Method for directly preparing alkynylation coupling product from azacyclo-olefin

Abstract

The invention belongs to the technical field of organic synthesis, and discloses a method for directly preparing an alkynylation coupling product from azacyclo-olefin, which comprises the following steps of: reacting azacyclo-olefin as shown in a formula I and alkynyl bromide as shown in a formula II in an organic solvent under the action of alkali and a proton source by taking the azacyclo-olefin as shown in a formula I and the alkynyl bromide as shown in a formula II as substrates and a bivalent nickel salt as a catalyst to obtain the alkynylation coupling product. The alkynylation coupling product as shown in the formula III is obtained. According to the method, the variety of alkynyl-containing heterocyclic compounds is widened, the reaction conditions are mild, the raw materials are low in price, industrial production is easy to realize, and the product has a certain application prospect in the aspect of pesticides.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of organic synthesis, and relates to a method for directly preparing an alkyne coupling product from a nitrogen-containing heterocyclic olefin. BACKGROUND

[0002] Nitrogen-containing heterocyclic compounds are widely present in biologically active molecules and drug molecules, and the carbon-carbon triple bond in the alkyne can be converted through various functional groups, thereby having certain effects in drug chemistry, natural product total synthesis and organic materials. By coupling the nitrogen-containing heterocyclic compound with alkyne bromide and utilizing the conversion of the functional groups, a series of biologically active compounds can be synthesized, and the biologically active molecules can be further modified. For example, fenchone is the first antibiotic that can treat human diseases; naproxen is a non-steroidal anti-inflammatory drug, which has anti-inflammatory, antipyretic and analgesic effects, and the active molecules of this type of drug can be further modified.

[0003]

[0004] At present, the alkyne coupling product can be synthesized by the following methods:

[0005] (1) coupling reaction of organic halide and terminal alkyne: Sonogashira coupling is a very classic reaction, which adopts aryl or alkenyl halide and terminal alkyne to be coupled under the catalysis of Pd / Cu, and the reaction generally has a high yield, and has good compatibility for many sensitive functional groups (such as ester, amide, halogen, nitro, etc.), and is suitable for the synthesis of complex molecules (such as drugs, natural products). However, the reaction depends on the noble metal palladium as a catalyst, resulting in high reaction cost, and the traditional method needs copper salt (such as cuprous iodide) as a co-catalyst, the by-product may bring about a treatment problem, and may cause a side reaction, such as the coupling of alkyne itself (reference: Kenkichi Sonogashira, Yasuo Tohda, Nobue Hagihara. A convenient synthesis of acetylenes: catalytic substitutions of acetylenic hydrogen with bromoalkenes, iodoarenes and bromopyridines. [J] Tetrahedron Lett. 1975, 16, 4467).

[0006] (2) Alkane C-H bond coupling with alkynyl bromide: In 2011, Naoto Chatani's group reported the Pd-catalyzed coupling reaction of aliphatic carboxylic acid with alkynyl bromide, and the functional group tolerance and applicability to natural product-based substrates have been proved, but this reaction also uses precious metal Pd as catalyst, which increases the reaction cost and is not conducive to large-scale production (reference: Yusuke Ano, Mamoru Tobisu, Naoto Chatani. Palladium-Catalyzed Direct Ethynylation of C(sp3)-H Bonds in Aliphatic Carboxylic Acid Derivatives. [J] J. Am. Chem. Soc. 2011, 133, 12984).

[0007] (3) Olefin C-H bond coupling with alkynyl bromide: In 2021, Shaolin Zhu's group reported the Ni-catalyzed hydroalkynylation reaction of olefins with alkynyl bromide, which obtained the corresponding alkynylated product with high yield and excellent regioselectivity, but there is no much proof for heterocyclic compounds (reference: Xiaoli Jiang, Bo Han, Yuhang Xue, Mei Duan, Zhuofan Gui, You Wang, Shaolin Zhu. Nickel-catalysed migratory hydroalkynylation and enantioselective hydroalkynylation of olefins with bromoalkynes. [J] Nat. Commun. 2021, 12, 3792).

[0008] In summary, different synthesis methods can be used for different substrates, and different directing groups can be used for induction, and the method using nitrogen heterocycle as directing group has not been mentioned, and nitrogen-containing heterocyclic compounds often have certain biological activity, therefore, it is of great significance to develop a synthesis method of alkynylated product with low cost and nitrogen-containing heterocyclic compound. SUMMARY

[0009] The present application aims at the technical problems existing in the synthesis of alkynylated product, and provides a method for directly preparing alkynylated coupling product from nitrogen heterocyclic olefin, which uses nitrogen heterocyclic olefin as directing group and divalent nickel as catalyst to prepare alkynylated coupling product, thereby widening the types of alkynyl-containing heterocyclic compounds, the reaction conditions are mild, the raw material price is low, and the industrial production is easy to realize, and the product has certain application prospect in pesticides.

[0010] To achieve the above object, the present application adopts the following technical solutions:

[0011] The present application provides a method for directly preparing alkynyl coupling products from azacycloalkenes, comprising the following steps: taking azacycloalkenes shown in formula I and alkynyl bromide shown in formula II as substrates, taking divalent nickel salt as catalyst, reacting in organic solvent under the action of base and proton source to obtain alkynyl coupling products shown in formula III; the specific synthesis route is as follows:

[0012]

[0013] Wherein: R1 is selected from one of indazolyl, pyridyl, pyrazolyl, pyrazinyl, isochinolyl; R2 is selected from triisopropylsilyl, phenyl, substituted phenyl, five-membered heterocyclic group, and the substituent on the substituted phenyl is selected from methoxy, trifluoromethyl or halogen.

[0014] In the above technical solution, R1 is selected from one of R2 is selected from triisopropylsilyl, cyclopropane, 1-chlorobutane.

[0015] In the above technical solution, the divalent nickel salt is selected from one of nickel (II) chloride glycol dimethyl ether complex, nickel (II) p-toluenesulfonic acid hexahydrate, acetylacetone nickel (II), nickel (II) tetrafluoroborate hexahydrate.

[0016] In the above technical solution, the base is selected from one of sodium fluoride, lithium carbonate, sodium phosphate or sodium methoxide.

[0017] In the above technical solution, the proton source is selected from one of diethoxymethylsilane, diphenylmethylsilane or triphenylsilane.

[0018] In the above technical solution, the organic solvent is selected from one of N, N-dimethylacetamide, N, N-dimethylformamide, dimethyl sulfoxide or N-methyl pyrrolidone.

[0019] In the above technical solution, the molar ratio of the azacycloalkene shown in formula I and the alkynyl bromide shown in formula II is 1:1-5.

[0020] In the above technical solution, the molar amount of the divalent nickel salt is 2-30% of the molar amount of the azacycloalkene shown in formula I.

[0021] In the technical solution, the molar ratio of the base to the azacycloalkene of formula I is 1-5:1, the molar ratio of the proton source to the azacycloalkene of formula I is 1-5:1, and the ratio of the amount of the organic solvent to the azacycloalkene of formula I is 5-20 mL:1 mmol.

[0022] In the technical solution, the reaction temperature is 80-120 DEG C, and the reaction time is 10-24 h.

[0023] Compared with the prior art, the present application has the following beneficial effects:

[0024] The present application uses azacycloalkene as a guiding group, and adopts divalent nickel to catalyze azacycloalkene and alkynyl bromide to couple and synthesize azacycloalkynyl compound, which widens the types of alkynyl-containing heterocyclic compounds, has mild reaction conditions, avoids the use of noble metal, has low raw material price, is easy to realize industrialized production, and can inhibit cucumber downy mildew, and has certain application prospect in pesticides. DETAILED DESCRIPTION

[0025] The following examples are used to illustrate the present application, but are not used to limit the protection scope of the present application. If not specifically indicated, the technical means used in the examples is the conventional means known by those skilled in the art. The test method in the following examples is the conventional method, unless otherwise specified.

[0026] In the reaction equation of the following examples, 1 represents azacycloalkene, 2 represents alkynyl bromide, and 3 represents the coupling product.

[0027] The azacycloalkene substrate 1 and the alkynyl bromide 2 used in the following examples can be prepared according to the following methods: (1) Hua-Dong He, Ravi Chitrakar, Zhi-Wei Cao, Dao-Ming Wang, Li-Qin She, Peng-Gang Zhao, Yichen Wu, Yuan-Qing Xu, Zhong-Yan Cao, and Peng Wang, Diphosphine Ligand-Enabled Nickel-Catalyzed Chelate-Assisted Inner-Selective Migratory Hydroarylation of Alkenes. [J]. Angew. Chem. Int. Ed. 2024, 63, e202313336; (2) Yiqiang Tian, Yi Li, and Chun Zhang. Visible Light Catalyzed Reductive Cross-Coupling of a-CF3-alkyl Bromide and Alkynyl Bromide. [J]. Chin. J. Chem. 2024, 42, 2479.

[0028] Example 1 Synthesis of 1-(3-methyl-5-(triisopropylsilyl)pent-4-yn-1-yl)-1H-indazole

[0029]

[0030] In an argon-filled glove box, 25 mL Schlenk reaction tube was charged with nickel chloride ethylene glycol dimethyl ether complex (10 mol%, 0.02 mmol), 1-(but-3-en-1-yl)-1H-indazole 1a (1.0 equivalent, 0.2 mmol), sodium fluoride (1.5 equivalents, 0.3 mmol), (bromoethynyl)triisopropylsilane 2a (1.5 equivalents, 0.3 mmol), N,N-dimethylacetamide (1 mL), diethoxymethylsilane (1.5 equivalents, 0.3 mmol). The resulting solution was stirred at 100 °C for 12 h. After the reaction was detected by TLC, extraction was carried out with ethyl acetate, dried with anhydrous sodium sulfate, and the organic phase was rotary evaporated. The crude mixture was purified by silica gel column chromatography using petroleum ether: ethyl acetate (50:1) as eluent to obtain the product 1-(3-methyl-5-(triisopropylsilyl)pent-4-yn-1-yl)-1H-indazole 3a 54.5 mg, yield 77% as a light yellow oily liquid.

[0031] The proton nuclear magnetic resonance data of the product 1-(3-methyl-5- (trisopropylsilyl)pent-4-yn-1-yl)-1H-indazole is as follows: 1 H NMR (400 MHz, CDC13) δ 8.00 (s, 1H), 7.72 (d, J = 8.1 Hz, 1H), 7.56 (d, J = 8.5 Hz, 1H), 7.40 - 7.31 (m, 1H), 7.18 - 7.10 (m, 1H), 4.63 - 4.52 (m, 2H), 2.49 - 2.38 (m, 1H), 2.20 - 2.10 (m, 1H), 2.00 - 1.89 (m, 1H), 1.21 (d, J = 7.0 Hz, 3H), 1.18 - 1.01 (m, 21H); 13 C NMR (101 MHz, CDC13) δ

[0032] 139.7, 133.1, 126.0, 123.8, 120.9, 120.4, 112.4, 109.2, 81.2, 46.9, 37.1, 24.8, 21.3, 18.7, 11.3; HRMS (EI) m / z Calcd for C 22 H 35 N2Si[M + H] + : 355.2564, found: 355.2556.

[0033] Example 2 Synthesis of 2-(3-methyl-5-(trisopropylsilyl)pent-4-yn-1-yl)pyridine

[0034]

[0035] In an argon-filled glove box, a 25 mL Schlenk tube was charged with nickel acetylacetonate (10 mol%, 0.02 mmol), 2-(but-3-en-1-yl)pyridine 1b (1.0 equiv, 0.2 mmol), sodium phosphate (1.5 equiv, 0.3 mmol), (bromoethynyl)trisopropylsilane 2a (1.5 equiv, 0.3 mmol), N,N-dimethylacetamide (1 mL), diethoxymethylsilane (1.5 equiv, 0.3 mmol). The resulting solution was stirred at 100 °C for 12 h. After the reaction was detected by TLC, extraction was carried out with ethyl acetate, dried over anhydrous sodium sulfate, and the organic phase was rotary evaporated, the crude mixture was purified by silica gel column chromatography using petroleum ether: ethyl acetate (5:1) as eluent to give the product 2-(3-methyl-5-(trisopropylsilyl)pent-4-yn-1-yl)pyridine 3b 33.5 mg, 53% yield.

[0036] The nuclear magnetic hydrogen spectrum data of the product 2-(3-methyl-5- (trisopropylsilyl)pent-4-yn-1-yl)pyridine is as follows: 1 H NMR (400 MHz, CDC13) δ 8.53 (d, J = 4.6 Hz, 1H), 7.63 - 7.53 (m, 1H), 7.17 (d, J = 7.8 Hz, 1H), 7.13 - 7.05 (m, 1H), 3.07 - 2.86 (m, 2H), 2.55 - 2.42 (m, 1H), 1.99 - 1.75 (m, 2H), 1.22 (d, J = 6.8 Hz, 3H), 1.15 - 0.96 (m, 21H); 13 C NMR (101 MHz, CDC13) δ 161.8, 149.2, 136.4, 123.1, 121.0, 113.3, 80.4, 36.9, 36.1, 26.7, 21.3, 18.7, 11.3; HRMS (EI) m / z Calcd for C 20 H 34 NSi[M+H] + : 316.2455, found: 316.2450.

[0037] Example 3 Synthesis of 1-(3-methyl-5-(trisopropylsilyl)pent-4-yn-1-yl)-1H- pyrazole

[0038]

[0039] In an argon-filled glove box, a 25 mL Schlenk tube was charged with nickel acetylacetonate (10 mol%, 0.02 mmol), 1-(but-3-en-1-yl)-1H-pyrazole 1c (1.0 equiv, 0.2 mmol), sodium phosphate (1.5 equiv, 0.3 mmol), (bromoethynyl)trisopropylsilane 2a (1.5 equiv, 0.3 mmol), N,N-dimethylacetamide (1 mL), diethoxymethylsilane (1.5 equiv, 0.3 mmol). The resulting solution was stirred at 100 °C for 12 h. After the reaction was detected by TLC, extraction was carried out with ethyl acetate, dried with anhydrous sodium sulfate, and the organic phase was rotary evaporated, and the crude mixture was purified by silica gel column chromatography using petroleum ether: ethyl acetate (5:1) as eluent to obtain the product 1-(3-methyl-5-(trisopropylsilyl)pent-4-yn-1-yl)-1H-pyrazole 3c 56.5 mg, yield 93% as a light yellow oily liquid.

[0040] The nuclear magnetic hydrogen spectrum data of the product 1-(3-methyl-5- (trisopropylsilyl)pent-4-yn-1-yl)-1H-pyrazole is as follows: 1H NMR (400 MHz, CDC13) δ 7.51 (s, 1H), 7.41 (d, J = 2.3 Hz, 1H), 6.22 (s, 1H), 4.42 - 4.21 (m, 2H), 2.40 - 2.28 (m, 1H), 2.17 - 2.05 (m, 1H), 1.88 - 1.77 (m, 1H), 1.19 (d, J = 6.9 Hz, 3H), 1.16 - 0.95 (m, 21H); 13 C NMR (101 MHz, CDC13) δ 139.4, 129.5, 111.8, 105.0, 81.4, 50.1, 37.2, 24.4, 21.2, 18.6, 11.2; HRMS (EI) m / z Calcd for C 18 H 33 N2Si[M + H] + : 305.2408, found: 305.2401.

[0041] Example 4 Synthesis of 3,5-dimethyl-l-(3-methyl-5-(triisopropylsilyl)pent-4-yn-l- yl)-lH-pyrazole

[0042]

[0043] In an argon-filled glove box, a 25 mL Schlenk tube was charged with nickel acetylacetonate (10 mol%, 0.02 mmol), 1-(but-3-en-l-yl)-3,5-dimethyl-lH-pyrazole Id (1.0 equiv, 0.2 mmol), sodium phosphate (1.5 equiv, 0.3 mmol), (bromoethynyl)triisopropylsilane 2a (1.5 equiv, 0.3 mmol), N,N-dimethylacetamide (1 mL), diethoxymethylsilane (1.5 equiv, 0.3 mmol). The resulting solution was stirred at 100 °C for 12 h. After the reaction was detected by TLC, extraction was carried out with ethyl acetate, dried over anhydrous sodium sulfate, and the organic phase was rotary evaporated, the crude mixture was purified by silica gel column chromatography using petroleum ether: ethyl acetate (5: 1) as eluent to give the product 3,5-dimethyl-l-(3-methyl-5-(triisopropylsilyl)pent-4-yn-l-yl)-lH-pyrazole 3d 37.2 mg, yield 56% as a light yellow oily liquid.

[0044] The nuclear magnetic hydrogen spectrum data of the product 3,5-dimethyl-l-(3-methyl-5- (triisopropylsilyl)pent-4-yn-l-yl)-lH-pyrazole are as follows: 1H NMR (400 MHz, CDC13) δ 5.72 (s, 1H), 4.08 - 3.88 (m, 2H), 3.13 - 2.90 (m, 1H), 2.22 (d, J = 25.5 Hz, 6H), 1.57 - 1.32 (m, 2H), 1.13 - 0.89 (m, 24H); 13 C NMR (101 MHz, CDC13) δ 147.5, 139.3, 108.6, 104.6, 83.0, 52.0, 36.1, 25.4, 18.5, 18.5, 13.5, 11.5, 11.3, 11.2; HRMS (EI) m / z Calcd for C 20 H 37 N2Si[M + H] + : 333.2721, found: 333.2716.

[0045] Example 5 Synthesis of 2-(3-methyl-5-(triisopropylsilyl)pent-4-yn-1-yl)pyrazine

[0046]

[0047] In an argon-filled glove box, a 25 mL Schlenk tube was charged with nickel p-toluenesulfonate hexahydrate (10 mol%, 0.02 mmol), 2-(but-3-en-1-yl)pyrazine 1e (1.0 equiv, 0.2 mmol), sodium fluoride (1.5 equiv, 0.3 mmol), (bromoethynyl)triisopropylsilane 2a (1.5 equiv, 0.3 mmol), N,N-dimethylacetamide (1 mL), diethoxymethylsilane (1.5 equiv, 0.3 mmol). The resulting solution was stirred at 100 °C for 12 h. After the end of the reaction, which was detected by TLC, extraction was performed with ethyl acetate, drying with anhydrous sodium sulfate, and the organic phase was evaporated, the crude mixture was purified by column chromatography on silica gel using petroleum ether: ethyl acetate (5:1) as eluent, obtaining the product 2-(3-methyl-5-(triisopropylsilyl)pent-4-yn-1-yl)pyrazine 3e 34.2 mg, yield 54% as a light yellow oily liquid.

[0048] The nuclear magnetic hydrogen spectrum data of the product 2-(3-methyl-5-(triisopropylsilyl)pent-4-yn-1-yl)pyrazine are as follows: 1H NMR (400 MHz, CDC13) δ 8.52 - 8.43 (m, 2H), 8.39 (d, J = 1.7 Hz, 1H), 3.10 - 2.89 (m, 2H), 2.58 - 2.42 (m, 1H), 2.00 - 1.88 (m, 1H), 1.87 - 1.75 (m, 1H), 1.22 (d, J = 6.9 Hz, 3H), 1.13 - 0.99 (m, 21H); 13 CNMR (101 MHz, CDC13) δ 157.4, 144.7, 144.1, 142.2, 112.6, 80.9, 36.3, 33.2, 26.6, 21.3, 18.6, 11.2; HRMS (EI) m / z Calcd for C 19 H 33 N2Si[M+H] + : 317.2408, found: 317.2401.

[0049] Example 6 Synthesis of 2-(3-methyl-5-(triisopropylsilyl)pent-4-yn-1-yl)pyrimidine

[0050]

[0051] In an argon-filled glove box, a 25 mL Schlenk tube was charged with nickel p-toluenesulfonate hexahydrate (10 mol%, 0.02 mmol), 2-(but-3-en-1-yl)pyrimidine 1f (1.0 equiv, 0.2 mmol), sodium fluoride (1.5 equiv, 0.3 mmol), (bromoethynyl)triisopropylsilane 2a (1.5 equiv, 0.3 mmol), N,N-dimethylformamide (1 mL), diethoxymethylsilane (1.5 equiv, 0.3 mmol). The resulting solution was stirred at 100 °C for 12 h. After the end of the reaction, which was checked by TLC, extraction was performed with ethyl acetate, drying with anhydrous sodium sulfate and, after the organic phase was evaporated, the crude mixture was purified by column chromatography on silica gel using petroleum ether: ethyl acetate (5:1) as eluent, obtaining the product 2-(3-methyl-5-(triisopropylsilyl)pent-4-yn-1-yl)pyrimidine 3f 34.2 mg, yield 54% as a light yellow oily liquid.

[0052] The nuclear magnetic hydrogen spectrum data of the product 2-(3-methyl-5-(triisopropylsilyl)pent-4-yn-1-yl)pyrimidine are as follows: 1H NMR (400 MHz, CDC13) δ 8.65 (d, J = 4.9 Hz, 2H), 7.10 (t, J = 4.9 Hz, 1H), 3.24 - 3.13 (m, 1H), 3.12 - 3.02 (m, 1H), 2.69 - 2.51 (m, 1H), 2.03 - 1.93 (m, 2H), 1.24 (d, J = 6.9 Hz, 3H), 1.12 - 0.93 (m, 21H); 13 C NMR (101 MHz, CDC13) δ 171.2, 156.9, 118.4, 113.1, 80.3, 37.3, 35.3, 26.8, 21.3, 18.6, 11.2; HRMS (EI) m / z Calcd for C 19 H 33 N2Si[M + H] + : 317.2408, found: 317.2407.

[0053] Example 7 Synthesis of 3-(3-methyl-5-(triisopropylsilyl)pent-4-yn-1-yl)isoquinoline

[0054]

[0055] Into a 25 mL Schlenk tube, in an argon filled glove box, was added nickel chloride ethylene glycol dimethyl ether complex (10 mol%, 0.02 mmol), 3-(but-3-en-1-yl)isoquinoline 1g (1.0 equiv, 0.2 mmol), lithium carbonate (1.5 equiv, 0.3 mmol), (bromoethynyl)triisopropylsilane 2a (1.5 equiv, 0.3 mmol), N,N-dimethylformamide (1 mL), diethoxymethylsilane (1.5 equiv, 0.3 mmol). The resulting solution was stirred at 100 °C for 12 h. After the end of the reaction, which was checked by TLC, extraction was performed with ethyl acetate, drying with anhydrous sodium sulfate and, after the organic phase was evaporated, the crude mixture was purified by column chromatography on silica gel using petroleum ether: ethyl acetate (5:1) as eluent, obtaining the product 3-(3-methyl-5-(triisopropylsilyl)pent-4-yn-1-yl)isoquinoline 3g 52.6 mg, yield 72% as a light yellow oily liquid.

[0056] The nuclear magnetic hydrogen spectrum data of the product 3-(3-methyl-5-(triisopropylsilyl)pent-4-yn-1-yl)isoquinoline are as follows: 1HNMR (400 MHz, CDC13) δ 9.20 (s, 1H), 7.93 (d, J = 8.1 Hz, 1H), 7.74 (d, J = 8.3 Hz, 1H), 7.69 - 7.61 (m, 1H), 7.59 - 7.46 (m, 2H), 3.22 - 3.01 (m, 2H), 2.59 - 2.39 (m, 1H), 2.08 - 1.97 (m, 1H), 1.95 - 1.83 (m, 1H), 1.23 (d, J = 6.9 Hz, 3H), 1.18 - 0.92 (m, 21H); 13 C NMR (101 MHz, CDC13) δ

[0057] 155.0, 152.1, 136.5, 130.3, 127.5, 127.1, 126.4, 126.1, 118.4, 113.4, 80.3, 37.0, 35.9, 26.5, 21.3, 18.7, 11.3; HRMS (EI) m / z Calcd for C 24 H 36 NSi [M+H] + : 366.2612, found: 366.2605.

[0058] Example 8 Synthesis of 1-(3-methyl-5-(triisopropylsilyl)pent-4-yn-1-yl)isoquinoline

[0059]

[0060] Into a 25 mL Schlenk tube, in an argon filled glove box, was added nickel chloride ethylene glycol dimethyl ether complex (10 mol%, 0.02 mmol), 1-(but-3-en-1-yl)isoquinoline 1h (1.0 equiv, 0.2 mmol), lithium carbonate (1.5 equiv, 0.3 mmol), (bromoethynyl)triisopropylsilane 2a (1.5 equiv, 0.3 mmol), N,N-dimethylformamide (1 mL), diethoxymethylsilane (1.5 equiv, 0.3 mmol). The resulting solution was stirred at 100 °C for 12 h. After the reaction was detected by TLC, extraction was carried out with ethyl acetate, dried over anhydrous sodium sulfate, and the organic phase was rotary evaporated, the crude mixture was purified by silica gel column chromatography using petroleum ether: ethyl acetate (5:1) as eluent to give the product 1-(3-methyl-5-(triisopropylsilyl)pent-4-yn-1-yl)isoquinoline 3h 52.6 mg, 72% yield.

[0061] The nuclear magnetic hydrogen spectrum data of the product 1-(3-methyl-5-(triisopropylsilyl)pent-4-yn-1-yl)isoquinoline is as follows: 1HNMR (400 MHz, CDC13) δ 8.43 (d, J = 5.8 Hz, 1H), 8.28 (d, J = 8.5 Hz, 1H), 7.82 (d, J = 8.1 Hz, 1H), 7.70 - 7.64 (m, 1H), 7.60 - 7.54 (m, 1H), 7.51 (d, J = 5.8 Hz, 1H), 3.68 - 3.58 (m, 1H), 3.45 - 3.33 (m, 1H), 2.74 - 2.62 (m, 1H), 2.12 - 1.88 (m, 2H), 1.28 (d, J = 7.0 Hz, 3H), 1.15 - 1.05 (m, 21H); 13 CNMR (101 MHz, CDC13) δ 161.9, 141.9, 136.2, 129.8, 127.3, 127.0, 125.4, 119.2, 113.3, 80.5, 36.6, 33.3, 27.3, 21.4, 18.7, 11.3; HRMS (EI) m / z Calcd for C 24 H 36 NSi[M+H] + :366.2612, found:366.2607.

[0062] Example 9 Synthesis of 4-methoxy-2-(3-methyl-5-(triisopropylsilyl)pent-4-yn-1- yl)pyridine

[0063]

[0064] Into a 25 mL Schlenk tube, which was filled with argon, acetylacetonatonickel (10 mol%, 0.02 mmol), 2-(but-3-en-1-yl)-4-methoxypyridine 1i (1.0 eq, 0.2 mmol), sodium phosphate (1.5 eq, 0.3 mmol), (bromoethynyl)triisopropylsilane 2a (1.5 eq, 0.3 mmol), N,N-dimethylacetamide (1 mL), diethoxymethylsilane (1.5 eq, 0.3 mmol) were sequentially added. The resulting solution was stirred at 100 °C for 12 h. After the reaction was detected by TLC, it was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the organic phase was rotary evaporated. The crude mixture was purified by silica gel column chromatography using petroleum ether: ethyl acetate (5:1) as eluent to give the product 4-methoxy-2-(3-methyl-5-(triisopropylsilyl)pent-4-yn-1-yl)pyridine 3i 39.4 mg, yield 57% as a light yellow oily liquid.

[0065] The product 4-methoxy-2-(3-methyl-5-(triisopropylsilyl)pent-4-yn-1-yl)pyridine has the following nuclear magnetic hydrogen spectrum data:1 H NMR (400 MHz, CDC13) δ 8.34 (d, J = 5.8 Hz, 1H), 6.78 - 6.55 (m, 2H), 3.82 (s, 3H), 3.02 - 2.80 (m, 2H), 2.56 - 2.39 (m, 1H), 1.98 - 1.72 (m, 2H), 1.21 (d, J = 6.9 Hz, 3H), 1.16 - 0.97 (m, 21H); 13 C NMR (101 MHz, CDC13) δ 166.0, 163.5, 150.4, 113.3, 108.7, 107.4, 80.3, 54.9, 36.8, 36.3, 26.6, 21.3, 18.7, 11.3; HRMS (El) m / z Calcd for C 21 H 36 NOSi[M+H] + : 346.2561, found: 346.2558.

[0066] Example 10 Synthesis of 1-(3-methyl-5-(4-methoxyphenyl)pent-4-yn-1-yl)-1H- indazole

[0067]

[0068] In an argon-filled glove box, a 25 mL Schlenk tube was charged with nickel acetylacetonate (10 mol%, 0.02 mmol), 1-(but-3-en-1-yl)-1H-indazole 1a (1.0 equiv, 0.2 mmol), sodium phosphate (1.5 equiv, 0.3 mmol), 1-(bromoethynyl)-4- methoxybenzene 2b (1.5 equiv, 0.3 mmol), N,N-dimethylacetamide (1 mL), diethoxymethylsilane (1.5 equiv, 0.3 mmol). The resulting solution was stirred at 100 °C for 12 h. After the reaction was detected by TLC, extraction was carried out with ethyl acetate, dried over anhydrous sodium sulfate, and the organic phase was rotary evaporated, the crude mixture was purified by silica gel column chromatography using petroleum ether: ethyl acetate (10:1) as eluent to give the product 1-(3-methyl-5-(4-methoxyphenyl)pent-4-yn-1-yl)-1H-indazole 3j 32.3 mg, 53% yield.

[0069] The product 1-(3-methyl-5-(4-methoxyphenyl)pent-4-yn-1-yl)-1H-indazole had the following NMR hydrogen spectrum data: 1H NMR (400 MHz, CDC13) δ 8.02 (s, 1H), 7.73 (d, J = 8.1 Hz, 1H), 7.53 (d, J = 8.6 Hz, 1H), 7.49 - 7.28 (m, 3H), 7.14 (t, J = 7.4 Hz, 1H), 6.86 (d, J = 9.0 Hz, 2H), 4.72 - 4.49 (m, 2H), 3.82 (s, 3H), 2.68 - 2.52 (m, 1H), 2.28 - 2.18 (m, 1H), 2.11 - 2.00 (m, 1H), 1.28 (d, J = 6.9 Hz, 3H); 13 CNMR (101 MHz, CDC13) δ 159.1, 139.6, 133.0, 132.9, 126.1, 123.8, 121.0, 120.4, 115.7, 113.8, 109.2, 91.5, 81.5, 55.2, 46.8, 36.9, 24.2, 21.1; HRMS (EI) m / z Calcd for C 20 H 21 N2O[M+H] + :305.1648, found:305.1651.

[0070] Example 11 Synthesis of 1-(3-methyl-5-(2-methoxyphenyl)pent-4-yn-1-yl)-1H-indazole

[0071]

[0072] Into a 25 mL Schlenk tube, in an argon filled glove box, was added nickel chloride ethylene glycol dimethyl ether complex (10 mol%, 0.02 mmol), 1-(but-3-en-1-yl)-1H-indazole 1a (1.0 eq, 0.2 mmol), sodium phosphate (1.5 eq, 0.3 mmol), 1-(bromoethynyl)-2-methoxybenzene 2c (1.5 eq, 0.3 mmol), N,N-dimethylacetamide (1 mL), diphenylmethylsilane (1.5 eq, 0.3 mmol). The resulting solution was stirred at 100 °C for 12 h. After the end of the reaction, which was checked by TLC, extraction was performed with ethyl acetate, drying with anhydrous sodium sulfate and, after the organic phase was evaporated, the crude mixture was purified by column chromatography on silica gel using petroleum ether: ethyl acetate (10:1) as eluent, obtaining the product 1-(3-methyl-5-(2-methoxyphenyl)pent-4-yn-1-yl)-1H-indazole 3k 49.3 mg, yield 81% as a light yellow oily liquid.

[0073] The nuclear magnetic hydrogen spectrum data of the product 1-(3-methyl-5-(2-methoxyphenyl)pent-4-yn-1-yl)-1H-indazole are as follows:1 H NMR (400 MHz, CDC13) δ 8.02 (s, 1H), 7.77-7.61 (m, 2H), 7.45-7.39 (m, 1H), 7.38-7.27 (m, 2H), 7.16-7.10 (m, 1H), 6.96-6.88 (m, 2H), 4.76-4.61 (m, 2H), 3.91 (s, 3H), 2.73-2.61 (m, 1H), 2.30-2.19 (m, 1H), 2.11-2.00 (m, 1H), 1.30 (d, J = 7.0 Hz, 3H); 13 C NMR (101 MHz, CDC13) δ 160.0, 139.8, 133.5, 133.0, 129.1, 126.1, 123.8, 120.9, 120.4, 112.8, 110.5, 109.4, 97.3, 78.0, 55.7, 46.9, 37.1, 24.6, 21.0; HRMS (El) m / z Calcd for C 20 H 21 N2O[M+H] + : 305.1648, found: 305.1641.

[0074] Example 12 Synthesis of l-(3-methyl-5-(2-trifluoromethylphenyl)pent-4-yn-l-yl)-lH- indazole

[0075]

[0076] Into a 25 mL Schlenk tube, in an argon filled glove box, was added nickel acetylacetonate (10 mol%, 0.02 mmol), 1-(but-3-en-1-yl)-1H-indazole 1a (1.0 eq, 0.2 mmol), sodium methoxide (1.5 eq, 0.3 mmol), 1-(bromoethynyl)-2- trifluoromethoxybenzene 2d (1.5 eq, 0.3 mmol), N,N-dimethylformamide (1 mL), diethoxymethylsilane (1.5 eq, 0.3 mmol). The resulting solution was stirred at 100 °C for 12 h. After the end of the reaction, checked by TLC, the extraction was performed with ethyl acetate, dried over anhydrous sodium sulfate, the organic phase was evaporated and the crude mixture was purified by column chromatography on silica gel using petroleum ether: ethyl acetate (10: 1) as eluent, obtaining the product 1-(3-methyl-5-(2-trifluoromethylphenyl)pent-4-yn-1-yl)-1H-indazole 3l 51.4 mg, yield 75% as a light yellow oil liquid.

[0077] The nuclear magnetic hydrogen spectrum data of the product 1-(3-methyl-5-(2- trifluoromethylphenyl)pent-4-yn-1-yl)-1H-indazole is as follows: 1 HNMR (400 MHz, CDC13) δ 8.02 (s, 1H), 7.73 (d, J = 8.1 Hz, 1H), 7.67 (d, J = 7.8 Hz, 1H), 7.63 - 7.43 (m, 3H), 7.43 - 7.29 (m, 2H), 7.18 - 7.09 (m, 1H), 4.68 - 4.54 (m, 2H), 2.73 - 2.57 (m, 1H), 2.31 - 2.20 (m, 1H), 2.15 - 2.03 (m, 1H), 1.31 (d, J = 6.9 Hz, 3H); 13 C NMR (101 MHz, CDC13) δ

[0078] 139.7, 134.0, 133.1, 131.4 (m, 2 J C-F = 30.1 Hz), 131.3, 127.5, 126.2, 125.7 (m, 3 J C-F = 5.1 Hz), 123.8, 123.7 (m, 1 J C-F = 274.3 Hz), 121.9 (m, 4 J C-F = 2.2 Hz), 120.9, 120.4, 109.1, 99.2, 77.9, 46.7, 36.7, 24.5, 20.7; 19 F NMR (376 MHz, CDC13) δ -62.20; HRMS (El) m / z Calcd for C 20 H 18 N2F3 [M + H] + : 343.1417, found: 343.1411.

[0079] Example 13 Synthesis of 1-(3-methyl-5-(3-bromophenyl)pent-4-yn-1-yl)-1H- indazole

[0080]

[0081] In an argon-filled glove box, a 25 mL Schlenk tube was charged with nickel chloride ethylene glycol dimethyl ether complex (10 mol%, 0.02 mmol), 1-(but-3-en-1-yl)-1H-indazole 1a (1.0 equiv, 0.2 mmol), sodium fluoride (1.5 equiv, 0.3 mmol), 1-bromo-3-(bromoethynyl)benzene 2e (1.5 equiv, 0.3 mmol), dimethylsulfoxide (1 mL), diethoxymethylsilane (1.5 equiv, 0.3 mmol). The resulting solution was stirred at 100 °C for 12 h. After the reaction was detected by TLC, extraction was carried out with ethyl acetate, dried over anhydrous sodium sulfate, and the organic phase was rotary evaporated, the crude mixture was purified by silica gel column chromatography using petroleum ether: ethyl acetate (20: 1) as eluent to give the product 1-(3-methyl-5-(3-bromophenyl)pent-4-yn-1-yl)-1H-indazole 3m 33.2 mg, yield 47% as a light yellow oily liquid.

[0082] The product 1-(3-methyl-5-(3-bromophenyl)pent-4-yn-1-yl)-1H-indazole had the following nuclear magnetic hydrogen spectrum data: 1 HNMR (400 MHz, CDC13) δ 8.02 (s, 1H), 7.73 (d, J = 8.1 Hz, 1H), 7.62 - 7.29 (m, 5H), 7.22 - 7.10 (m, 2H), 4.71 - 4.47 (m, 2H), 2.70 - 2.52 (m, 1H), 2.29 - 2.18 (m, 1H), 2.13 - 2.01 (m, 1H), 1.28 (d, J = 7.0 Hz, 3H); 13 C NMR (101 MHz, CDC13) δ 139.6, 134.4, 133.1, 130.9, 130.1, 129.7, 126.2, 125.6, 123.9, 122.0, 121.1, 120.5, 109.1, 94.6, 80.4, 46.7, 36.7, 24.2, 20.9; HRMS (EI) m / z Calcd for C 19 H 18 N2Br [M+H] + : 353.0648, found: 353.0642.

[0083] Example 14 Synthesis of 1-(3-methyl-5-(thiophen-3-yl)pent-4-yn-1-yl)-1H-indazole

[0084]

[0085] In an argon-filled glove box, a 25 mL Schlenk tube was charged with nickel chloride ethylene glycol dimethyl ether complex (10 mol%, 0.02 mmol), 1-(but-3-en-1-yl)-1H-indazole 1a (1.0 equiv, 0.2 mmol), sodium fluoride (1.5 equiv, 0.3 mmol), 3-(bromoethynyl)thiophene 2f (1.5 equiv, 0.3 mmol), N-methylpyrrolidone (1 mL), diethoxymethylsilane (1.5 equiv, 0.3 mmol). The resulting solution was stirred at 100 °C for 12 h. After the reaction was detected by TLC, extraction was carried out with ethyl acetate, dried over anhydrous sodium sulfate, and the organic phase was rotary evaporated, the crude mixture was purified by silica gel column chromatography using petroleum ether: ethyl acetate (20: 1) as eluent to give the product 1-(3-methyl-5-(thiophen-3-yl)pent-4-yn-1-yl)-1H-indazole 3n 33.6 mg, yield 60% as a light yellow oily liquid.

[0086] The product 1-(3-methyl-5-(thiophen-3-yl)pent-4-yn-1-yl)-1H-indazole had the following nuclear magnetic hydrogen spectrum data: 1 HNMR (400 MHz, CDC13) δ 8.02 (s, 1H), 7.73 (d, J = 8.1 Hz, 1H), 7.52 (d, J = 8.5 Hz, 1H), 7.42 - 7.32 (m, 2H), 7.29 - 7.26 (m, 1H), 7.18 - 7.07 (m, 2H), 4.67 - 4.53 (m, 2H), 2.65 - 2.53 (m, 1H), 2.28 - 2.15 (m, 1H), 2.12 - 1.99 (m, 1H), 1.28 (d, J = 6.9 Hz, 3H); 13 C NMR (101 MHz, CDC13) δ 139.6, 133.1, 130.0, 127.9, 126.1, 125.1, 123.9, 122.6, 121.0, 120.4, 109.1, 92.6, 76.8, 46.8, 36.8, 24.2, 21.0; HRMS (EI) m / z Calcd for C 17 H 17 N2S [M+H] + : 281.1107, found: 281.1100.

[0087] Example 15 Synthesis of 1-(5-cyclopropyl-3-methylpent-4-yn-1-yl)-1H-indazole

[0088]

[0089] In an argon-filled glove box, a 25 mL Schlenk tube was charged with nickel chloride ethylene glycol dimethyl ether complex (10 mol%, 0.02 mmol), 1-(but-3-en-1-yl)-1H-indazole 1a (1.0 equiv, 0.2 mmol), sodium phosphate (1.5 equiv, 0.3 mmol), (bromoethynyl)cyclopropane 2g (1.5 equiv, 0.3 mmol), N-methylpyrrolidone (1 mL), diethoxymethylsilane (1.5 equiv, 0.3 mmol). The resulting solution was stirred at 100 °C for 12 h. After the reaction was detected by TLC, extraction was carried out with ethyl acetate, dried over anhydrous sodium sulfate, and the organic phase was rotary evaporated, the crude mixture was purified by silica gel column chromatography using petroleum ether: ethyl acetate (20: 1) as eluent to give the product 1-(5-cyclopropyl-3-methylpent-4-yn-1-yl)-1H-indazole 3o 32.9 mg, yield 69% as a light yellow oily liquid.

[0090] The product 1-(5-cyclopropyl-3-methylpent-4-yn-1-yl)-1H-indazole had the following nuclear magnetic hydrogen spectrum data: 1 H NMR (400 MHz, CDC13) δ 8.00 (s, 1H), 7.72 (d, J = 8.1 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.43 - 7.33 (m, 1H), 7.14 (t, J = 7.4 Hz, 1H), 4.60 - 4.44 (m, 2H), 2.46 - 2.25 (m, 1H), 2.16 - 2.03 (m, 1H), 1.97 - 1.82 (m, 1H), 1.29 - 1.24 (m, 1H), 1.14 (d, J = 6.9 Hz, 3H), 0.87 - 0.53 (m, 4H); 13 C NMR (101 MHz, CDC13) δ

[0091] 139.6, 132.9, 126.0, 123.8, 121.0, 120.4, 109.1, 84.6, 78.7, 46.9, 37.1, 23.6, 21.4, 8.1, -0.5; HRMS (EI) m / z Calcd for C 16 H 19 N2[M+H] + : 239.1543, found: 239.1535.

[0092] Example 16 Synthesis of 1-(9-chloro-3-methylnon-4-yn-1-yl)-1H-indazole

[0093]

[0094] In an argon-filled glove box, a 25 mL Schlenk tube was charged with nickel chloride ethylene glycol dimethyl ether complex (10 mol%, 0.02 mmol), 1-(but-3-en-1-yl)-1H-indazole 1a (1.0 equiv, 0.2 mmol), sodium methoxide (1.5 equiv, 0.3 mmol), 1-bromo-6-chlorohex-1-yne 2h (1.5 equiv, 0.3 mmol), N,N-dimethylformamide (1 mL), diphenylmethylsilane (1.5 equiv, 0.3 mmol). The resulting solution was stirred at 100 °C for 12 h. After the reaction was detected by TLC, extraction was carried out with ethyl acetate, dried over anhydrous sodium sulfate, and the organic phase was rotary evaporated, the crude mixture was purified by silica gel column chromatography using petroleum ether: ethyl acetate (20: 1) as eluent to give the product 1-(9-chloro-3-methylnon-4-yn-1-yl)-1H-indazole 3p 27.7 mg, yield 48% as a light yellow oily liquid.

[0095] The product 1-(9-chloro-3-methylnon-4-yn-1-yl)-1H-indazole had the following nuclear magnetic hydrogen spectrum data: 1 H NMR (400 MHz, CDC13) δ 8.00 (s, 1H), 7.73 (d, J = 8.1 Hz, 1H), 7.49 (d, J = 8.5 Hz, 1H), 7.43 - 7.34 (m, 1H), 7.19 - 7.09 (m, 1H), 4.62 - 4.44 (m, 2H), 3.66 - 3.50 (m, 2H), 2.42 - 2.32 (m, 1H), 2.31 - 2.22 (m, 2H), 2.15 - 2.05 (m, 1H), 1.98 - 1.85 (m, 3H), 1.86 - 1.47 (m, 3H), 1.17 (d, J = 6.9 Hz, 3H); 13 C NMR (101 MHz, CDC13) δ 139.6, 133.0, 126.1, 123.9, 121.0, 120.4, 109.1, 84.1, 80.6, 46.9, 44.6, 37.1, 31.6, 26.2, 23.7, 21.4, 18.1; HRMS (EI) m / z Calcd for C 17 H 22 N2Cl [M+H] + : 289.1466, found: 289.1457.

[0096] Example 17

[0097] Introducing heterocyclic rings, especially nitrogen-containing heterocyclic rings into the chemical structure of pesticides can not only improve biological activity, but also change selectivity. Nitrogen-containing heterocyclic compounds containing pyridine, pyrazole, pyrimidine, indazole, pyrazine, quinoline and isoquinoline are often used as pesticides such as insecticides, fungicides and herbicides. In order to explore the application prospect of the nitrogen-containing heterocyclic compounds synthesized in the application, the following experiments are carried out.

[0098] Cucumber downy mildew is the most important and common disease of cucumber, and poor control can cause serious losses. In this example, 3 potting cucumber seedlings, with an average of 9.6 leaves, were selected. The leaves showed yellowish green spots and gradually turned yellow irregularly, indicating that the cucumber seedlings were infected with cucumber downy mildew. The product 1-(3-methyl-5-(triisopropylsilyl)pent-4-yn-1-yl)-1H-indazole prepared in Example 1 was used. The first spray was applied at the early stage of the disease, and the second spray was applied one week later. The spraying method was twice dilution (concentration: 400 mg / L), and the whole plant stem and leaf were sprayed. Three cucumber seedlings turned normal after the second spray. The results showed that the compound could inhibit cucumber downy mildew by 100% at 400 ppm.

[0099] The above-mentioned examples are only preferred embodiments of the present application, and are used to explain the present application, but not to limit the scope of the present application. For those skilled in the art, other embodiments can be easily obtained by substitution or change based on the technical content disclosed in the present specification. Therefore, any changes and improvements made on the principle of the present application shall be included in the scope of the present application.

Claims

1. A process for the direct preparation of alkynylated coupling products from azacycloalkenes, characterized in that, The method comprises the following steps: The azacycloalkene shown in formula I and the alkynyl bromide shown in formula II are used as substrates, a divalent nickel salt is used as a catalyst, and the reaction is carried out in an organic solvent under the action of a base and a proton source to obtain an alkynyl coupling product shown in formula III; the specific synthesis route is as follows: R1 is selected from one of indazolyl, pyridyl, pyrazolyl, pyrazinyl, pyrimidyl and isoquinolyl; R2 is selected from triisopropylsilyl, phenyl, substituted phenyl, and five-membered heterocyclic group, and the substituent group on the substituted phenyl is selected from methoxy, trifluoromethyl or halogen.

2. The method of claim 1, wherein, R1 is selected from One of them; R2 is selected from triisopropylsilyl, Cyclopropylidene, 1-chlorobutyricide.

3. The method of claim 1, wherein, The divalent nickel salt is selected from one of nickel(II) chloride glycol dimethyl ether complex, nickel(II) p-toluenesulfonate hexahydrate, nickel(II) acetylacetone, and nickel(II) tetrafluoroborate hexahydrate.

4. The method of claim 1, wherein, The base is selected from one of sodium fluoride, lithium carbonate, sodium phosphate or sodium methoxide.

5. The method of claim 1, wherein, The proton source is selected from one of diethoxymethylsilane, diphenylmethylsilane or triphenylsilane.

6. The method of claim 1, wherein, The organic solvent is selected from one of N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide or N-methyl pyrrolidone.

7. The method of claim 1, wherein, The molar ratio of the azacycloalkene shown in formula I to the alkynyl bromide shown in formula II is 1:1-5.

8. The method of claim 1, wherein, The molar amount of the divalent nickel salt is 2-30% of the molar amount of the azacycloalkene shown in formula I.

9. The method of claim 1, wherein, The molar ratio of the base to the azacycloalkene shown in formula I is 1-5:1, the molar ratio of the proton source to the azacycloalkene shown in formula I is 1-5:1, and the amount ratio of the organic solvent to the azacycloalkene shown in formula I is 5-20 mL:1 mmol.

10. The method of claim 1, wherein, The reaction temperature is 80-120°C, and the reaction time is 10-24 h.

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