A method for preparing fully substituted 1-butene-3-yne derivatives

Abstract

The invention discloses a method for preparing a fully substituted 1-butene-3-yne derivative, belonging to the technical field of pharmaceutical intermediates and organic synthesis. The invention uses an allyl compound and a terminal alkyne as raw materials, and a coupling reaction occurs under the catalysis of a transition metal to generate a fully substituted 1-butene-3-yne derivative. The fully substituted 1-butene-3-yne derivative synthesized by the invention contains a fully substituted 1,3-enyne structure and an extremely high degree of unsaturation, and can be used as a good precursor for drug synthesis and modification.

Description

Technical Field

[0001] The invention relates to a method for preparing a fully substituted 1-butene-3-yne derivative, belonging to the technical field of pharmaceutical intermediates and organic synthesis. Background Art

[0002] Conjugated enynes refer to compounds that contain two conjugated triple bonds and double bonds in the molecule. The 1,3-enyne skeleton contained in this type of compound is widely present in natural products, drugs and functional materials (Rudi, A., etal. J. Nat. Prod., 2000, 63, 1434; Fontana, A., et al. J. Nat. Prod., 2001,64, 131; Liu, Y., et al. J. Am. Chem. Soc., 2006, 128, 5592; Lan, P., et al.J. Nat. Prod., 2015, 78, 1963.). At the same time, because of their unique 1,3-eneyne skeleton and high degree of unsaturation, they can also serve as precursors and drug intermediates for various functional groups (Trost, BM, et al. Chem. Soc.Rev., 2016, 45, 2212; Zhu, X., et al. J. Am. Chem. Soc., 2019, 141, 548; Kuang, Z., et al. Chem., 2020, 6, 2347; Dherbassy, ​​D., et al. Chem. Sci.,2020, 11, 11380; Fu, L., et al. Chin. J. Chem., 2020, 38, 91; Zhou, Y., etal. J. Am. Chem. Soc., 2020, 142, 9908.).

[0003] The synthesis of fully substituted 1,3-enynes mainly includes cross-coupling reactions of terminal alkynes and polysubstituted halogenated alkenes (Bates, CG, et al. Org. Lett., 2004, 6, 1441; Liu, F., et al. J. Org. Chem., 2007, 72, 4844; Hatakeyama, T., et al. Org. Lett., 2008, 10, 5341.); cross-addition reactions between alkynes (Sakai, N., et al. Org. Lett., 2010, 12, 1300; Pell, CJ,et al. ACS Catal., 2014, 4, 3470; Shao, YL, et al. Org. Lett., 2012, 14,5242; Sakurada, T., et al. J. Org. Chem., 2013, 78, 3583.); Selective functionalization of 1,3-diynes (Ilies, L., et al. Synlett., 2014, 25, 0527.), and other methods (Wang, NN, et al. Org. Lett., 2016, 18, 1298; Ye, CQ, et al. Org. Lett., 2018,20, 3202.).

[0004] Although the synthesis of fully substituted 1,3-enynes has made great progress, most of them start from complex raw materials and undergo coupling reactions or functional group modifications to obtain 1,3-enynes. There has never been a report on the method of synthesizing fully substituted 1,3-enynes from simple and readily available raw materials. Summary of the invention

[0005] In view of the problems of the 1,3-enyne synthesis method in the prior art, the present invention provides a method for synthesizing a fully substituted 1-butene-3-yne derivative. The present invention uses terminal alkynes and allyl compounds as raw materials, and undergoes a coupling reaction under the catalysis of transition metals to synthesize fully substituted 1-butene-3-yne derivatives.

[0006] The compound structure of the fully substituted 1-butene-3-yne derivative is shown in Formula I or Formula II:

[0007]

[0008] in:

[0009] R 1is H, CH3, OCH3, C2H5, Cl, F or CF3;

[0010] R 2 is H or CH3;

[0011] R 3 It is CH2OCH3, thienyl, cyclopropyl or n-pentyl.

[0012] The synthesis method of the present invention is as follows:

[0013] The terminal alkyne, an allyl compound, a catalyst and a base are added to a solvent to obtain a reaction system, and the reaction is carried out under a protective atmosphere at 100°C to 120°C for 6 to 18 hours. After the solvent is removed by vacuum distillation, column chromatography is performed to obtain a fully substituted 1-butene-3-yne derivative.

[0014] The molar ratio of the terminal alkyne, the allyl compound, the catalyst, the base and the solvent in the reaction system is (1-3): 1: (0.01-0.1): (1-4): (10-100).

[0015] The allyl compound is allyl bromide, allyl chloride, allyl acetate or 3-bromo-2-methylpropene.

[0016] The catalyst is bis(tri-p-chlorophenylphosphine)palladium dichloride, bis(tri-p-fluorophenylphosphine)palladium dichloride, bis(tri-p-methoxyphenylphosphine)palladium dichloride or bis(triphenylphosphine)palladium dichloride.

[0017] The base is lithium hydroxide, potassium carbonate, cesium carbonate or potassium phosphate.

[0018] The solvent is acetonitrile, 1,4-dioxane, tetrahydrofuran, toluene or 1,2-dichloroethane.

[0019] The terminal alkyne is phenylacetylene, p-methylphenylacetylene, m-methylphenylacetylene, o-methylphenylacetylene, p-chlorophenylacetylene, m-chlorophenylacetylene, o-chlorophenylacetylene, p-ethylphenylacetylene, p-fluorophenylacetylene, p-trifluoromethylphenylacetylene, p-methoxyphenylacetylene, 3,5-dimethylphenylacetylene, 2-ethynylthiophene, 3-ethynylthiophene, ethynylcyclopropane or 1-heptyne.

[0020] The protective atmosphere is argon or nitrogen.

[0021] The fully substituted 1-butene-3-yne derivative contains a fully substituted 1,3-enyne structure and extremely high unsaturation, and can be used as a precursor for drug synthesis and modification.

[0022] The beneficial effects of the present invention are as follows: using readily available allyl compounds and terminal alkynes as starting materials, a coupling reaction occurs under transition metal catalysis conditions, and a 1,3-enyne skeleton structure is constructed in one step. The synthesized fully substituted 1-butene-3-yne derivative contains a 1,3-enyne structure and has an extremely high degree of unsaturation, and can be used as a good drug synthesis and modification precursor. DETAILED DESCRIPTION

[0023] The present invention will be further described in detail below in conjunction with specific embodiments, but the protection scope of the present invention is not limited to the contents. If no specific techniques or conditions are specified in the embodiments, the techniques or conditions described in the literature in this field or the product instructions are used. If the manufacturer of the reagents or instruments used is not specified, they are all conventional products that can be purchased.

[0024] Example 1: The structural formula of the fully substituted 1-butene-3-yne derivative of this example is as follows (1,4-diphenyl-1,2-diallyl-1-butene-3-yne 3aa):

[0025]

[0026] The synthesis method of 1,4-diphenyl-1,2-diallyl-1-butene-3-yne 3aa is as follows:

[0027] According to the molar ratio of phenylacetylene (1a), allyl bromide (2a), bis(tri-p-chlorophenylphosphine)palladium dichloride, potassium carbonate and tetrahydrofuran of 2:1:0.01:3:100, 0.8mmol phenylacetylene, 0.4mmol allyl bromide, 0.004mmol bis(tri-p-chlorophenylphosphine)palladium dichloride, 1.2mmol potassium carbonate and 40mmol tetrahydrofuran are added into a reactor in sequence, and argon is introduced. The reaction is carried out at a temperature of 120°C for 12h. The solvent is removed by vacuum distillation at 45°C to obtain a crude product. The crude product is subjected to column chromatography (300 mesh silica gel) to obtain 37mg of a fully substituted 1-butene-3-yne derivative (1,4-diphenyl-1,2-diallyl-1-butene-3-yne 3aa), and the eluent for column chromatography is petroleum ether.

[0028] The reaction equation is as follows:

[0029]

[0030] The NMR spectrum characterization data of the product are as follows: 1 H NMR (600 MHz, CDCl3) δ 7.47 (dd, J=7.8, 1.6 Hz, 2H), 7.35 – 7.31 (m, 4H), 7.19 – 7.14 (m, 2H), 5.93 (ddt, J =16.7, 10.1, 6.5 Hz, 1H), 5.80 (ddt, J = 16.9, 10.0, 6.8 Hz, 1H), 5.12 – 5.02(m, 3H), 4.98 (dd, J = 10.0, 1.4 Hz, 1H), 3.52 (d, J = 6.8 Hz, 2H), 2.89 (d, J = 6.4 Hz, 2H); 13 C NMR (151 MHz, CDCl3) δ 146.63, 140.56, 136.03, 135.13,131.49, 128.34, 128.22, 128.11, 128.04, 127.19, 123.72, 118.73, 116.19,115.89, 94.12, 89.42, 42.31, 37.88.

[0031] The yield of 1,4-diphenyl-1,2-diallyl-1-butene-3-yne 3aa in this example is 65%.

[0032] Example 2: The structural formula of the fully substituted 1-butene-3-yne derivative of this example is as follows (1,4-di(p-methylphenyl)-1,2-diallyl-1-butene-3-yne 3ba):

[0033]

[0034] The synthesis method of 1,4-di(p-methylphenyl)-1,2-diallyl-1-butene-3-yne 3ba is as follows:

[0035] According to the molar ratio of p-methylphenylacetylene (1b), allyl bromide (2a), bis(tri-p-chlorophenylphosphine)palladium dichloride, potassium carbonate and toluene of 1.2:1:0.05:3:70, 0.48mmol p-methylphenylacetylene, 0.4mmol allyl bromide, 0.02mmol bis(tri-p-chlorophenylphosphine)palladium dichloride, 1.2mmol potassium carbonate and 28mmol toluene are added into a reactor in sequence, and argon is introduced. The reaction is carried out at a temperature of 120°C for 12h. The solvent is removed by vacuum distillation at 40°C to obtain a crude product. The crude product is then subjected to column chromatography (300 mesh silica gel) to obtain 42mg of a fully substituted 1-butene-3-yne derivative (1,4-di(p-methylphenyl)-1,2-diallyl-1-butene-3-yne 3ba), and the eluent for the column chromatography is petroleum ether.

[0036] The reaction equation is as follows:

[0037]

[0038] The NMR spectrum characterization data of the product are as follows: 1 H NMR (600 MHz, CDCl3) δ 7.41 (d, J = 7.9Hz, 2H), 7.19 (t, J = 8.7 Hz, 4H), 7.12 (d, J = 7.8 Hz, 2H), 6.03 – 5.89 (m,1H), 5.89 – 5.78 (m, 1H), 5.18 – 5.04 (m, 3H), 5.02 (d, J = 10.0 Hz, 1H),3.56 (d, J = 6.7 Hz, 2H), 2.95 (d, J = 6.4 Hz, 2H), 2.40 (s, 6H); 13 C NMR (151MHz, CDCl3) δ 146.22, 138.10, 137.65, 136.83, 136.23, 135.39, 131.39, 129.11,128.82, 128.16, 120.75, 118.64, 116.04, 115.80, 94.24, 88.95, 42.34, 37.96,21.57, 21.29.

[0039] In this example, the yield of 1,4-di(p-methylphenyl)-1,2-diallyl-1-butene-3-yne 3ba was 67%.

[0040] Example 3: The structural formula of the fully substituted 1-butene-3-yne derivative of this example is as follows (1,4-di(p-methylphenyl)-1,2-diallyl-1-butene-3-yne 3ba):

[0041]

[0042] The synthesis method of 1,4-di(p-methylphenyl)-1,2-diallyl-1-butene-3-yne 3ba is as follows:

[0043] 0.6 mmol of p-methylphenylacetylene (1b), allyl chloride (2c), bis(tri-p-chlorophenylphosphine)palladium dichloride, potassium carbonate and acetonitrile were added into a reactor in the molar ratio of 1.5:1:0.05:3:70, and argon was introduced. The reaction was carried out at 120°C for 12 hours. The solvent was removed by vacuum distillation at 40°C to obtain a crude product. The crude product was subjected to column chromatography (300 mesh silica gel) to obtain 39 mg of a fully substituted 1-butene-3-yne derivative (1,4-di(p-methylphenyl)-1,2-diallyl-1-butene-3-yne 3ba). The eluent for the column chromatography was petroleum ether.

[0044] The reaction equation is as follows:

[0045]

[0046] The NMR spectrum characterization data of the product are as follows: 1 H NMR (600 MHz, CDCl3) δ 7.41 (d, J = 7.9Hz, 2H), 7.19 (t, J = 8.7 Hz, 4H), 7.12 (d, J = 7.8 Hz, 2H), 6.03 – 5.89 (m,1H), 5.89 – 5.78 (m, 1H), 5.18 – 5.04 (m, 3H), 5.02 (d, J = 10.0 Hz, 1H),3.56 (d, J = 6.7 Hz, 2H), 2.95 (d, J = 6.4 Hz, 2H), 2.40 (s, 6H); 13C NMR (151MHz, CDCl3) δ 146.22, 138.10, 137.65, 136.83, 136.23, 135.39, 131.39, 129.11,128.82, 128.16, 120.75, 118.64, 116.04, 115.80, 94.24, 88.95, 42.34, 37.96,21.57, 21.29.

[0047] In this example, the yield of 1,4-di(p-methylphenyl)-1,2-diallyl-1-butene-3-yne 3ba was 62%.

[0048] Example 4: The structural formula of the fully substituted 1-butene-3-yne derivative of this example is as follows (1,4-di(m-methylphenyl)-1,2-diallyl-1-butene-3-yne 3ca):

[0049]

[0050] The synthesis method of 1,4-di(m-methylphenyl)-1,2-diallyl-1-butene-3-yne 3ca is as follows:

[0051] According to the molar ratio of m-methylphenylacetylene (1c), allyl bromide (2a), bis(tri-p-chlorophenylphosphine)palladium dichloride, potassium carbonate and acetonitrile of 1.5:1:0.01:3:50, 0.6mmol m-methylphenylacetylene, 0.4mmol allyl bromide, 0.004mmol bis(tri-p-chlorophenylphosphine)palladium dichloride, 1.2mmol potassium carbonate and 20mmol acetonitrile were added into a reactor in sequence, and argon was introduced. The reaction was carried out at a temperature of 120°C for 12h. The solvent was removed by vacuum distillation at 45°C to obtain a crude product. The crude product was then subjected to column chromatography (300 mesh silica gel) to obtain 40mg of a fully substituted 1-butene-3-yne derivative (1,4-di(m-methylphenyl)-1,2-diallyl-1-butene-3-yne 3ca), and the eluent for the column chromatography was petroleum ether.

[0052] The reaction equation is as follows:

[0053]

[0054] The NMR spectrum characterization data of the product are as follows: 1 H NMR (600 MHz, CDCl3) δ 7.35 (d, J = 10.6Hz, 2H), 7.28 (q, J = 7.5 Hz, 2H), 7.16 (dd, J= 18.8, 7.5 Hz, 2H), 7.07 –7.00 (m, 2H), 6.07 – 5.95 (m, 1H), 5.86 (qdd, J = 8.1, 6.8, 3.4 Hz, 1H), 5.18– 5.00 (m, 4H), 3.57 (d, J = 6.7 Hz, 2H), 2.95 (d, J = 6.4 Hz, 2H), 2.41 (d, J = 6.4 Hz, 6H); 13 C NMR (151 MHz, CDCl3) δ 146.64, 140.57, 138.02, 137.66,136.22, 135.28, 132.04, 128.94, 128.86, 128.62, 128.27, 127.99, 127.95,125.34, 123.61, 118.65, 116.10, 115.82, 94.27, 89.19, 42.32, 38.00, 21.57,21.33.

[0055] In this example, the yield of 1,4-di(m-methylphenyl)-1,2-diallyl-1-butene-3-yne 3ca was 64%.

[0056] Example 5: The structural formula of the fully substituted 1-butene-3-yne derivative of this example is as follows (1,4-di(p-ethylphenyl)-1,2-diallyl-1-butene-3-yne 3da):

[0057]

[0058] The synthesis method of 1,4-di(p-ethylphenyl)-1,2-diallyl-1-butene-3-yne 3da is as follows:

[0059] 0.6 mmol of p-ethylphenylacetylene (1d), allyl bromide (2a), bis(tri-p-chlorophenylphosphine)palladium dichloride, potassium carbonate and acetonitrile were added into a reactor in the molar ratio of 1.5:1:0.01:3:70, and argon was introduced. The reaction was carried out at 100°C for 8 hours. The solvent was removed by vacuum distillation at 40°C to obtain a crude product. The crude product was subjected to column chromatography (300 mesh silica gel) to obtain 42 mg of a fully substituted 1-butene-3-yne derivative (1,4-di(p-ethylphenyl)-1,2-diallyl-1-butene-3-yne 3da). The eluent for the column chromatography was petroleum ether.

[0060] The reaction equation is as follows:

[0061]

[0062] The NMR spectrum characterization data of the product are as follows: 1 H NMR (600 MHz, CDCl3) δ 7.31 (d, J = 8.1Hz, 2H), 7.08 (dd, J = 8.0, 6.4 Hz, 4H), 7.01 (d, J = 8.1 Hz, 2H), 5.86 (ddt, J = 16.7, 10.1, 6.5 Hz, 1H), 5.73 (ddt, J = 16.8, 10.0, 6.8 Hz, 1H), 4.99(tdd, J = 6.4, 3.3, 1.7 Hz, 3H), 4.89 (dd, J = 10.0, 1.7 Hz, 1H), 3.43 (d, J = 6.7 Hz, 2H), 2.83 (d, J = 6.5 Hz, 2H), 2.57 (qd, J = 7.6, 3.6 Hz, 4H), 1.16(dt, J = 11.4, 7.6 Hz, 6H); 13C NMR (151 MHz, CDCl3) δ 146.27, 144.42, 143.10,137.92, 136.29, 135.44, 131.50, 128.20, 127.94, 127.58, 121.04, 118.67,116.00, 115.81, 94.31, 89.00, 42.35, 37.99, 28.91, 28.62, 15.55, 15.47.

[0063] The yield of 1,4-di(p-ethylphenyl)-1,2-diallyl-1-butene-3-yne 3da in this example is 62%.

[0064] Example 6: The structural formula of the fully substituted 1-butene-3-yne derivative of this example is as follows (1,4-di(p-methoxyphenyl)-1,2-diallyl-1-butene-3-yne 3ea):

[0065]

[0066] The synthesis method of 1,4-di(p-methoxyphenyl)-1,2-diallyl-1-butene-3-yne 3ea is as follows:

[0067] 0.6 mmol of p-methoxyphenylacetylene (1e), allyl bromide (2a), bis(tri-p-chlorophenylphosphine)palladium dichloride, potassium carbonate and acetonitrile were added into a reactor in the molar ratio of 1.5:1:0.1:2:70, and argon was introduced. The reaction was carried out at 120°C for 12 hours. The solvent was removed by vacuum distillation at 45°C to obtain a crude product. The crude product was subjected to column chromatography (300 mesh silica gel) to obtain 57 mg of a fully substituted 1-butene-3-yne derivative (1,4-di(p-methoxyphenyl)-1,2-diallyl-1-butene-3-yne 3ea). The eluent for the column chromatography was ethyl acetate / petroleum ether (volume ratio was 1 / 10).

[0068] The reaction equation is as follows:

[0069]

[0070] The NMR spectrum characterization data of the product are as follows: 1 H NMR (600 MHz, CDCl3) δ 7.32 (d, J = 8.8Hz, 2H), 7.03 (d, J= 8.7 Hz, 2H), 6.78 (dd, J = 11.2, 8.7 Hz, 4H), 5.86(ddt, J = 16.6, 10.1, 6.4 Hz, 1H), 5.72 (ddt, J = 16.8, 10.0, 6.8 Hz, 1H), 5.06 – 4.92 (m, 3H), 4.88 (dd, J = 10.0, 1.5 Hz, 1H), 3.73 (s, 6H), 3.42 (d, J = 6.7 Hz, 2H), 2.83 (d, J = 6.4 Hz, 2H); 13 C NMR (151 MHz, CDCl3) δ 159.41,158.64, 145.47, 136.32, 135.51, 132.89, 129.47, 118.57, 115.98, 115.76,113.98, 113.46, 94.03, 88.38, 55.33, 55.23, 42.36, 38.00.

[0071] In this example, the yield of 1,4-di(p-methoxyphenyl)-1,2-diallyl-1-butene-3-yne 3ea was 83%.

[0072] Example 7: The structural formula of the fully substituted 1-butene-3-yne derivative of this example is as follows (1,4-di(3,5-dimethylphenyl)-1,2-diallyl-1-butene-3-yne 3fa):

[0073]

[0074] The synthesis method of 1,4-bis(3,5-dimethylphenyl)-1,2-diallyl-1-butene-3-yne 3fa, the specific steps are as follows:

[0075] 0.6 mmol 3,5-dimethylphenylacetylene (1f), allyl bromide (2a), bis(tri(p-chlorophenylphosphine)palladium dichloride), potassium carbonate and acetonitrile were added into a reactor in the molar ratio of 1.5:1:0.01:3:70, and argon was introduced. The reaction was carried out at 120°C for 12 hours. The solvent was removed by vacuum distillation at 40°C to obtain a crude product. The crude product was subjected to column chromatography (300 mesh silica gel) to obtain 46 mg of a fully substituted 1-butene-3-yne derivative (1,4-bis(3,5-dimethylphenyl)-1,2-diallyl-1-butene-3-yne 3fa). The eluent for the column chromatography was petroleum ether.

[0076] The reaction equation is as follows:

[0077]

[0078] The NMR spectrum characterization data of the product are as follows: 1 H NMR (500 MHz, CDCl3) δ 7.15 (s, 2H), 6.97 (d, J = 17.3 Hz, 2H), 6.84 (s, 2H), 5.99 (ddt, J = 16.8, 10.2, 6.5 Hz,1H), 5.86 (ddt, J = 16.8, 10.0, 6.8 Hz, 1H), 5.19 – 5.07 (m, 3H), 5.03 (dd, J = 10.0, 1.9 Hz, 1H), 3.55 (d, J = 6.7 Hz, 2H), 2.94 (d, J = 6.5 Hz, 2H), 2.39– 2.32 (m, 12H); 13 C NMR (126 MHz, CDCl3) δ 146.60, 140.57, 137.86, 137.46,136.35, 135.39, 129.92, 129.15, 128.78, 125.96, 123.47, 118.54, 115.93,115.67, 94.35, 88.91, 42.25, 38.04, 21.40, 21.17.

[0079] In this example, the yield of 1,4-bis(3,5-dimethylphenyl)-1,2-diallyl-1-butene-3-yne 3fa was 68%.

[0080] Example 8: The structural formula of the fully substituted 1-butene-3-yne derivative of this example is as follows (1,4-di(2-thienyl)-1,2-diallyl-1-butene-3-yne 3ga):

[0081]

[0082] The synthesis method of 1,4-di(2-thienyl)-1,2-diallyl-1-butene-3-yne 3ga, the specific steps are as follows:

[0083] According to the molar ratio of 2-ethynylthiophene (1 g), allyl bromide (2a), bis(tri-p-chlorophenylphosphine)palladium dichloride, potassium carbonate and acetonitrile of 2:1:0.03:3:70, 0.8 mmol 2-ethynylthiophene, 0.4 mmol allyl bromide, 0.012 mmol bis(tri-p-chlorophenylphosphine)palladium dichloride, 1.2 mmol potassium carbonate and 28 mmol acetonitrile were added into the reactor in sequence, and argon was introduced. The reaction was carried out at 120°C for 12 hours. The solvent was removed by vacuum distillation at 40°C to obtain a crude product. The crude product was then subjected to column chromatography (300 mesh silica gel) to obtain 32 mg of a fully substituted 1-butene-3-yne derivative (1,4-di(2-thienyl)-1,2-diallyl-1-butene-3-yne 3ga). The eluent for the column chromatography was petroleum ether.

[0084] The reaction equation is as follows:

[0085]

[0086] The NMR spectrum characterization data of the product are as follows: 1 H NMR (600 MHz, CDCl3) δ 7.24 (dd, J =4.5, 1.7 Hz, 1H), 7.20 – 7.17 (m, 1H), 7.14 – 7.10 (m, 1H), 6.96 – 6.87 (m,3H), 5.90 (ddt, J = 16.4, 10.1, 6.2 Hz, 1H), 5.78 (ddt, J = 16.7, 10.0, 6.6Hz, 1H), 5.16 – 4.89 (m, 4H), 3.47 (d, J = 6.6 Hz, 2H), 3.12 (d, J = 6.2 Hz,2H).

[0087] In this example, the yield of 1,4-di(2-thienyl)-1,2-diallyl-1-butene-3-yne 3ga was 54%.

[0088] Example 9: The structural formula of the fully substituted 1-butene-3-yne derivative of this example is as follows (1,4-di(3-thienyl)-1,2-diallyl-1-butene-3-yne 3ha):

[0089]

[0090] The synthesis method of 1,4-di(3-thienyl)-1,2-diallyl-1-butene-3-yne 3ha, the specific steps are as follows:

[0091] 0.6 mmol 3-ethynylthiophene (1h), allyl bromide (2a), bis(tri(p-chlorophenylphosphine)palladium dichloride), potassium carbonate and acetonitrile were added into a reactor in the molar ratio of 1.5:1:0.01:3:70, and argon was introduced. The reaction was carried out at 120°C for 12h. The solvent was removed by distillation under reduced pressure at 40°C to obtain a crude product. The crude product was subjected to column chromatography (300 mesh silica gel) to obtain 36 mg of a fully substituted 1-butene-3-yne derivative (1,4-di(3-thienyl)-1,2-diallyl-1-butene-3-yne 3ha). The eluent for the column chromatography was petroleum ether.

[0092] The reaction equation is as follows:

[0093]

[0094] The NMR spectrum characterization data of the product are as follows: 1 H NMR (600 MHz, CDCl3) δ 7.41 – 7.32 (m,1H), 7.20 (ddd, J = 10.9, 4.9, 3.0 Hz, 2H), 7.07 (dd, J = 15.9, 3.4 Hz, 2H), 6.98 – 6.92 (m, 1H), 5.90 (ddt, J = 16.4, 10.2, 6.2 Hz, 1H), 5.75 (ddt, J =16.7, 10.0, 6.6 Hz, 1H), 5.12 – 4.82 (m, 4H), 3.41 (d, J= 6.6 Hz, 2H), 2.96(d, J = 6.1 Hz, 2H).

[0095] In this example, the yield of 1,4-di(3-thienyl)-1,2-diallyl-1-butene-3-yne 3ha was 61%.

[0096] Example 10: The structural formula of the fully substituted 1-butene-3-yne derivative of this example is as follows (1,4-diphenyl-1,2-di(2-methylallyl)-1-butene-3-yne 3ab):

[0097]

[0098] The synthesis method of 1,4-diphenyl-1,2-di(2-methylallyl)-1-butene-3-yne 3ab is as follows:

[0099] 0.4 mmol of phenylacetylene (1a), 3-bromo-2-methylpropene (2b), bis(tri-p-chlorophenylphosphine)palladium dichloride, potassium carbonate and acetonitrile were added into a reactor in the molar ratio of 1:1:0.01:3:70, and argon was introduced. The reaction was carried out at 120°C for 12 hours. The solvent was removed by vacuum distillation at 45°C to obtain a crude product. The crude product was then subjected to column chromatography (300 mesh silica gel) to obtain 28 mg of a fully substituted 1-butene-3-yne derivative (1,4-diphenyl-1,2-di(2-methylallyl)-1-butene-3-yne 3ab). The eluent for the column chromatography was petroleum ether.

[0100] The reaction equation is as follows:

[0101]

[0102] The NMR spectrum characterization data of the product are as follows: 1 H NMR (500 MHz, CDCl3) δ 7.48 (dt, J =8.3, 2.2 Hz, 2H), 7.38 – 7.26 (m, 6H), 7.23 – 7.16 (m, 2H), 4.89 (d, J = 6.4Hz, 2H), 4.72 (s, 1H), 4.65 (d, J= 1.0 Hz, 1H), 3.57 (s, 2H), 2.90 (s, 2H), 1.79 (s, 3H), 1.73 (s, 3H); 13 C NMR (126 MHz, CDCl3) δ 147.13, 143.79, 142.94,140.50, 131.45, 128.29, 128.13, 127.92, 127.91, 127.06, 123.90, 119.57,112.36, 111.71, 93.48, 90.09, 46.19, 41.72, 22.68, 22.40.

[0103] In this example, the yield of 1,4-diphenyl-1,2-di(2-methylallyl)-1-butene-3-yne 3ab was 45%.

[0104] Example 11: The structural formula of the fully substituted 1-butene-3-yne derivative of this example is as follows (1,4-diphenyl-1,2-diallyl-1-butene-3-yne 3aa):

[0105]

[0106] The synthesis method of 1,4-diphenyl-1,2-diallyl-1-butene-3-yne 3aa is as follows:

[0107] According to the molar ratio of phenylacetylene (1a), allyl bromide (2a), bis(triphenylphosphine)palladium dichloride, lithium hydroxide and acetonitrile of 2:1:0.1:1:20, 0.8mmol phenylacetylene, 0.4mmol allyl bromide, 0.04mmol bis(triphenylphosphine)palladium dichloride, 0.4mmol lithium hydroxide and 8mmol acetonitrile were added to the reactor in sequence, and argon was introduced. The reaction was carried out at a temperature of 120°C for 18h. The solvent was removed by vacuum distillation at 45°C to obtain a crude product. The crude product was then subjected to column chromatography (300 mesh silica gel) to obtain 33mg of a fully substituted 1-butene-3-yne derivative (1,4-diphenyl-1,2-diallyl-1-butene-3-yne 3aa). The eluent for the column chromatography was petroleum ether.

[0108] The reaction equation is as follows:

[0109]

[0110] The NMR spectrum characterization data of the product are as follows: 1 H NMR (600 MHz, CDCl3) δ 7.47 (dd, J=7.8, 1.6 Hz, 2H), 7.35 – 7.31 (m, 4H), 7.19 – 7.14 (m, 2H), 5.93 (ddt, J =16.7, 10.1, 6.5 Hz, 1H), 5.80 (ddt, J = 16.9, 10.0, 6.8 Hz, 1H), 5.12 – 5.02(m, 3H), 4.98 (dd, J = 10.0, 1.4 Hz, 1H), 3.52 (d, J = 6.8 Hz, 2H), 2.89 (d, J = 6.4 Hz, 2H); 13 C NMR (151 MHz, CDCl3) δ 146.63, 140.56, 136.03, 135.13,131.49, 128.34, 128.22, 128.11, 128.04, 127.19, 123.72, 118.73, 116.19,115.89, 94.12, 89.42, 42.31, 37.88.

[0111] The yield of 1,4-diphenyl-1,2-diallyl-1-butene-3-yne 3aa in this example is 58%.

Claims

1. A method for preparing a fully substituted 1-butene-3-yne derivative, characterized in that: Add terminal alkyne, allyl compound, catalyst and base to a solvent to obtain a reaction system, react under a protective atmosphere at 100°C to 120°C for 6 to 18 hours, remove the solvent by vacuum distillation, and perform column chromatography to obtain a fully substituted 1-butene-3-yne derivative; The compound structural formula of the fully substituted 1-butene-3-yne derivative is shown in Formula I or Formula II: ； Where: R 1 is H, CH3, OCH3, C2H5, Cl, F or CF3; R 2 is H or CH3; R 3 is thienyl, cyclopropyl or n-pentyl; The allyl compound is allyl bromide, allyl chloride, allyl acetate or 3-bromo-2-methylpropene; the catalyst is bis(tri-p-chlorophenylphosphine)palladium dichloride, bis(tri-p-fluorophenylphosphine)palladium dichloride, bis(tri-p-methoxyphenylphosphine)palladium dichloride or bis(triphenylphosphine)palladium dichloride; the base is lithium hydroxide, potassium carbonate, cesium carbonate or potassium phosphate; The terminal alkyne is phenylacetylene, p-methylphenylacetylene, m-methylphenylacetylene, o-methylphenylacetylene, p-chlorophenylacetylene, m-chlorophenylacetylene, o-chlorophenylacetylene, p-ethylphenylacetylene, p-fluorophenylacetylene, p-trifluoromethylphenylacetylene, p-methoxyphenylacetylene, 3,5-dimethylphenylacetylene, 2-ethynylthiophene, 3-ethynylthiophene, ethynylcyclopropane or 1-heptyne.

2. The method for preparing the fully substituted 1-butene-3-yne derivative according to claim 1, characterized in that: The molar ratio of terminal alkyne, allyl compound, catalyst, base and solvent is (1~3): 1: (0.01~0.1): (1~4): (10~100).

3. The method for preparing the fully substituted 1-butene-3-yne derivative according to claim 1, characterized in that: The solvent is acetonitrile, 1,4-dioxane, tetrahydrofuran, toluene or 1,2-dichloroethane.

4. The method for preparing the fully substituted 1-butene-3-yne derivative according to claim 1, characterized in that: The protective atmosphere is argon or nitrogen.

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