WO2022016743A1 - 一种多取代环己-2-烯酮的一步合成方法 - Google Patents

一种多取代环己-2-烯酮的一步合成方法 Download PDF

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WO2022016743A1
WO2022016743A1 PCT/CN2020/127129 CN2020127129W WO2022016743A1 WO 2022016743 A1 WO2022016743 A1 WO 2022016743A1 CN 2020127129 W CN2020127129 W CN 2020127129W WO 2022016743 A1 WO2022016743 A1 WO 2022016743A1
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cyclohex
enone
polysubstituted
reaction
synthesis method
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French (fr)
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张志华
蒋达洪
王煦
李磊
孙婧
张桂禧
鲍琳
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广东石油化工学院
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/72—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups
    • C07C45/74—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups combined with dehydration
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/14—All rings being cycloaliphatic
    • C07C2602/26—All rings being cycloaliphatic the ring system containing ten carbon atoms
    • C07C2602/28—Hydrogenated naphthalenes

Definitions

  • the invention relates to the field of biomedicine, and more particularly, to a one-step synthesis method of polysubstituted cyclohex-2-enone.
  • cyclohex-2-enone derivatives are an important means of constructing carbocyclic skeletons. Such compounds also play an important role in the synthesis of some physiologically active natural products and drug molecules. They are also used to prepare some special structures. Phenols, such as raw materials for meta-substituted phenols (Liang Y.; Song S.; Ai L.; Lia X.; Jiao N. Green Chem., 2016, 18, 6462–6467).
  • Cyclohex-2-enone derivatives can be prepared from 3-hydroxycyclohexanone dicarboxylate by dehydration and decarboxylation in a mixed solvent of concentrated hydrochloric acid and glacial acetic acid for a long time (Kamatchi, S.; Mohan, S. Gomathi, R. et al. K. Indian Journal of Chemistry: Section B, 2009, 48B, 553-562).
  • the raw materials of this method need to be prepared first, and the excess hydrochloric acid and glacial acetic acid need to be neutralized with ammonia water, which is not friendly to the environment.
  • One-step preparation of cyclohex-2-enone derivatives is a classical method using aryl formaldehyde and acetone as raw materials, and is prepared by Aldol condensation-Robinson ring enlargement reaction (Wang, F.; Liu, Y.; Qi, Z. et al. . Tetrahedron Letters, 2014, 55, 6399-6402).
  • This one-step reaction greatly simplifies the synthesis steps, it requires noble metal rhodium catalyst and stoichiometric amount of silver, and the corrosion of acetone to the equipment sealing ring under high temperature and high pressure reaction conditions often leads to the failure of the reaction.
  • This method generally uses two reactants, the types of cyclohex-2-enone derivatives synthesized are limited, and the scope of application of substrates is also narrow.
  • the present invention aims to overcome at least one defect (deficiency) of the above-mentioned prior art, and provides a one-step synthesis method of polysubstituted cyclohex-2-enone, which is low in cost, easy to operate, short in time, and suitable for substrates. It can freely adjust the substituents at the 3, 4, and 5-positions of cyclohex-2-enone according to the kinds of terminal alkynes and ketones.
  • the technical scheme adopted in the present invention is: a one-step synthesis method of polysubstituted cyclohex-2-enone, using terminal alkyne, ketone and ethyl acetoacetate as reaction raw materials, in an aprotic polar solvent, a strong base exists The following reaction gave polysubstituted cyclohex-2-enone.
  • terminal alkyne and ketone are first reacted in the presence of a strong base and aprotic polar solvent, and then ethyl acetoacetate is added for the reaction.
  • the reaction of alkynes and ketones needs to be carried out in a strong base environment, and ethyl acetoacetate will neutralize the strong base if added at the beginning.
  • step B Add ethyl acetoacetate in the reaction flask of step A, heat the reaction for 5 to 8 hours, use TLC dot plate to judge that the reaction is complete, and stop stirring;
  • step C Extract the product obtained in step B with ethyl acetate and distilled water twice, wash with saturated NaCl solution, combine the organic phases, dry the organic phase with anhydrous magnesium sulfate, filter to remove magnesium sulfate, and remove the solvent ethyl acetate by rotary evaporation ester, purified by column chromatography to obtain cyclohex-2-enone derivatives.
  • terminal alkyne is one of aryl terminal alkyne, six-membered heterocyclic terminal alkyne, and alkyl terminal alkyne.
  • Described six-membered heterocyclic terminal alkyne structural formula is:
  • Described alkyl terminal alkyne structural formula is:
  • R is selected from one of H, halogen group, alkyl group, alkoxy group, nitro group or ester group;
  • R 1 is selected from H, phenyl group, halogen group, alkyl group, alkoxy group or nitro group One;
  • R 2 is selected from one of alkyl and aryl;
  • R 3 is selected from one of H and alkyl;
  • R 4 is selected from heteroaryl or cyclopropyl.
  • the aprotic polar solvent is dimethyl sulfoxide or N,N-dimethylformamide.
  • the purpose of using the aprotic polar solvent dimethyl sulfoxide or N,N-dimethylformamide is to improve the nucleophilicity of the nucleophile and promote the formation of the nucleophilic addition reaction.
  • the strong base is sodium tert-butoxide or potassium tert-butoxide.
  • Sodium tert-butoxide and potassium tert-butoxide are non-new nuclear strong bases, which can not only satisfy the ⁇ -H reaction with ketones, but also avoid the direct addition of triple bonds with alkynes.
  • the molar ratio of the terminal alkyne, ketone and ethyl acetoacetate is 1:1.1-1.2:1.1-1.2.
  • the molar ratio of the terminal alkyne and the strong base is 1:1.2-1.5.
  • reaction equation Taking aryl terminal alkynes and ketones as raw materials, adding ethyl acetoacetate, and reacting in the presence of dimethyl sulfoxide and sodium tert-butoxide, the reaction equation is as follows:
  • reaction mechanism involved in this method is as follows:
  • ⁇ -H acidity of ketone 2 is stronger than that of terminal alkyne 1, it preferentially reacts with strong base to form carbanion, and the carbanion and alkyne triple bond undergo nucleophilic addition to form 4; 4 is dehydrated to obtain two intermediates 5 and 6, The Michael addition reaction was carried out under strong base conditions to form 7; 7 was hydrolyzed and decarboxylated to obtain the product 3.
  • non-nucleophilic strong bases such as sodium tert-butoxide and potassium tert-butoxide here is not only to satisfy the ⁇ -H reaction with ketones, but also to avoid the direct addition of triple bonds with alkynes.
  • aprotic polar solvent dimethyl sulfoxide (DMSO) or N,N-dimethylformamide (DMF) is to improve the nucleophilicity of the nucleophile and promote the nucleophilic addition reaction to generate 4 and Michael addition The reaction produces 7.
  • the use of a reaction temperature of 100°C facilitates the final decarboxylation reaction to produce product 3.
  • reaction equation and reaction mechanism of the reaction in the presence of dimethyl sulfoxide and sodium tert-butoxide are the same as the above-mentioned using aryl-terminated alkynes and ketones as raw materials, adding ethyl acetoacetate, in dimethyl sulfoxide and tert-butyl
  • the reaction equation and reaction mechanism of the reaction in the presence of sodium alkoxide are basically the same, and will not be repeated here.
  • the beneficial effects of the present invention are as follows: the raw materials used in the present invention are cheap, the reaction process does not need noble metal catalysts, the operation is simple, the time is short, the substrate is suitable for a wide range, and the types of terminal alkynes and ketones can be freely used. Adjust the substituents at the 3,4,5-position of cyclohex-2-enone.
  • Phenylacetylene (102 mg, 1.0 mmol), acetophenone (144 mg, 1.2 mmol), sodium tert-butoxide (144 mg, 1.5 mmol), and dimethyl sulfoxide (3 mL) were sequentially added to the reaction flask, and the temperature was raised to 100 ° C with stirring , keep stirring for 30 minutes. Then, ethyl acetoacetate (156 mg, 1.2 mmol) was added to the reaction flask, and after the reaction was incubated for 5 hours, the plate was spotted by TLC, and the starting point disappeared, that is, the reaction was complete, and the stirring was stopped.
  • Phenylacetylene (102 mg, 1.0 mmol), acetophenone (132 mg, 1.1 mmol), potassium tert-butoxide (134 mg, 1.2 mmol), and dimethyl sulfoxide (3 mL) were sequentially added to the reaction flask, and the temperature was raised to 110 ° C with stirring , keep stirring for 40 minutes. Then, ethyl acetoacetate (143 mg, 1.1 mmol) was added to the reaction flask, and after the reaction was incubated for 6 hours, the plate was spotted by TLC and the raw material point disappeared, that is, the reaction was complete, and the stirring was stopped.
  • Phenylacetylene (102 mg, 1.0 mmol), cyclohexanone (118 mg, 1.2 mmol), sodium tert-butoxide (144 mg, 1.5 mmol), DMSO (3 mL) were added to the reaction flask successively, and the temperature was raised to 100° C. under stirring, and kept stirring. 30 minutes. Then, ethyl acetoacetate (156 mg, 1.2 mmol) was added to the reaction flask, and after the reaction was incubated for 7 hours, the plate was spotted by TLC, and the raw material point disappeared, that is, the reaction was complete, and the stirring was stopped. Distilled water was added, extracted twice with ethyl acetate, and the organic phases were combined.
  • Phenylacetylene (102 mg, 1.0 mmol), pentan-2-one (103 mg, 1.2 mmol), sodium tert-butoxide (144 mg, 1.5 mmol), DMSO (3 mL) were added to the reaction flask in turn, and the temperature was raised to 100 ° C with stirring, Keep stirring for 30 minutes. Then, ethyl acetoacetate (156 mg, 1.2 mmol) was added to the reaction flask, and after the reaction was incubated for 8 hours, the plate was spotted by TLC, and the raw material point disappeared, that is, the reaction was complete, and the stirring was stopped. Distilled water was added, extracted twice with ethyl acetate, and the organic phases were combined.
  • Phenylacetylene (102 mg, 1.0 mmol), 1-phenylbutan-1-one (178 mg, 1.2 mmol), sodium tert-butoxide (144 mg, 1.5 mmol), and DMSO (3 mL) were added to the reaction flask in turn, and the temperature was raised under stirring. to 100°C, and stirring for 30 minutes. Then, ethyl acetoacetate (156 mg, 1.2 mmol) was added to the reaction flask, and after the reaction was incubated for 5 hours, the plate was spotted by TLC, and the starting point disappeared, that is, the reaction was complete, and the stirring was stopped. Distilled water was added, extracted twice with ethyl acetate, and the organic phases were combined.
  • Phenylacetylene (102 mg, 1.0 mmol), ⁇ -naphthalene ethyl ketone (204 mg, 1.2 mmol), sodium tert-butoxide (144 mg, 1.5 mmol), and DMSO (3 mL) were added to the reaction flask in turn, and the temperature was raised to 100 ° C with stirring , keep stirring for 30 minutes. Then, ethyl acetoacetate (156 mg, 1.2 mmol) was added to the reaction flask, and after the reaction was incubated for 6 hours, the plate was spotted by TLC, and the raw material point disappeared, that is, the reaction was complete, and the stirring was stopped.
  • the aryl-terminated alkyne Taking R selected from H, halogen, alkyl or alkoxy as an example, in addition, R can also be selected from nitro or ester; ketone Taking R 1 selected from H as an example, in addition, R 1 can also be selected from one of phenyl group, halogen group, alkyl group, alkoxy group or nitro group.

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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Abstract

一种多取代环己-2-烯酮的一步合成方法，以末端炔烃、酮、乙酰乙酸乙酯为反应原料，在非质子极性溶剂中，强碱存在下反应得到多取代环己-2-烯酮；采用的原料廉价，反应过程无需贵金属催化剂，操作简便，时间短，底物适用范围广，还可通过炔烃与酮的种类自由调节环己-2-烯酮3,4,5-位的取代基。

Description

一种多取代环己-2-烯酮的一步合成方法 技术领域
本发明涉及生物医药领域，更具体地，涉及一种多取代环己-2-烯酮的一步合成方法。
背景技术
环己-2-烯酮衍生物的制备是构建碳环骨架的重要手段，该类化合物也在合成某些具有生理活性的天然产物、药物分子中发挥着重要作用，它还是制备某些特殊结构酚类，如间位取代酚的原料(Liang Y.；Song S.；Ai L.；Lia X.；Jiao N.Green Chem.,2016,18,6462–6467)。环己-2-烯酮衍生物可由3-羟基环己酮二甲酸酯为原料，在浓盐酸和冰醋酸混合溶剂中长时间回流经脱水脱羧而制备(Kamatchi,S.；Mohan,S.；Gomathi,R.et al.K.Indian Journal of Chemistry:Section B,2009,48B,553-562)。然而此方法的原料需先行制备，过量的盐酸和冰醋酸需用氨水中和，对环境不友好。一步法制备环己-2-烯酮衍生物经典方法是以芳基甲醛和丙酮为原料，采用Aldol缩合-Robinson增环反应制备(Wang,F.；Liu,Y.；Qi,Z.et al.Tetrahedron Letters,2014,55,6399-6402)。这种一步反应虽然极大地简化了合成步骤，却需要耗费贵金属铑催化剂和化学计量的银，并且高温高压反应条件下丙酮对设备密封圈的腐蚀也经常导致反应失败。这种方法一般为两种反应物，合成的环己-2-烯酮衍生物类型有限，底物适用范围也较窄。
因此，寻找原料廉价、操作简便、无需贵金属催化剂、反应时间短、产物易调控、底物范围广的多种组份一步合成多取代的环己-2-烯酮方法仍然具有重要意义。
发明内容
本发明旨在克服上述现有技术的至少一种缺陷(不足)，提供一种多取代环己-2-烯酮的一步合成方法，该方法成本低、操作简便、时间短、底物适用范围广， 能够根据末端炔烃和酮的种类自由调节环己-2-烯酮3,4,5-位的取代基。
本发明采取的技术方案是：一种多取代环己-2-烯酮的一步合成方法，以末端炔烃、酮、乙酰乙酸乙酯为反应原料，在非质子极性溶剂中，强碱存在下反应得到多取代环己-2-烯酮。
进一步地，所述的末端炔烃与酮在强碱及非质子极性溶剂存在下先进行反应，再加入乙酰乙酸乙酯进行反应。炔烃与酮的反应需在强碱环境下进行，而乙酰乙酸乙酯如果一开始加入会中和强碱。
进一步地，包括如下步骤：
A.将末端炔烃、酮、强碱、非质子极性溶剂依次加入反应瓶中，搅拌下升温至100～110℃,保温搅拌30～40分钟；
B.在A步骤的反应瓶中加入乙酰乙酸乙酯，保温反应5～8个小时，用TLC点板判断反应完全，停止搅拌；
C.对步骤B所得产物用乙酸乙酯和蒸馏水萃取两次，再用饱和NaCl溶液洗涤，合并有机相，再用无水硫酸镁干燥有机相，过滤除去硫酸镁，旋蒸蒸除溶剂乙酸乙酯，柱层析提纯得到环己-2-烯酮衍生物。
进一步地，所述的末端炔烃为芳基末端炔烃、六元杂环末端炔烃、烷基末端炔烃中的一种。
进一步地，所述的芳基末端炔烃结构式为：
Figure PCTCN2020127129-appb-000001
所述的六元杂环末端炔烃结构式为：
Figure PCTCN2020127129-appb-000002
所述的烷基末端炔烃结构式为：
Figure PCTCN2020127129-appb-000003
所述酮的结构式为：
Figure PCTCN2020127129-appb-000004
所述多取代环己-2-烯酮的结构式为：
Figure PCTCN2020127129-appb-000005
其中，R选自H，卤素基，烷基，烷氧基，硝基或酯基中的一种；R 1选自H，苯基，卤素基，烷基，烷氧基或硝基中的一种；R 2选自烷基、芳基中的一种；R 3选自H、烷基中的一种；R 4选自杂芳基或环丙基。
进一步地，所述的非质子极性溶剂为二甲亚砜或N,N-二甲基甲酰胺。采用非质子极性溶剂二甲亚砜或N,N-二甲基甲酰胺的目的是为了提高亲核试剂的亲核性，促进亲核加成反应生成。
进一步地，所述的强碱为叔丁醇钠或叔丁醇钾。叔丁醇钠、叔丁醇钾为非新核强碱，既能满足与酮的α-H反应，又能避免其直接与炔烃三键加成。
进一步地，所述端基炔烃、酮、乙酰乙酸乙酯的摩尔比为1:1.1～1.2:1.1～1.2。
进一步地，所述端基炔烃、强碱的摩尔比为1:1.2～1.5。
以芳基末端炔烃、酮为原料，加入乙酰乙酸乙酯，在二甲亚砜和叔丁醇钠存在条件下进行反应，反应方程式如下：
Figure PCTCN2020127129-appb-000006
本方法所涉及的反应机理如下：
Figure PCTCN2020127129-appb-000007
由于酮2的α-H酸性强于末端炔烃1而优先与强碱反应形成碳负离子，碳负离子与炔烃三键发生亲核加成生成4；4脱水得到5跟6两种中间体，在强碱条件下进行Michael加成反应生成7；7进行水解反应、脱羧反应得到产物3。这里采用非亲核强碱如叔丁醇钠、叔丁醇钾的目的是既能满足与酮的α-H反应，又能避免其直接与炔烃三键加成。采用非质子极性溶剂二甲亚砜(DMSO)或N,N-二甲基甲酰胺(DMF)的目的是为了提高亲核试剂的亲核性，促进亲核加成反应生成4和Michael加成反应生成7。采用100℃的反应温度有利于最后的脱羧反应生成产物3。
以六元杂环末端炔烃、酮为原料，加入乙酰乙酸乙酯，在二甲亚砜和叔丁醇钠存在条件下进行反应及以烷基末端炔烃、酮为原料，加入乙酰乙酸乙酯，在二甲亚砜和叔丁醇钠存在条件下进行反应的反应方程式与反应机理与上述以芳基末端炔烃、酮为原料，加入乙酰乙酸乙酯，在二甲亚砜和叔丁醇钠存在条件下进行反应的反应方程式与反应机理基本相同，这里不再赘述。
与现有技术相比，本发明的有益效果为：本发明采用的原料廉价，反应过程无需贵金属催化剂，操作简便，时间短，底物适用范围广，还可通过末端炔烃与酮的种类自由调节环己-2-烯酮3,4,5-位的取代基。
具体实施方式
本发明仅用于示例性说明，不能理解为对本发明的限制。为了让本领域技术人员更好地理解本发明的技术方案，下面对本发明作进一步阐述。
实施例1
5-苄基-3-苯基环己-2-烯酮的制备
Figure PCTCN2020127129-appb-000008
将苯乙炔(102mg，1.0mmol)，苯乙酮(144mg，1.2mmol)，叔丁醇钠(144mg，1.5mmol)，二甲亚砜(3mL)依次加入反应瓶中，搅拌下升温至100℃，保温搅拌30分钟。然后向反应瓶中加入乙酰乙酸乙酯(156mg，1.2mmol)，保温反应5个小时后，TLC点板，原料点消失，即反应完全，停止搅拌。用乙酸乙酯和蒸馏水萃取两次，再用饱和NaCl溶液洗涤，合并有机相，无水硫酸镁干燥有机相，过滤除去硫酸镁，旋蒸蒸除溶剂乙酸乙酯，柱层析提纯得无色油状物5-苄基-3-苯基环己-2-烯酮(217mg，产率83％)。产物经 1H NMR和 13C NMR确征如下： 1H NMR(400MHz,CDCl 3)，δ×10 -6：7.56～7.48(m,2H),7.42(m,3H),7.34(t,J＝7.3Hz,2H),7.28～7.22(m,1H),7.23～7.17(m,2H),6.44(s,1H),2.82(t,J＝9.6Hz,3H),2.57(ddd,J＝15.1,14.3,3.1Hz,3H),2.27(dd,J＝15.7,11.9Hz,1H)； 13C NMR(101MHz,CDCl3)，δ×10 -6：199.69,158.93,138.94,138.73,130.04,129.12,128.78,128.57,126.46,126.16,125.39,43.34,42.08,36.95,34.24。
实施例2
5-苄基-3-苯基环己-2-烯酮的制备
Figure PCTCN2020127129-appb-000009
将苯乙炔(102mg，1.0mmol)，苯乙酮(132mg，1.1mmol)，叔丁醇钾(134mg，1.2mmol)，二甲亚砜(3mL)依次加入反应瓶中，搅拌下升温至110℃，保温搅拌40分钟。然后向反应瓶中加入乙酰乙酸乙酯(143mg，1.1mmol)，保温反应6个小时后，TLC点板，原料点消失，即反应完全，停止搅拌。加入蒸馏水，用乙酸乙酯萃取两次，合并有机相。再用饱和NaCl溶液洗涤，无水硫酸镁干燥有机相，过滤除去硫酸镁，旋蒸蒸除溶剂，柱层析提纯得无色油状物5-苄基-3-苯基环己-2-烯酮(212mg，产率81％)。产物经1H NMR和13C NMR确征如下：1H NMR(400MHz,CDCl3)，δ×10-6：7.56～7.48(m,2H),7.42(m,3H),7.34(t,J＝7.3Hz,2H),7.28～7.22(m,1H),7.23～7.17(m,2H),6.44(s,1H),2.82(t,J＝9.6Hz,3H),2.57(ddd,J＝15.1,14.3,3.1Hz,3H),2.27(dd,J＝15.7,11.9Hz,1H)；13C  NMR(101MHz,CDCl3)，δ×10-6：199.69,158.93,138.94,138.73,130.04,129.12,128.78,128.57,126.46,126.16,125.39,43.34,42.08,36.95,34.24。
实施例3
4-苄基-4,4a,5,6,7,8-六氢化萘-2(3H)-酮的制备
Figure PCTCN2020127129-appb-000010
将苯乙炔(102mg，1.0mmol)，环己酮(118mg，1.2mmol)，叔丁醇钠(144mg，1.5mmol)，DMSO(3mL)依次加入反应瓶中，搅拌下升温至100℃，保温搅拌30分钟。然后向反应瓶中加入乙酰乙酸乙酯(156mg，1.2mmol)，保温反应7个小时后，TLC点板，原料点消失，即反应完全，停止搅拌。加入蒸馏水，用乙酸乙酯萃取两次，合并有机相。再用饱和NaCl溶液洗涤，无水硫酸镁干燥有机相，过滤除去硫酸镁，旋蒸蒸除溶剂乙酸乙酯，柱层析提纯得无色油状物4-苄基-4,4a,5,6,7,8-六氢化萘-2(3H)-酮(206mg，产率86％)。产物经 1H NMR和 13C NMR确征如下： 1H NMR(400MHz,CDCl 3)，δ×10 -6：7.33～7.31(m,2H),7.26～7.24(m,2H),7.23～7.21(m,1H),6.46(s,1H),2.90(m,1H),2.80～2.69(m,2H),2.24～2.71(m,2H),2.06～2.04(m,2H),1.97～1.95,1.37～1.35(m,2H),1.76～1.74,1.30～1.28(m,2H),1.67～1.65,1.21～1.19(m,2H),2.26(dd,J＝15.7,11.8Hz,1H)； 13C NMR(101MHz,CDCl3)，δ×10 -6：199.58,160.9,139.1,137.0,129.4,128.6,126.7,52.7,43.4,40.3,34.2,32.3,26.2,25.4,24.4。
实施例4
5-苄基-4-乙基-3-甲基环己-2-烯酮的制备
Figure PCTCN2020127129-appb-000011
将苯乙炔(102mg，1.0mmol)，戊-2-酮(103mg，1.2mmol)，叔丁醇钠(144mg，1.5mmol)，DMSO(3mL)依次加入反应瓶中，搅拌下升温至100℃，保温搅拌30分钟。然后向反应瓶中加入乙酰乙酸乙酯(156mg，1.2mmol)，保温反应8个小时后，TLC点板，原料点消失，即反应完全，停止搅拌。加入蒸馏水，用乙酸乙酯萃取两次，合并有机相。再用饱和NaCl溶液洗涤，无水硫酸镁干燥有机相，过滤除去硫酸镁，旋蒸蒸除溶剂，柱层析提纯得无色油状物5-苄基-4-乙 基-3-甲基环己-2-烯酮(162mg，产率71％)。产物经 1H NMR和 13C NMR确征如下： 1H NMR(400MHz,CDCl 3)，δ×10 -6：7.30～7.26(m,2H),7.23～7.19(m,3H),6.46(s,1H),3.00(dd,J＝13.9Hz,J＝6.4Hz,1H),2.86～2.74,2.55～2.59(m,2H),2.77～2.71(m,2H),2.26(m,1H),1.88(s,3H),1.25～1.46,1.40～1.35(m,2H),0.74(t,3J＝7.3Hz,3H)； 13C NMR(101MHz,CDCl3)，δ×10 -6：199.6,157.5,138.7,136.8,129.4,128.3,126.5,56.2,43.4,41.1,34.1,23.1,11.5,10.4。
实施例5
5-苄基-4-乙基-3-苯基环己-2-烯酮的制备
Figure PCTCN2020127129-appb-000012
将苯乙炔(102mg，1.0mmol)，1-苯基丁-1-酮(178mg，1.2mmol)，叔丁醇钠(144mg，1.5mmol)，DMSO(3mL)依次加入反应瓶中，搅拌下升温至100℃，保温搅拌30分钟。然后向反应瓶中加入乙酰乙酸乙酯(156mg，1.2mmol)，保温反应5个小时后，TLC点板，原料点消失，即反应完全，停止搅拌。加入蒸馏水，用乙酸乙酯萃取两次，合并有机相。再用饱和NaCl溶液洗涤，无水硫酸镁干燥有机相，过滤除去硫酸镁，旋蒸蒸除溶剂，柱层析提纯得无色油状物5-苄基-4-乙基-3-苯基环己-2-烯酮(189mg，产率65％)。产物经 1H NMR和 13C NMR确征如下： 1H NMR(400MHz,CDCl 3)，δ×10 -6：7.63～7.61(m,2H),7.36～7.34(m,3H),7.30～7.27(m,2H),7.22～7.19(m,3H),6.44(s,1H),3.29(ddd,J＝8.4Hz,J＝3.5Hz,J＝3.5Hz,1H),3.06(dd,J＝13.6Hz,J＝6.3Hz,1H),2.78～2.83,2.55～2.58(m,2H),2.70(dd,J＝13.6Hz,J＝7.6Hz,1H),2.26～2.29(m,1H),1.58～1.51,1.50～1.43(m,2H),0.68(t,J＝7.4Hz,3H)； 13C NMR(101MHz,CDCl3)，δ×10 -6：199.6,159.0,138.9,136.8,129.9,129.6,129.3,128.8,128.6,127.0,126.8,53.0,43.2,41.1,34.3,24.2,10.6。
实施例6
5-苄基-3-(萘-2-基)环己-2-烯酮的制备
Figure PCTCN2020127129-appb-000013
将苯乙炔(102mg，1.0mmol)，β-萘乙酮(204mg，1.2mmol)，叔丁醇钠(144 mg，1.5mmol)，DMSO(3mL)依次加入反应瓶中，搅拌下升温至100℃，保温搅拌30分钟。然后向反应瓶中加入乙酰乙酸乙酯(156mg，1.2mmol)，保温反应6个小时后，TLC点板，原料点消失，即反应完全，停止搅拌。加入蒸馏水，用乙酸乙酯萃取两次，合并有机相。再用饱和NaCl溶液洗涤，无水硫酸镁干燥有机相，过滤除去硫酸镁，旋蒸蒸除溶剂，柱层析提纯得无色油状物5-苄基-3-(萘-2-基)环己-2-烯酮(231mg，产率74％)。产物经 1H NMR和 13C NMR确征如下： 1H NMR(400MHz,CDC l3)，δ×10 -6：7.97～7.95(m,1H),7.84～7.81(m,2H),7.51～7.49,7.35～7.27(m,9H),6.42(s,1H),3.42(dd,J＝16.4Hz,J＝10.2Hz,1H),3.21(dd,J＝13.8Hz,J＝6.2Hz,1H),3.17(dd,J＝16.4Hz,J＝7.4Hz,1H),2.92(dd,J＝13.8Hz,J＝7.4Hz,1H),2.79～2.83(m,1H),2.52～2.59(m,1H),2.24～2.27(m,1H)； 13C NMR(101MHz,CDC l3)，δ×10 -6：199.7,156.5,139.0,136.9,129.4,128.6,126.7,133.9,132.9,128.4,128.3,127.8,127.0,126.6,123.5,43.4,41.0,39.3,34.1。
实施例7
5-(4-氯苯甲基)-3-苯基环己-2-烯酮的制备
Figure PCTCN2020127129-appb-000014
将4-氯苯乙炔(136mg，1.0mmol)，苯乙酮(144mg，1.2mmol)，叔丁醇钠(144mg，1.5mmol)，DMSO(3mL)依次加入反应瓶中，搅拌下升温至100℃，保温搅拌30分钟。然后向反应瓶中加入乙酰乙酸乙酯(156mg，1.2mmol)，保温反应5个小时后，TLC点板，原料点消失，即反应完全，停止搅拌。加入蒸馏水，用乙酸乙酯萃取两次，合并有机相。再用饱和NaCl溶液洗涤，无水硫酸镁干燥有机相，过滤除去硫酸镁，旋蒸蒸除溶剂，柱层析提纯得淡黄色油状物5-(4-氯苯甲基)-3-苯基环己-2-烯酮(266mg，产率90％)。产物经 1H NMR和 13C NMR确征如下： 1H NMR(400MHz,CDC l3)，δ×10 -6：7.55～7.46(m,2H),7.46～7.38(m,3H),7.30(d,J＝8.3Hz,2H),7.13(d,J＝8.2Hz,2H),6.44(s,1H),2.84～2.73(m,3H),2.55(dd,J＝25.5,16.8Hz,3H),2.25(dd,J＝15.8,11.8Hz,1H)； 13C NMR(101MHz,CDC l3)，δ×10 -6：199.36,158.73,138.59,137.39,132.30,130.40,130.13,128.82,128.71,126.13,125.38,43.20,41.33,36.84,34.09。
实施例8
5-(4-甲基苯甲基)-3-苯基环己-2-烯酮的制备
Figure PCTCN2020127129-appb-000015
将4-甲基苯乙炔(116mg，1.0mmol)，苯乙酮(144mg，1.2mmol)，叔丁醇钠(144mg，1.5mmol)，DMSO(3mL)依次加入反应瓶中，搅拌下升温至100℃，保温搅拌30分钟。然后向反应瓶中加入乙酰乙酸乙酯(156mg，1.2mmol)，保温反应5个小时后，TLC点板，原料点消失，即反应完全，停止搅拌。加入蒸馏水，用乙酸乙酯萃取两次，合并有机相。再用饱和NaCl溶液洗涤，无水硫酸镁干燥有机相，过滤除去硫酸镁，旋蒸蒸除溶剂，柱层析提纯得无色油状物5-(4-甲基苯甲基)-3-苯基环己-2-烯酮(234mg，产率85％)。 1H NMR(400MHz,CDC l3)，δ×10 -6：7.55～7.49(m,2H),7.45～7.39(m,3H),7.14(d,J＝7.9Hz,2H),7.09(d,J＝8.0Hz,2H),6.43(d,J＝1.7Hz,1H),2.82(d,J＝13.5Hz,1H),2.77(d,J＝6.6Hz,2H),2.64～2.48(m,3H),2.36(s,3H),2.26(dd,J＝16.0,12.2Hz,1H)； 13C NMR(101MHz,CDC l3)，δ×10 -6：199.78,158.99,138.78,135.94,135.82,130.00,129.23,129.00,128.76,126.16,125.39,43.37,41.63,37.02,34.22,21.03。
实施例9
5-(4-甲氧基苯甲基)-3-苯基环己-2-烯酮的制备
Figure PCTCN2020127129-appb-000016
将4-甲氧基苯乙炔(132mg，1.0mmol)，苯乙酮(144mg，1.2mmol)，叔丁醇钠(144mg，1.5mmol)，DMSO(3mL)依次加入反应瓶中，搅拌下升温至100℃，保温搅拌30分钟。然后向反应瓶中加入乙酰乙酸乙酯(156mg，1.2mmol)，保温反应5个小时后，TLC点板，原料点消失，即反应完全，停止搅拌。加入蒸馏水，用乙酸乙酯萃取两次，合并有机相。再用饱和NaCl溶液洗涤，无水硫酸镁干燥有机相，过滤除去硫酸镁，旋蒸蒸除溶剂，柱层析提纯得无色油状物5-(4-甲氧基苯甲基)-3-苯基环己-2-烯酮(228mg，产率78％)。 1H NMR(400MHz,CDC l3)，δ×10 -6：7.57～7.47(m,2H),7.46～7.38(m,3H),7.11(d,J＝8.6Hz,2H),6.93～6.83(m,2H),6.43(s,1H),3.82(s,3H),2.82(d,J＝13.5Hz,1H),2.75(d,J＝ 6.7Hz,2H),2.64～2.44(m,3H),2.25(dd,J＝16.1,12.1Hz,1H)； 13C NMR(101MHz,CDC l3)，δ×10 -6：199.79,158.98,158.23,138.76,130.98,130.04,130.02,128.77,126.16,125.38,113.98,55.30,43.32,41.14,37.12,34.18。
实施例10
5-环丙基甲基-3-苯基环己-2-烯酮的制备
Figure PCTCN2020127129-appb-000017
将环丙基乙炔(66mg，1.0mmol)，苯乙酮(144mg，1.2mmol)，叔丁醇钾(168mg，1.5mmol)，DMF(3mL)依次加入反应瓶中，搅拌下升温至110℃，保温搅拌40分钟。然后向反应瓶中加入乙酰乙酸乙酯(143mg，1.1mmol)，保温反应8个小时后，TLC点板，原料点消失，即反应完全，停止搅拌。加入蒸馏水，用乙酸乙酯萃取两次，合并有机相。再用饱和NaCl溶液洗涤，无水硫酸镁干燥有机相，过滤除去硫酸镁，旋蒸蒸除溶剂，柱层析提纯得无色油状物5-环丙基甲基-3-苯基环己-2-烯酮(158mg，产率70％)。 1H NMR(400MHz,CDC l3)，δ×10 -6：7.67(t,J＝8.3Hz,2H),7.47(dd,J＝16.7,9.6Hz,3H),6.38(s,1H),2.80～2.71(m,3H),2.52～2.41(m,1H),2.19(dd,J＝15.8,11.8Hz,1H),1.25～1.11(m,3H),0.40～0.15(m,4H)； 13C NMR(101MHz,CDC l3)，δ×10 -6：199.18,128.82,128.50,128.48,128.23,127.51,126.20,41.65,40.46,26.58,17.35,13.16,4.82.
上述实施例中，芳基末端炔烃
Figure PCTCN2020127129-appb-000018
以R选自H，卤素基，烷基或烷氧基作为举例，除此之外，R还可以选自硝基或酯基；酮
Figure PCTCN2020127129-appb-000019
以R 1选自H作为举例，除此之外，R 1还可以选自苯基，卤素基，烷基，烷氧基或硝基中的一种。
显然，本发明的上述实施例仅仅是为清楚地说明本发明技术方案所作的举例，而并非是对本发明的具体实施方式的限定。凡在本发明权利要求书的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明权利要求的保护范围之内。

Claims (10)

  1. 一种多取代环己-2-烯酮的一步合成方法，其特征在于，以末端炔烃、酮、乙酰乙酸乙酯为反应原料，在非质子极性溶剂中，强碱存在下反应得到多取代环己-2-烯酮。
  2. 根据权利要求1所述的一种多取代环己-2-烯酮的一步合成方法，其特征在于，所述的末端炔烃与酮在强碱及非质子极性溶剂存在下先进行反应，再加入乙酰乙酸乙酯进行反应。
  3. 根据权利要求2所述的一种多取代环己-2-烯酮的一步合成方法，其特征在于，包括如下步骤：
    A.将末端炔烃、酮、强碱、非质子极性溶剂依次加入反应瓶中，搅拌下升温，再保温搅拌；
    B.在A步骤的反应瓶中加入乙酰乙酸乙酯，保温反应完全后，停止搅拌；
    C.对步骤B所得产物用乙酸乙酯和蒸馏水萃取两次，再用饱和NaCl溶液洗涤，合并有机相，干燥有机相，去除溶剂乙酸乙酯，提纯得到多取代环己-2-烯酮。
  4. 根据权利要求3所述的一种多取代环已-2-烯酮的一步合成方法，其特征在于，
    所述步骤A中搅拌下升温至100～110℃，再保温搅拌30～40分钟；
    或所述步骤B中保温反应5～8个小时，用TLC点板判断反应完全；
    或所述步骤C中用无水硫酸镁干燥有机相，过滤除去硫酸镁，旋蒸蒸除溶剂乙酸乙酯，柱层析提纯得到多取代环已-2烯酮。
  5. 根据权利要求1-4任一所述的一种多取代环己-2-烯酮的一步合成方法，其特征在于，所述的末端炔烃为芳基末端炔烃、六元杂环末端炔烃、烷基末端炔烃中的一种。
  6. 根据权利要求5所述的多取代环己-2-烯酮的一步合成方法，其特征在于，所述芳基末端炔烃结构式为：
    Figure PCTCN2020127129-appb-100001
    所述六元杂环末端炔烃结构式为：
    Figure PCTCN2020127129-appb-100002
    所述烷基末端炔烃结构式为：
    Figure PCTCN2020127129-appb-100003
    所述酮的结构式为：
    Figure PCTCN2020127129-appb-100004
    所述多取代环己-2-烯酮的结构式为：
    Figure PCTCN2020127129-appb-100005
    其中，R选自H，卤素基，烷基，烷氧基，硝基或酯基中的一种；R 1选自H，苯基，卤素基，烷基，烷氧基或硝基中的一种；R 2选自烷基、芳基中的一种；R 3选自H、烷基中的一种；R 4选自杂芳基或环丙基。
  7. 根据权利要求1所述的一种多取代环己-2-烯酮的一步合成方法，其特征在于，所述的非质子极性溶剂为二甲亚砜或N,N-二甲基甲酰胺。
  8. 根据权利要求1所述的一种多取代环己-2-烯酮的一步合成方法，其特征在于，所述的强碱为叔丁醇钠或叔丁醇钾。
  9. 根据权利要求1所述的一种多取代环己-2-烯酮的一步合成方法，其特征在于，所述端基炔烃、酮、乙酰乙酸乙酯的摩尔比为1:1.1～1.2:1.1～1.2。
  10. 根据权利要求1所述的一种多取代环己-2-烯酮的一步合成方法，其特征在于，所述端基炔烃与强碱的摩尔比为1:1.2～1.5。
PCT/CN2020/127129 2020-07-22 2020-11-06 一种多取代环己-2-烯酮的一步合成方法 WO2022016743A1 (zh)

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