 eq, 0.01 mmol), tricyclohexylphosphine tetrafluoroborate (0.10 eq, 0.02 mmol), toluene / cyclohexane (v / v=3:1, 2.0 mL) and water (2.0 eq, 0.4 mmol) were added respectively, nitrogen was charged, and the mixture was placed in an oil bath at 120° C. for sufficient reaction for 12 h. After the reaction was completed, a saturated ammonium chloride solution was used to quench the reaction, and ethyl acetate (15 mL×3) was used for extraction. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The mixture was separated by silica gel column chromatography (petroleum ether / ethyl acetate=12 / 1-10 / 1) to obtain a light yellow solid fused ring pyridine compound IIb with a yield of 72%;
[0041] in,
[0042] The structural formula of the [2-(phenylethynyl)phenyl]acetonitrile is as follows:
[0043]
[0044] The structural characterization data of the above-mentioned fused ring pyridine compound IIa are as follows:
[0045] 1 H NMR(400MHz,Chloroform-d)δ7.57(d,J=7.4Hz,1H),7.43(d,J=8.2Hz,2H),7.32-7.25(m,3H),7.10-6.98(m,7H),6.88(d,J=7.4Hz,1H),6.65(d,J=7.8Hz, 1H),6.57(d,J=7.5Hz,1H),4.28(dd,J=9.9,4.2Hz,1H),4.14(s,2H),3.89(dd ,J=13.6,4.3Hz,1H),2.80(dd,J=13.6,9.9Hz,1H),2.57(s,3H),2.32(s,3H). 13 C NMR(101MHz,Chloroform-d)δ165.72,162.86,145.37,141.70,139.92,139. 00,138.94,138.29,136.24,135.65,133.94,131.97,130.96,130.36,130.3 3,129.50,128.83,127.88,127.85,126.83,126.70,126.47,125.29,125.01 ,123.03,122.81,49.49,38.57,38.39,21.66,21.15.HRMS-ESI(m / z):calcd for C 34 H 27 N,[M+H] + :450.2222,found,450.2239.
[0046] According to the above data, the structure of the obtained product is inferred to be:
[0047]
[0048] Example 3
[0049] A method for synthesizing condensed ring pyridine compounds by cycloaddition of alkyne-nitrile compounds, the difference between this embodiment and embodiment 1 is that the mass of the [2-(phenylethynyl)phenyl]acetonitrile is replaced by a structure of The remaining ingredients and amounts are the same as those in Example 1.
[0050] Example 4
[0051] A method for synthesizing condensed ring pyridine compounds by cycloaddition of alkyne-nitrile compounds, the difference between this embodiment and embodiment 1 is that the mass of the [2-(phenylethynyl)phenyl]acetonitrile is replaced by a structure of The remaining ingredients and amounts are the same as those in Example 1.
[0052] Example 5
[0053] A method for synthesizing condensed ring pyridine compounds by cycloaddition of alkyne-nitrile compounds, the difference between this embodiment and embodiment 1 is that the mass of the [2-(phenylethynyl)phenyl]acetonitrile is replaced by a structure of The remaining ingredients and amounts are the same as those in Example 1.
[0054] Example 6
[0055] A method for synthesizing condensed ring pyridine compounds by cycloaddition of alkyne-nitrile compounds, the difference between this embodiment and embodiment 1 is that the mass of the [2-(phenylethynyl)phenyl]acetonitrile is replaced by a structure of The remaining ingredients and amounts are the same as those in Example 1.
[0056] Example 7
[0057] A method for synthesizing condensed ring pyridine compounds by cycloaddition of alkyne-nitrile compounds, the difference between this embodiment and embodiment 1 is that the mass of the [2-(phenylethynyl)phenyl]acetonitrile is replaced by a structure of The remaining ingredients and amounts are the same as those in Example 1.
[0058] Example 8
[0059] A method for synthesizing condensed ring pyridine compounds by cycloaddition of alkyne-nitrile compounds, the difference between this embodiment and embodiment 1 is that the mass of the [2-(phenylethynyl)phenyl]acetonitrile is replaced by a structure of The remaining ingredients and amounts are the same as those in Example 1.
[0060] Example 9
[0061] A method for synthesizing condensed ring pyridine compounds by cycloaddition of alkyne-nitrile compounds, the difference between this embodiment and embodiment 1 is that the mass of the [2-(phenylethynyl)phenyl]acetonitrile is replaced by a structure of The remaining ingredients and amounts are the same as those in Example 1.
[0062] Example 10
[0063] A method for synthesizing condensed ring pyridine compounds by cycloaddition of alkyne-nitrile compounds, the difference between this embodiment and embodiment 1 is that the mass of the [2-(phenylethynyl)phenyl]acetonitrile is replaced by a structure of The remaining ingredients and amounts are the same as those in Example 1.
[0064] Embodiment 11
[0065] A method for synthesizing condensed ring pyridine compounds by cycloaddition of alkyne-nitrile compounds, the difference between this embodiment and embodiment 1 is that the mass of the [2-(phenylethynyl)phenyl]acetonitrile is replaced by a structure of The remaining ingredients and amounts are the same as those in Example 1.
[0066] Example 12
[0067] A method for synthesizing condensed ring pyridine compounds by cycloaddition of alkyne-nitrile compounds, the difference between this embodiment and embodiment 1 is that the mass of the [2-(phenylethynyl)phenyl]acetonitrile is replaced by a structure of The remaining ingredients and amounts are the same as those in Example 1.
[0068] Example 13
[0069] A method for synthesizing condensed ring pyridine compounds by cycloaddition of alkyne-nitrile compounds, the difference between this embodiment and embodiment 1 is that the mass of the [2-(phenylethynyl)phenyl]acetonitrile is replaced by a structure of The remaining ingredients and amounts are the same as those in Example 1.
[0070] Embodiment 14
[0071] A method for synthesizing condensed ring pyridine compounds by cycloaddition of alkyne-nitrile compounds, the difference between this embodiment and embodiment 1 is that the mass of the [2-(phenylethynyl)phenyl]acetonitrile is replaced by a structure of The remaining ingredients and amounts are the same as those in Example 1.
[0072] Embodiment 15
[0073] A method for synthesizing condensed ring pyridine compounds by cycloaddition of alkyne-nitrile compounds, the difference between this embodiment and embodiment 1 is that the mass of the [2-(phenylethynyl)phenyl]acetonitrile is replaced by a structure of The remaining ingredients and amounts are the same as those in Example 1.
[0074] Example 16
[0075] A method for synthesizing condensed ring pyridine compounds by cycloaddition of alkyne-nitrile compounds, the difference between this embodiment and embodiment 1 is that the mass of the [2-(phenylethynyl)phenyl]acetonitrile is replaced by a structure of The remaining ingredients and amounts are the same as those in Example 1.
[0076] Embodiment 17
[0077] A method for synthesizing condensed ring pyridine compounds by cycloaddition of alkyne-nitrile compounds, the difference between this embodiment and embodiment 1 is that the mass of the [2-(phenylethynyl)phenyl]acetonitrile is replaced by a structure of The remaining ingredients and amounts are the same as those in Example 1.
[0078] Embodiment 18
[0079] A method for synthesizing condensed ring pyridine compounds by cycloaddition of alkyne-nitrile compounds, the difference between this embodiment and embodiment 1 is that the mass of the [2-(phenylethynyl)phenyl]acetonitrile is replaced by a structure of The remaining ingredients and amounts are the same as those in Example 1.
[0080] Embodiment 19
[0081] A method for synthesizing condensed ring pyridine compounds by cycloaddition of alkyne-nitrile compounds, the difference between this embodiment and embodiment 1 is that the mass of the [2-(phenylethynyl)phenyl]acetonitrile is replaced by a structure of The remaining ingredients and amounts are the same as those in Example 1.
[0082] Embodiment 20
[0083] A method for synthesizing condensed ring pyridine compounds by cycloaddition of alkyne-nitrile compounds, the difference between this embodiment and embodiment 1 is that the mass of the [2-(phenylethynyl)phenyl]acetonitrile is replaced by a structure of The remaining ingredients and amounts are the same as those in Example 1.
[0084] Embodiment 21
[0085] A method for synthesizing condensed ring pyridine compounds by cycloaddition of alkyne-nitrile compounds, the difference between this embodiment and embodiment 1 is that the mass of the [2-(phenylethynyl)phenyl]acetonitrile is replaced by a structure of The remaining ingredients and amounts are the same as those in Example 1.
[0086] Embodiment 22
[0087] A method for synthesizing fused-ring pyridine compounds by cycloaddition of alkyne-nitrile compounds. The difference between this embodiment and embodiment 1 is that the mass of the nickel acetylacetonate is replaced by bis(triphenylphosphine)nickel dichloride, and the remaining components and amounts are the same as those in embodiment 1.
[0088] Embodiment 23
[0089] A method for synthesizing fused-ring pyridine compounds by cycloaddition of alkyne-nitrile compounds. The difference between this embodiment and embodiment 1 is that the mass of the nickel acetylacetonate is replaced by di(tricyclohexylphosphine)nickel dichloride, and the remaining components and amounts are the same as those in embodiment 1.
[0090] Embodiment 24
[0091] A method for synthesizing fused-ring pyridine compounds by cycloaddition of alkyne-nitrile compounds. The difference between this embodiment and embodiment 1 is that the mass of the nickel acetylacetonate is replaced by nickel tetrafluoroborate hexahydrate, and the remaining components and amounts are the same as those in embodiment 1.
[0092] Embodiment 25
[0093] A method for synthesizing fused-ring pyridine compounds by cycloaddition of alkyne-nitrile compounds. The difference between this embodiment and embodiment 1 is that the mass of nickel acetylacetonate is replaced by nickel acetate tetrahydrate, and the remaining components and amounts are the same as those in embodiment 1.
[0094] Embodiment 26
[0095] A method for synthesizing fused-ring pyridine compounds by cycloaddition of alkyne-nitrile compounds. The difference between this embodiment and embodiment 1 is that the mass of the nickel acetylacetonate is replaced by nickel iodide, and the remaining components and amounts are the same as those in embodiment 1.
[0096] Embodiment 27
[0097] A method for synthesizing condensed-ring pyridine compounds by cycloaddition of alkyne-nitrile compounds. The difference between this embodiment and embodiment 1 is that the mass of nickel acetylacetonate is replaced by nickel chloride hexahydrate, and the remaining components and amounts are the same as those in embodiment 1.
[0098] Embodiment 28
[0099] A method for synthesizing fused-ring pyridine compounds by cycloaddition of alkyne-nitrile compounds. The difference between this embodiment and embodiment 1 is that the mass of the nickel acetylacetonate is replaced by bis(1,5-cyclooctadiene)nickel, and the remaining components and amounts are the same as those in embodiment 1.
[0100] Embodiment 29
[0101] A method for synthesizing fused-ring pyridine compounds by cycloaddition of alkyne-nitrile compounds. The difference between this embodiment and embodiment 1 is that the mass of tricyclohexylphosphine tetrafluoroborate is replaced by tri-n-butylphosphine tetrafluoroborate, and the remaining components and amounts are the same as those in embodiment 1.
[0102] Embodiment 30
[0103] A method for synthesizing fused-ring pyridine compounds by cycloaddition of alkyne-nitrile compounds. The difference between this embodiment and embodiment 1 is that the mass of the tricyclohexylphosphine tetrafluoroborate is replaced by tri-tert-butylphosphine tetrafluoroborate, and the remaining components and amounts are the same as those in embodiment 1.
[0104] Embodiment 31
[0105] A method for synthesizing condensed ring pyridine compounds by cycloaddition of alkyne-nitrile compounds. The difference between this embodiment and embodiment 1 is that the mass of the tricyclohexylphosphine tetrafluoroborate is replaced by triisopropylphosphine tetrafluoroborate, and the remaining components and amounts are the same as those in embodiment 1.
[0106] Embodiment 32
[0107] A method for synthesizing condensed ring pyridine compounds by cycloaddition of alkyne-nitrile compounds. The difference between this embodiment and embodiment 1 is that the mass of the tetrafluoroborate tricyclohexylphosphine is replaced by di-tert-butyl (methyl)phosphine tetrafluoroborate, and the remaining components and amounts are the same as those in embodiment 1.
[0108] Embodiment 33
[0109] A method for synthesizing fused-ring pyridine compounds by cycloaddition of alkyne-nitrile compounds. The difference between this embodiment and embodiment 1 is that the amount of nickel acetylacetonate is adjusted to 0.03 mmol, the amount of tricyclohexylphosphine tetrafluoroborate is adjusted to 0.01 mmol, and the remaining components and amounts are the same as those in embodiment 1.
[0110] Embodiment 34
[0111] A method for synthesizing fused-ring pyridine compounds by cycloaddition of alkyne-nitrile compounds. The difference between this embodiment and embodiment 1 is that the amount of nickel acetylacetonate is adjusted to 0.03 mmol, the amount of tricyclohexylphosphine tetrafluoroborate is adjusted to 0.03 mmol, and the remaining components and amounts are the same as those in embodiment 1.
[0112] The present invention uses alkyne-nitrile compounds as substrates, and uses biboronic acid pinacol ester (B2pin2) as a reducing agent under a nickel catalyst and a phosphine ligand catalytic system to perform a [2+2+2] cycloaddition reaction. In the above embodiments, the difference between Embodiment 1 and Embodiments 22-28 is that different nickel catalysts are used, and their effects on product yields are shown in Table 1.
[0113] Table 1 Effect of different nickel catalysts on product yield
[0114]
[0115] As can be seen from the results in Table 1, Examples 1 and Examples 22-28 use different nickel catalysts, including nickel acetylacetonate, bis(triphenylphosphine)nickel dichloride, bis(tricyclohexylphosphine)nickel dichloride, nickel tetrafluoroborate hexahydrate, nickel acetate tetrahydrate, nickel iodide, nickel chloride hexahydrate, and bis(1,5-cyclooctadiene)nickel. We found that the reaction yield was the best (yield 80%) when nickel acetylacetonate was used as the nickel catalyst.
[0116] In the above examples, the difference between Example 1 and Examples 29-32 is that different phosphine ligands are used, and their effects on the product yield are shown in Table 2.
[0117] Table 2 Effect of different phosphine ligands on product yield
[0118]
[0119] As can be seen from the results in Table 2, Examples 1 and 29-32 use different phosphine ligands, including tricyclohexylphosphine tetrafluoroborate, tri-n-butylphosphine tetrafluoroborate, tri-tert-butylphosphine tetrafluoroborate, triisopropylphosphine tetrafluoroborate, and di-tert-butyl(methyl)phosphine tetrafluoroborate. We found that the reaction yield is best when tricyclohexylphosphine tetrafluoroborate is used as the phosphine ligand (yield 80%).
[0120] In the above examples, Examples 1-21 explored the applicability of substrates for the [2+2+2] cycloaddition method of different alkyne-nitrile compounds, and conducted a confirmatory exploration of the above-mentioned optimization conditions. The results are shown in Table 3.
[0121] Table 3 Investigation of the suitability of reaction substrates
[0122]
[0123]
[0124]
[0125]
[0126] It can be seen from the results in Table 3 that Examples 1-21 of the present invention use alkyne-nitrile compounds Ia-Iz as substrates, and carry out self-molecular [2+2+2] cycloaddition reaction under the catalytic system of the optimal nickel catalyst and phosphine ligand to generate fused-ring pyridine compounds in high yield (yield 42-80%).
[0127] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above and that the present invention can be implemented in other specific forms without departing from the spirit or essential features of the present invention. Therefore, the embodiments should be considered exemplary and non-restrictive in all respects, and the scope of the present invention is defined by the appended claims rather than the above description, and it is intended that all changes falling within the meaning and scope of the equivalent elements of the claims be included in the present invention.
[0128] In addition, it should be understood that although the present specification is described according to implementation modes, not every implementation mode contains only one independent technical solution. This description of the specification is only for the sake of clarity. Those skilled in the art should regard the specification as a whole. The technical solutions in each embodiment may also be appropriately combined to form other implementation modes that can be understood by those skilled in the art.
Claims
1. A method for synthesizing fused-ring pyridine compounds by cycloaddition of alkyne-nitrile compounds, characterized in that: The steps include: The alkyne-nitrile compound, pinacol diboronate, nickel catalyst, phosphine ligand, organic solvent and inorganic solvent are mixed, heated to react under the protection of inert gas, and after the reaction is completed, quenched, purified, washed and dried to obtain a condensed ring pyridine compound; The chemical structural formula of the alkyne-nitrile compound is shown in Formula I, and the chemical structural formula of the fused-ring pyridine compound is shown in Formula II: in, R 1 and R 2 Each of them is independently selected from one or more of hydrogen, C1-C6 alkyl, methoxy, halogen, nitro, cyano, trifluoromethyl, ester, silyl ether, thiophene or C6-C14 aryl.
2. The method for synthesizing fused-ring pyridine compounds by cycloaddition of alkyne-nitrile compounds according to claim 1, characterized in that: The molar ratio of the alkyne-nitrile compound, the biboric acid pinacol ester, the nickel catalyst and the phosphine ligand is 0.2:(0.24-0.4):(0.01-0.03):(0.01-0.04).
3. The method for synthesizing fused-ring pyridine compounds by cycloaddition of alkyne-nitrile compounds according to claim 1, characterized in that: The alkyne-nitrile compound is selected from one or more of the following compounds:
4. The method for synthesizing fused-ring pyridine compounds by cycloaddition of alkyne-nitrile compounds according to claim 1, characterized in that: The nickel catalyst is selected from one or more of nickel acetylacetonate, bis(triphenylphosphine)nickel dichloride, bis(tricyclohexylphosphine)nickel dichloride, nickel tetrafluoroborate hexahydrate, nickel acetate tetrahydrate, nickel iodide, nickel chloride hexahydrate or bis(1,5-cyclooctadiene)nickel.
5. The method for synthesizing fused-ring pyridine compounds by cycloaddition of alkyne-nitrile compounds according to claim 1, characterized in that: The phosphine ligand is selected from one or more of tri-n-butylphosphine tetrafluoroborate, tri-tert-butylphosphine tetrafluoroborate, triisopropylphosphine tetrafluoroborate, di-tert-butyl(methyl)phosphine tetrafluoroborate or tricyclohexylphosphine tetrafluoroborate.
6. The method for synthesizing condensed-ring pyridine compounds by cycloaddition of alkyne-nitrile compounds according to claim 1, characterized in that: The organic solvent is selected from one or more of cyclohexane, toluene, trifluorotoluene, acetonitrile, methanol, ethanol, isopropanol or tert-butanol.
7. The method for synthesizing fused-ring pyridine compounds by cycloaddition of alkyne-nitrile compounds according to claim 1, characterized in that: The inorganic solvent is water.
8. The method for synthesizing fused-ring pyridine compounds by cycloaddition of alkyne-nitrile compounds according to claim 1, characterized in that: The heating temperature is 90-150° C., and the reaction time is 6-18 hours.
9. The method for synthesizing fused-ring pyridine compounds by cycloaddition of alkyne-nitrile compounds according to claim 1, characterized in that: The inert gas is selected from one or more of nitrogen, argon or helium.