Preparation method of substituted 1, 3-enyne compound

Abstract

The invention provides a method for synthesizing a series of substituted 1, 3-enyne compounds by carrying out coupling reaction on 2-alkynyl allyl ether compounds and hydrazone compounds under the conditions of palladium catalysis and alkali promotion. The method has the characteristics of mild reaction conditions, good functional group tolerance, simple post-treatment, low pollution, high economic benefit and the like.

Description

Technical Field

[0001] This invention belongs to the field of organic compound synthesis technology, specifically relating to a substituted 1,3-enyne compound and its preparation method. Background Technology

[0002] The construction of carbon-carbon bonds is the cornerstone of organic chemistry. Organometallic reagents are among the most reliable and versatile nucleophiles for this purpose. The polarization of the metal-carbon bond in these reagents enables them to react with a wide range of electrophiles, thus achieving chemical diversity. Although organometallic reagents are widely used as important carbon nucleophiles, their application in chemical reactions is subject to several limitations. These include the stoichiometry of the metal and the organohalides that are often used as precursors, which in turn generate a large amount of metal halide waste; the strict removal of oxygen and moisture from organometallic reagents, and the relatively cumbersome preparation process. Hydrazones, as an alternative to organometallic reagents, achieve a polarity reversal of the carbonyl group as an alkyl carbanion equivalent through a series of hydrazone formation, deprotonation-tautomerism, and nitrogen release processes (Chem. Soc. Rev., 2021, 50, 10733), breaking the inherent reaction pattern of carbonyl compounds as electrophiles. Compared to traditional organometallic reagents (such as Grignard reagents), hydrazones are less sensitive to air and moisture, and can be prepared and stored without strictly anhydrous and oxygen-free conditions, reducing the difficulty of experimental operations. Allyl compounds play a central role as coupling reagents in organic synthesis (Acc. Chem. Res., 2019, 52, 2657-2672). Palladium-catalyzed allyl substitution reactions have been widely used in coupling reactions, achieving regioselective attack of nucleophiles through the formation of π-allylpalladium intermediates, thereby efficiently constructing carbon-carbon bonds. Substituted 1,3-enyne compounds are a class of unsaturated organic molecules containing both carbon-carbon double and triple bonds. Due to their unique structure and reactivity, they have significant value in organic synthesis, medicinal chemistry, and materials science.

[0003] Based on the above research background, we have developed a method for the coupling of 2-alkynyl allyl ethers and hydrazones to substituted 1,3-enyne compounds under palladium-catalyzed base promotion. This method has a wide substrate range and is simple to operate. Summary of the Invention

[0004] The purpose of this section is to outline some aspects of embodiments of the present invention and to briefly describe some preferred embodiments. Simplifications or omissions may be made in this section, as well as in the abstract and title of this application, to avoid obscuring the purpose of these documents; however, such simplifications or omissions should not be construed as limiting the scope of the invention.

[0005] In view of the problems existing in the above and / or prior art, the present invention is proposed.

[0006] One object of the present invention is to provide a substituted 1,3-enyne compound.

[0007] To solve the above-mentioned technical problems, the present invention provides the following technical solution: a substituted 1,3-enyne compound, the structural formula of which is shown in Formula I;

[0008]

[0009] Wherein, R is selected from one of phenyl, methyl-substituted phenyl, methoxy-substituted phenyl, tert-butyl-substituted phenyl, halogen-substituted phenyl, trifluoromethyl-substituted phenyl, 2-naphthyl, thiophene, n-hexyl, and cyclohexyl;

[0010] R 1 It is selected from one of phenyl, methyl-substituted phenyl, isopropyl-substituted phenyl, biphenyl, methoxy-substituted phenyl, halogen-substituted phenyl, trifluoromethyl-substituted phenyl, trifluoromethoxyphenyl, cyano-substituted phenyl, 1-naphthyl, furanyl, thiophene, benzofuranyl, benzothiophene, and cyclohexyl.

[0011] Another object of this invention is to provide a method for preparing the substituted 1,3-enyne compounds as described above. This invention features mild reaction conditions, good functional group tolerance, simple post-processing, green procedures, low pollution, and high economic efficiency. Specific methods include:

[0012] The 2-alkynyl allyl ether compound shown in Formula II and the hydrazone compound shown in Formula III were coupled in a solvent under palladium catalysis and base promotion to obtain the target compound shown in Formula I.

[0013]

[0014] Among them, R and R in equations II and III 1 With Equation I, R, R 1 Consistent correspondence;

[0015] As a preferred embodiment of the coupling reaction method of 2-alkynyl allyl ether compounds with hydrazone compounds under palladium catalysis and base-promoted conditions according to the present invention, wherein: the 2-alkynyl allyl ether compounds include 1-chloro-4-[(2-methyl-3-methylene-5-phenylpentan-4-yn-2-yl)oxy]benzene, 1-chloro-4-[(2-methyl-3-methylene-5-(p-tolyl)pentan-4-yn-2-yl)oxy]benzene, 1-chloro-4-[(5-(4-methoxyphenyl)-2-methyl-3-methylenepentan-4-yn-2-yl)oxy]benzene, 1-(tert-butyl)-4-[4-(4-chlorophenoxy)-4-methyl-3-methylenepentan-1-yn-1-yl]benzene, 1-chloro-4-[(5-(4-fluorophenyl)-2-methyl- One of the following: 3-methylenepent-4-yn-2-yl)oxy]benzene, 1-chloro-4-[(5-(4-chlorophenyl)-2-methyl-3-methylenepent-4-yn-2-yl)oxy]benzene, 1-chloro-4-[(5-(4-trifluoromethylphenyl)-2-methyl-3-methylenepent-4-yn-2-yl)oxy]benzene, 2-(4-(4-chlorophenoxy)-4-methyl-3-methylenepent-1-yn-1-yl)naphthalene, 2-(4-(4-chlorophenoxy)-4-methyl-3-methylenepent-1-yn-1-yl)thiophene, 1-chloro-4-[(2-methyl-3-methyleneundec-4-yn-2-yl)oxy]benzene, and 1-chloro-4-[(5-cyclohexyl-2-methyl-3-methylenepent-4-yn-2-yl)oxy]benzene.

[0016] As a preferred embodiment of the coupling reaction method of 2-alkynyl allyl ether compounds with hydrazones catalyzed by the present invention, wherein the hydrazone compounds include one of the following: benzylmethylhydrazine, p-methylbenzylmethylhydrazine, p-isopropylbenzylmethylhydrazine, ([1,1′-biphenyl]-4-ylmethylene)hydrazine, p-methoxybenzylmethylhydrazine, p-fluorobenzylmethylhydrazine, p-chlorobenzylmethylhydrazine, p-bromobenzylmethylhydrazine, p-trifluoromethylbenzylmethylhydrazine, p-trifluoromethoxybenzylmethylhydrazine, 4-(hydrazylmethyl)benzonitrile, 1-naphthylmethylhydrazine, 2-furanylmethylhydrazine, 2-thiophenemethylhydrazine, 2-benzofuranylmethylhydrazine, 2-benzothiophenemethylhydrazine, and cyclohexylmethylhydrazine.

[0017] As a preferred embodiment of the coupling reaction method of 2-alkynyl allyl ether compounds and hydrazone compounds under palladium catalysis and base-promoted conditions of the present invention, wherein the palladium catalyst is a PEPPSI-IPr palladium complex.

[0018] As a preferred embodiment of the coupling reaction of 2-alkynyl allyl ether compounds and hydrazone compounds under palladium catalysis and base promotion conditions of the present invention, wherein the molar ratio of the 2-alkynyl allyl ether compound to the hydrazone compound is 1:2 to 3; preferably the molar ratio is 1:3.

[0019] As a preferred embodiment of the coupling reaction method of 2-alkynyl allyl ether compounds and hydrazone compounds under palladium catalysis and base-promoted conditions of the present invention, the solvent includes one of acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, and tetrahydrofuran; the preferred solvent is acetonitrile.

[0020] As a preferred embodiment of the coupling reaction method of 2-alkynyl allyl ether compounds and hydrazone compounds under palladium catalysis and base promotion conditions of the present invention, wherein: the base includes one of lithium tert-butoxide, potassium tert-butoxide, sodium tert-butoxide, cesium carbonate, potassium phosphate, potassium carbonate, potassium hydroxide, sodium hydroxide, and triethylenediamine; preferably, the base is sodium tert-butoxide.

[0021] As a preferred embodiment of the coupling reaction method of 2-alkynyl allyl ether compounds and hydrazone compounds under palladium catalysis and base promotion conditions of the present invention, wherein: the coupling reaction is carried out at a reaction temperature of room temperature to 120°C; preferably, the reaction temperature is room temperature.

[0022] As a preferred embodiment of the coupling reaction method of 2-alkynyl allyl ether compounds and hydrazone compounds under palladium catalysis and base promotion conditions of the present invention, the coupling reaction takes 12 to 24 hours; preferably 12 hours.

[0023] As a preferred embodiment of the coupling reaction method of 2-alkynyl allyl ether compounds and hydrazone compounds under palladium catalysis and base promotion conditions of the present invention, wherein the molar ratio of the 2-alkynyl allyl ether compound and sodium tert-butoxide is 1:2.

[0024] In summary, the optimal reaction equation for this invention is as follows:

[0025]

[0026] Compared with the prior art, the present invention has the following beneficial effects:

[0027] This invention provides a method for preparing a series of substituted 1,3-enyne compounds by coupling 2-alkynyl allyl ethers with hydrazones under the promotion of a base using PEPPSI-IPr palladium as a catalyst. The reaction conditions are mild, the functional groups are well tolerated, and the method has the advantages of simple post-processing, green steps, low pollution, and high economic benefits. Attached Figure Description

[0028] To more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings used in the following description of the embodiments will be briefly introduced. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0029] Figure 1 The proton spectrum of target product a in Example 1 of this invention;

[0030] Figure 2 The carbon spectrum of target product a in Example 1 of this invention;

[0031] Figure 3 The proton spectrum of target product b in Example 2 of this invention;

[0032] Figure 4 The carbon spectrum of target product b in Example 2 of this invention;

[0033] Figure 5 The proton spectrum of target product c in Example 3 of this invention;

[0034] Figure 6 The carbon spectrum of target product c in Example 3 of this invention;

[0035] Figure 7 The proton spectrum of the target product d in Example 4 of this invention;

[0036] Figure 8 The carbon spectrum of the target product d in Example 4 of this invention;

[0037] Figure 9 The proton spectrum of target product e in Example 5 of this invention;

[0038] Figure 10 The carbon spectrum of the target product e in Example 5 of this invention. Detailed Implementation

[0039] To make the above-mentioned objects, features and advantages of the present invention more apparent and understandable, the specific embodiments of the present invention will be described in detail below with reference to the examples in the specification.

[0040] Many specific details are set forth in the following description in order to provide a full understanding of the invention. However, the invention may also be practiced in other ways different from those described herein, and those skilled in the art can make similar extensions without departing from the spirit of the invention. Therefore, the invention is not limited to the specific embodiments disclosed below.

[0041] Secondly, the term "one embodiment" or "embodiment" as used herein refers to a specific feature, structure, or characteristic that may be included in at least one implementation of the present invention. The phrase "in one embodiment" appearing in different places in this specification does not necessarily refer to the same embodiment, nor is it a single or selective embodiment that is mutually exclusive with other embodiments.

[0042] The 2-alkynyl allyl ether compounds used in the examples were prepared according to the methods reported in the reference (Org. Lett. 2018, 16, 5071-5074). The hydrazone compounds used in the examples were prepared according to the methods reported in the reference (Angew. Chem. Int. Ed. 2020, 59, 6466-6472). Other raw materials, unless otherwise specified, were commercially available.

[0043] The synthesis method of 2-alkynyl allyl ether compounds from raw material is as follows:

[0044]

[0045] Step 1: 2-(4-chlorophenoxy)-2-methylpropionic acid (4292.9 mg, 20 mmol, 1 equivalent, I) was dissolved in dichloromethane (50 mL), and carbodiimide (4293.9 mg, 26 mmol, 1.3 equivalent) was added in portions. The reaction mixture was stirred at room temperature for 1 hour. Then, N,O-dimethylhydroxylamine hydrochloride (3901.6 mg, 40 mmol, 2 equivalent) was added, and the mixture was stirred at room temperature for 16 hours. After the reaction was complete, hydrochloric acid solution (2 M, 100 mL) was added. The aqueous layer was extracted with dichloromethane (50 mL × 3). The combined organic layers were washed with saturated sodium bicarbonate solution (100 mL) and saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was rapidly purified by silica gel (300-400 mesh) using petroleum ether / ethyl acetate (4 / 1 to 2 / 1) as eluent to give the target Weinreb amide II.

[0046] Step 2: Diisopropylamine (2023.0 mg, 20 mmol, 1.3 equivalents) was dissolved in anhydrous tetrahydrofuran (60 mL), cooled to -78 °C, and then n-butyllithium (14.4 mL, 1.6 M hexane solution, 1.15 equivalents) was added. The solution was then stirred at 0 °C for 1 hour. Further cooling to -78 °C, a terminal alkyne (20 mmol, 1 equivalent, III) was slowly added. After stirring at -78 °C for 1 hour, Weinreb amide II (5154.3 mg, 20 mmol, 1 equivalent) was added. The solution was stirred for 18 hours while being heated to room temperature. After the reaction was complete, hydrochloric acid solution (2 M, 100 mL) was added, and the aqueous layer was extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with saturated sodium bicarbonate solution (100 mL) and saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was rapidly purified by silica gel (300-400 mesh) chromatography, using petroleum ether / ethyl acetate (20 / 1 to 10 / 1) as the eluent to obtain the target acetylene IV.

[0047] Step 3: At 0°C, 7.5 mL of butyllithium (1.6 M hexane solution, 1.2 equivalents) was added to a tetrahydrofuran (30 mL) solution of triphenylphosphine methyl bromide (3572.2 mg, 10 mmol, 1.3 equivalents), and the reaction mixture was stirred for 40 minutes. Then, a tetrahydrofuran (10 mL) solution of acetylene (10 mmol, 1 equivalent, IV) was added at -78°C, and the resulting reaction mixture was stirred at -78°C for 24 hours. After the reaction was complete, 100 mL of saturated ammonium chloride solution was added, and the aqueous layer was extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with 100 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was rapidly purified by silica gel (300-400 mesh) using petroleum ether as the eluent to obtain the 2-alkynyl allyl ether.

[0048] The synthesis method of the raw material hydrazone compound is as follows:

[0049]

[0050] Under room temperature and air conditions, carbonyl compound (0.9 mmol, 1.0 equivalent), hydrazine hydrate (59 μL, 1.17 mmol, 64-65 wt%, 1.3 equivalent), and tetrahydrofuran (2.0 mL) were added to a dried 25 mL flask equipped with a magnetic stir bar. After stirring the reaction mixture at room temperature for 1 hour, anhydrous sodium sulfate (50 mg) and... Molecular sieve (50 mg). The resulting mixture was filtered and concentrated, and used directly in the next reaction without further purification.

[0051] Example 1

[0052] (1) 1-chloro-4-[(2-methyl-3-methylene-5-phenylpent-4-yn-2-yl)oxy]benzene (89.0 mg, 0.3 mmol, 1 equivalent), benzenemethylhydrazine (108.14 mg, 0.9 mmol, 3 equivalent), PEPPSI-IPr (5.1 mg, 0.0075 mmol, 0.025 equivalent), sodium tert-butoxide (57.7 mg, 0.6 mmol, 2 equivalent) and acetonitrile (2 mL) were added sequentially to a 10 mL Schlenk tube and stirred at room temperature for 12 h under a nitrogen atmosphere.

[0053] (2) After the reaction in step (1) was completed, the mixture was quenched with saturated NH4Cl solution and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the crude product. The crude product was purified by rapid column chromatography on silica gel (300-400 mesh) using petroleum ether as the eluent to obtain 73.4 mg of the target product a.

[0054] The target product a was characterized as follows: Figure 1 and 2 As shown, the result is: a colorless oily substance;

[0055] 1 H NMR (400MHz, CDCl3): δ=7.58-7.55(m, 2H), 7.41-7.37(m, 3H), 7.32-7.25(m, 5H), 5.51( d, J=1.3Hz, 1H), 5.17 (d, J=1.3Hz, 1H), 2.92 (d, J=1.8Hz, 2H), 1.23 (d, J=1.8Hz, 6H) ppm.

[0056] 13 C NMR (100MHz, CDCl3): δ=139.6, 138.9, 131.7, 130.6, 128.5, 128.2, 127.7, 126.1, 123.6, 120.2, 90.7, 89.8, 47.5, 40.7, 26.8ppm.

[0057] HRMS(m / z): calcd for C 20 H 21 [M+H] + 261.1638, found: 261.1630.

[0058] Characterization data revealed that the obtained reaction product was (4,4-dimethyl-3-methylenepent-1-yn-1,5-diyl)diphenyl (purity > 98%), and the structural formula of this compound is:

[0059]

[0060] The product yield was calculated to be 94%.

[0061] Example 2

[0062] (1) 1-chloro-4-[(2-methyl-3-methylene-5-(p-tolyl)pent-4-yn-2-yl)oxy]benzene (93.2 mg, 0.3 mmol, 1 equivalent), benzenemethylhydrazine (108.14 mg, 0.9 mmol, 3 equivalent), PEPPSI-IPr (5.1 mg, 0.0075 mmol, 0.025 equivalent), sodium tert-butoxide (57.7 mg, 0.6 mmol, 2 equivalent) and acetonitrile (2 mL) were added sequentially to a 10 mL Schlenk tube and stirred at room temperature for 12 h under a nitrogen atmosphere.

[0063] (2) After the reaction in step (1) was completed, the reaction was quenched with saturated NH4Cl solution and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the crude product. The crude product was purified by rapid column chromatography on silica gel (300-400 mesh) using petroleum ether as the eluent to obtain 74.9 mg of the target product b.

[0064] The target product b was characterized as follows: Figure 3 and 4 As shown, the result is: a colorless oily substance;

[0065] 1 H NMR (400MHz, CDCl3): δ=7.41-7.39 (m, 2H), 7.25-7.18 (m, 5H), 7.14 (d, J=7.9Hz, 2H), 5 .42 (d, J=1.2Hz, 1H), 5.08 (d, J=1.3Hz, 1H), 2.85 (s, 2H), 2.35 (s, 3H), 1.16 (s, 6H)ppm.

[0066] 13 C NMR (100MHz, CDCl3): δ=139.7, 138.9, 138.3, 131.6, 130.6, 129.2, 127.7, 126.1, 120.5, 119.8, 90.9, 89.1, 47.5, 40.7, 26.8, 21.6ppm.

[0067] HRMS(m / z): calcd for C 21 H 23 [M+H] + 275.1794, found: 275.1793.

[0068] Characterization data revealed that the obtained reaction product was (1-(4,4-dimethyl-3-methylene-5-phenylpent-1-yn-1-yl)-4-methylbenzene (purity > 98%), and the structural formula of this compound is:

[0069]

[0070] The product yield was calculated to be 91%.

[0071] Example 3

[0072] (1) 1-chloro-4-[(2-methyl-3-methylene-5-phenylpentan-4-yn-2-yl)oxy]benzene (89.0 mg, 0.3 mmol, 1 equivalent), ([1,1′-biphenyl]-4-ylmethylene)hydrazine (176.63 mg, 0.9 mmol, 3 equivalent), PEPPSI-IPr (5.1 mg, 0.0075 mmol, 0.025 equivalent), sodium tert-butoxide (57.7 mg, 0.6 mmol, 2 equivalent) and acetonitrile (2 mL) were added sequentially to a 10 mL Schlenk tube and stirred at room temperature for 12 h under a nitrogen atmosphere.

[0073] (2) After the reaction in step (1) was completed, the mixture was quenched with saturated NH4Cl solution and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the crude product. The crude product was purified by rapid column chromatography on silica gel (300-400 mesh) using petroleum ether as the eluent to obtain 83.8 mg of the target product c.

[0074] The target product c was characterized as follows: Figure 5 and 6 As shown, the result is: a colorless oily substance;

[0075] 1 H NMR (400MHz, CDCl3): δ=7.54-7.52(m, 2H), 7.48-7.43(m, 4H), 7.36(t, J=7.7Hz, 2H), 7.29-7.22(m, 6H), 5.43(s, 1H), 5.10(s, 1H), 2.85(s, 2H), 1.15(s, 6H)ppm.

[0076] 13 C NMR (100MHz, CDCl3): δ=141.2, 139.6, 138.9, 138.0, 131.7, 131.0, 128.8, 128.5 , 128.3, 127.10, 127.07, 126.4, 123.6, 120.3, 90.8, 89.8, 47.2, 40.7, 26.8ppm.

[0077] HRMS(m / z): calcd for C 26 H 25 [M+H] + 337.1951, found: 337.1950.

[0078] Characterization data revealed that the obtained reaction product was (4-(2,2-dimethyl-3-methylene-5-phenylpentan-4-yn-1-yl)-1,1′-biphenyl (purity > 98%), and the structural formula of this compound is:

[0079]

[0080] The product yield was calculated to be 83%.

[0081] Example 4

[0082] (1) 1-Chloro-4-[(2-methyl-3-methylene-5-phenylpent-4-yn-2-yl)oxy]benzene (89.0 mg, 0.3 mmol, 1 equivalent), p-chlorobenzylmethylhydrazine (139.14 mg, 0.9 mmol, 3 equivalent), PEPPSI-IPr (5.1 mg, 0.0075 mmol, 0.025 equivalent), sodium tert-butoxide (57.7 mg, 0.6 mmol, 2 equivalent) and acetonitrile (2 mL) were added sequentially to a 10 mL Schlenk tube and stirred at room temperature for 12 h under a nitrogen atmosphere.

[0083] (2) After the reaction in step (1) was completed, the mixture was quenched with saturated NH4Cl solution and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the crude product. The crude product was purified by rapid column chromatography on silica gel (300-400 mesh) using petroleum ether as the eluent to obtain 76.1 mg of the target product d.

[0084] The target product d was characterized as follows: Figure 7 and 8 As shown, the result is: a colorless oily substance;

[0085] 1 H NMR (400MHz, CDCl3): δ=7.54-7.52(m, 2H), 7.39-7.35(m, 3H), 7.25-7.22(m, 2H), 7.17- 7.14 (m, 2H), 5.48 (d, J=1.1Hz, 1H), 5.12 (d, J=1.2Hz, 1H), 2.84 (s, 2H), 1.19 (s, 6H)ppm.

[0086] 13 C NMR (100MHz, CDCl3): δ=139.1, 137.3, 132.0, 131.8, 131.7, 128.5, 128.3, 127.8, 123.5, 120.5, 90.9, 89.6, 46.8, 40.6, 26.7ppm.

[0087] HRMS(m / z): calcd for C 20 H 20 Cl[M+H] + 295.1248, found: 295.1247.

[0088] Characterization data revealed that the obtained reaction product was 1-chloro-4-(2,2-dimethyl-3-methylene-5-phenylpentan-4-yn-1-yl)benzene (purity > 98%), and the structural formula of this compound is:

[0089]

[0090] The product yield was calculated to be 86%.

[0091] Example 5

[0092] (1) 1-chloro-4-[(2-methyl-3-methylene-5-phenylpentan-4-yn-2-yl)oxy]benzene (89.0 mg, 0.3 mmol, 1 equivalent, 1), (naphthyl-2-ylmethylene)hydrazine (153.19 mg, 0.9 mmol, 3 equivalent, 2), PEPPSI-IPr (5.1 mg, 0.0075 mmol, 0.025 equivalent), sodium tert-butoxide (57.7 mg, 0.6 mmol, 2 equivalent) and acetonitrile (2 mL) were added sequentially to a 10 mL Schlenk tube and stirred at room temperature for 12 h under a nitrogen atmosphere.

[0093] (2) After the reaction in step (1) was completed, the mixture was quenched with saturated NH4Cl solution and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the crude product. The crude product was purified by rapid column chromatography on silica gel (300-400 mesh) using petroleum ether as the eluent to obtain 78.2 mg of the target product e.

[0094] The target product e is characterized as follows: Figure 9 and 10 As shown, the result is: a colorless oily substance;

[0095] 1H NMR (400MHz, CDCl3): δ=8.27 (d, J=8.3Hz, 1H), 7.88-7.86 (m, 1H), 7.76 (dd, J=7.2, 2.0Hz, 1H), 7.60-7.58 (m, 2H), 7.52-7.44 (m, 4H), 7.43-7.37 (m, 3H), 5.53 (d, J=1.1Hz, 1H), 5.22 (d, J=1.1Hz, 1H), 3.43 (s, 2H), 1.24 (s, 6H)ppm.

[0096] 13 C NMR (100MHz, CDCl3): δ=140.3, 135.3, 133.9, 133.5, 131.7, 129.0, 128.8, 128.5, 128. 3, 127.0, 125.5, 125.2, 125.1, 125.0, 123.6, 120.1, 90.9, 89.9, 42.1, 41.6, 27.1ppm.

[0097] HRMS(m / z): calcd for C 24 H 23 [M+H] + 311.1794, found: 311.1789.

[0098] Characterization data revealed that the obtained reaction product was 1-(2,2-dimethyl-3-methylene-5-phenylpentan-4-yn-1-yl)naphthalene (purity > 98%), and the structural formula of this compound is as follows:

[0099]

[0100] The product yield was calculated to be 84%.

[0101] Example 6

[0102] Example 6 is basically the same as Example 1, except that in step (1), the PEPPSI-IPr catalyst is 0.05 equivalents, tetrahydrofuran is used as the solvent, the molar ratio of 2-alkynyl allyl ether compound to hydrazone compound is 1:3, and the base is different at the reaction temperature of 60℃, as shown in Table 1 below:

[0103] Table 1

[0104]

[0105]

[0106] As can be seen from Table 1, under the same reaction conditions, the reaction yield is the highest at 62% when sodium tert-butoxide (tBuONa) is used as the base.

[0107] Example 7

[0108] Example 7 is basically the same as Example 1, except that in step (1), the PEPPSI-IPr catalyst is 0.05 equivalents, the molar ratio of 2-alkynyl allyl ether compound to hydrazone compound is 1:3, tetrahydrofuran is used as solvent, and the temperature is different, as shown in Table 2 below:

[0109] Table 2

[0110] Temperature (°C) Yield (%) room temperature 78 55 69 65 62

[0111] As can be seen from Table 2, under the same reaction conditions, the reaction yield is the highest at room temperature, reaching 78%.

[0112] Example 8

[0113] Example 8 is basically the same as Example 1, except that in step (1), the PEPPSI-IPr catalyst is 0.05 equivalents, the molar ratio of 2-alkynyl allyl ether compound to hydrazone compound is 1:3, the reaction temperature is room temperature, and the reaction solvent is different, as shown in Table 3 below:

[0114] Table 3

[0115]

[0116]

[0117] As can be seen from Table 3, under the same reaction conditions, when using solvents such as dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), toluene, acetonitrile (MeCN), and 1,4-dioxane as solvents, the acetonitrile reaction yield is the highest at 82%.

[0118] Example 9

[0119] Example 9 is basically the same as Example 1, except that in step (1), the molar ratio of 2-alkynyl allyl ether compound to hydrazone compound is 1:3, and the metal catalyst used is different, as shown in Table 4 below:

[0120] Table 4

[0121] Catalyst (x equivalents) Yield (%) PEPPSI-IPr(0.025) 94 PEPPSI-IPr(0.05) 82 PEPPSI-IPr(0.0125) 82 <![CDATA[Ni(Ph3P)2Cl2(0.025) / NHC(0.05)]]> trace <![CDATA[CoCl2(0.025) / NHC(0.05)]]> trace

[0122] As can be seen from Table 4, under the same reaction conditions, the reaction yield is the highest at 94% when using 0.025 equivalents of PEPPSI-IPr catalyst.

[0123] Example 10

[0124] Example 10 is basically the same as Example 1, except that in step (1), the molar ratio of 2-alkynyl allyl ether compounds to hydrazone compounds is different, as shown in Table 5 below:

[0125] Table 5

[0126]

[0127] As can be seen from Table 5, under the same reaction conditions, the reaction yield is the highest at a molar ratio of 2-alkynylallyl ethers to hydrazones of 1:3, reaching 92%.

[0128] Example 11

[0129] Example 11 is basically the same as Example 1, except that the 2-alkynyl allyl ether compound used in step (1) is different. The specific target products obtained are shown in Table 6 below:

[0130] Table 6

[0131]

[0132]

[0133] Example 12

[0134] Example 12 is basically the same as Example 1, except that the hydrazone compound is different in step (1). The specific target products obtained are shown in Table 7 below:

[0135] Table 7

[0136]

[0137]

Claims

1. A substituted 1,3-alkynyl enyne compound, characterized in that it has a structure as shown in formula I; wherein R is selected from one of phenyl, methyl-substituted phenyl, methoxy-substituted phenyl, t-butyl-substituted phenyl, halogen-substituted phenyl, trifluoromethyl-substituted phenyl, 2-naphthyl, thienyl, n-hexyl, and cyclohexyl; R 1 one selected from the group consisting of phenyl, methyl-substituted phenyl, isopropyl-substituted phenyl, biphenyl, methoxy-substituted phenyl, halogen-substituted phenyl, trifluoromethyl-substituted phenyl, trifluoromethoxy phenyl, cyano-substituted phenyl, 1-naphthyl, furanyl, thienyl, benzofuranyl, benzothienyl, cyclohexyl.

2. The method for preparing a substituted 1,3-enyne compound as described in claim 1, characterized in that: comprising, coupling a 2-alkynyl allyl ether compound shown in formula II with a hydrazone compound shown in formula III in a solvent with palladium as a catalyst and a base to facilitate the reaction to obtain the compound shown in formula I; wherein R, R 1 correspond to R, R 1 in formula I.

3. The method for preparing a substituted 1,3-enyne compound as described in claim 2, characterized in that: The molar ratio of the 2-alkynyl allyl ether compound to the hydrazone compound is 1:2-3.

4. A process for the preparation of a substituted 1,3- enyne compound according to any one of claims 2 to 3, characterized in that: The solvent includes one of tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide, 1,4-dioxane, acetonitrile, and toluene.

5. A process for the preparation of a substituted 1,3- enyne compound according to any one of claims 2 to 4, characterized in that: The reaction temperature is room temperature to 60°C.

6. A process for the preparation of a substituted 1,3- enyne compound as claimed in claims 2 to 5, characterized in that: The reaction time for the coupling reaction is 12-24 hours.

7. A process for the preparation of a substituted 1,3- enyne compound as claimed in claims 2 to 6, characterized in that: The molar ratio of the 2-alkynyl allyl ether compound to the base is 1:

2.

8. A process for the preparation of a substituted 1,3- enyne compound according to any one of claims 2 to 7, characterized in that: The base includes lithium tert-butoxide, potassium tert-butoxide, sodium tert-butoxide, cesium carbonate, potassium phosphate, potassium carbonate, potassium hydroxide, sodium hydroxide, and triethylenediamine.

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