WO2021031756A1 - Method for synthesizing carboxylic acid or ketone compounds from alcohol or aldehyde using oxygen or oxygen in air as oxidant - Google Patents

Method for synthesizing carboxylic acid or ketone compounds from alcohol or aldehyde using oxygen or oxygen in air as oxidant Download PDF

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WO2021031756A1
WO2021031756A1 PCT/CN2020/102499 CN2020102499W WO2021031756A1 WO 2021031756 A1 WO2021031756 A1 WO 2021031756A1 CN 2020102499 W CN2020102499 W CN 2020102499W WO 2021031756 A1 WO2021031756 A1 WO 2021031756A1
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alcohol
oxygen
reaction
hydroxy
carboxylic acid
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麻生明
刘金仙
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浙江大学
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    • C07C45/32—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation with molecular oxygen
    • C07C45/37—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation with molecular oxygen of >C—O—functional groups to >C=O groups
    • C07C45/38—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation with molecular oxygen of >C—O—functional groups to >C=O groups being a primary hydroxyl group
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    • C07C45/32—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation with molecular oxygen
    • C07C45/37—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation with molecular oxygen of >C—O—functional groups to >C=O groups
    • C07C45/39—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation with molecular oxygen of >C—O—functional groups to >C=O groups being a secondary hydroxyl group
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07C51/16—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation
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    • C07C51/23—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation with molecular oxygen of oxygen-containing groups to carboxyl groups
    • C07C51/235—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation with molecular oxygen of oxygen-containing groups to carboxyl groups of —CHO groups or primary alcohol groups
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
    • C07C53/15—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen containing halogen
    • C07C53/19—Acids containing three or more carbon atoms
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
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    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
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    • C07C57/46—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings and other rings, e.g. cyclohexylphenylacetic acid
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    • C07C59/40—Unsaturated compounds
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings

Definitions

  • the present invention relates to a chemical synthesis method. Specifically, it is a new method for synthesizing carboxylic acid or ketone compounds from alcohols or aldehydes using oxygen or oxygen in the air as an oxidant. ,2,6,6-Tetramethylpiperidine oxide is used to oxidize alcohol or aldehyde to the corresponding carboxylic acid or ketone compound.
  • Carboxylic acid is a kind of basic chemical raw material and has a pivotal and important position in the chemical industry. Oxidation reaction is the main synthesis route of carboxylic acid compounds.
  • the environmental burden brought by traditional oxidation methods (heavy metal oxides) is often an insurmountable obstacle in industrial production. Therefore, air oxidation-based synthesis methods have attracted more and more attention. .
  • people have carried out some work in the air oxidation reaction of alcohols catalyzed by cheap metals, and developed some air oxidation systems based on cheap metal catalysts to achieve one-step conversion from alcohol to carboxylic acid (Tetrahedron Lett., 1995, 36, 6923) -6926; Chem.
  • the present invention has researched and developed a nitrate/4-hydroxy-2,2,6,6-tetramethylpiperidine oxide based on oxygen or oxygen in the air as the oxidant
  • the purpose of the present invention is to provide a simple, efficient, fast and more economical synthesis novel based on nitrate/4-hydroxy-2,2,6,6-tetramethylpiperidine oxide catalytic oxidation carboxylic acid or ketone compound method.
  • the present invention discloses a new method for synthesizing carboxylic acid or ketone compound from alcohol or corresponding aldehyde with oxygen or oxygen in the air as oxidant. It is used in nitrate/4-hydroxy-2,2,6,6-tetramethyl Under the catalysis of piperidine oxide and the action of additives, the reaction substrate alcohol or the corresponding aldehyde is oxidized to the corresponding carboxylic acid or ketone compound.
  • the reaction formula is as follows:
  • the method of the present invention specifically includes the following steps: adding nitrate, 4-hydroxy-2,2,6,6-tetramethylpiperidine oxide and additives into a container, ventilating, and then removing the reaction substrate alcohol Or the corresponding aldehyde is added to the reaction system at a time or dropwise, and the reaction is stirred; concentrated, fast column chromatography or direct distillation and steaming to obtain carboxylic acid or ketone compound.
  • the alcohol is primary alcohol RCH 2 OH or secondary alcohol R 1 CHOHR 2 .
  • R is C3-C15 linear or branched alkanes, or unsaturated hydrocarbons containing benzene rings or alkenes or alkynes, and the substrate is compatible with functional groups such as alkoxy and halogen; the reaction substrate or the corresponding primary alcohol Of aldehydes.
  • the primary alcohol is a primary monohydric alcohol or a primary dihydric alcohol
  • the primary dihydric alcohol is a primary dihydric alcohol with a carbon number greater than 6.
  • R 1 is C1-C15 linear or branched alkanes, or unsaturated hydrocarbons containing benzene rings or alkenes or alkynes
  • R 2 is C1-C15 linear or branched alkanes, or containing benzene rings or Unsaturated hydrocarbons such as alkenes or alkynes.
  • the secondary alcohol is a secondary fatty alcohol, benzyl alcohol, allyl alcohol or propargyl alcohol.
  • the additives are 1,2-dichloroethane, 1,1-dichloroethane, 1,2-dichloropropane, 1,3-dichloropropane, dichloromethane, nitromethane
  • 1,2-dichloroethane, 1,1-dichloroethane, 1,2-dichloropropane, 1,3-dichloropropane, dichloromethane, nitromethane One or more of benzene, toluene, acetonitrile, ethyl acetate, tetrahydrofuran, etc.; preferably, acetonitrile.
  • the nitrate is one or a mixture of iron nitrate nonahydrate and copper nitrate trihydrate; preferably, it is iron nitrate nonahydrate.
  • the molar ratio of the alcohol or the corresponding aldehyde, nitrate, 4-hydroxy-2,2,6,6-tetramethylpiperidine oxide is 100: (1-10): (1 ⁇ 10); Preferably, it is 100:5:5.
  • the molar ratio of the alcohol or the corresponding aldehyde and the additive is 1:(1-6); preferably, it is 1:3.
  • the inorganic chloride includes one or more of lithium chloride, sodium chloride, potassium chloride, rubidium chloride, cesium chloride, etc. ; Preferably, it is potassium chloride.
  • the molar ratio of the alcohol or corresponding aldehyde and inorganic chloride is 100:(1-10); preferably, it is 100:5.
  • the gas for pumping is pure oxygen or oxygen in the air.
  • the reaction temperature is room temperature to 50°C; preferably, it is room temperature.
  • the invention has the advantages of mild reaction conditions, easy operation, high yield, rich substrate diversity, environmental friendliness and the like.
  • nonahydrate ferric nitrate, 2,2,6,6-tetramethyl nitroxide, potassium chloride catalytic system (Aso Ming Jiang Xingguo, a method of oxygen oxidation of alcohol or aldehyde to produce acid, Application number: 201610141434.2, 2016.03.11)
  • it has the following advantages: 1) The price of the catalyst is extremely low, and the production cost is greatly reduced; 2) Additives such as acetonitrile can significantly promote the reaction; 3) The amount of solvent is greatly reduced ; 4)
  • the reaction can be carried out without adding chloride.
  • the invention is not only suitable for laboratory synthesis but also suitable for industrial synthesis of carboxylic acid compounds.
  • Figure 1 is a graph showing the effect of chloride addition on the oxidation reaction of isononanol.
  • the method for synthesizing carboxylic acid or ketone compound of the present invention is catalyzed by nitrate/4-hydroxy-2,2,6,6-tetramethylpiperidine oxide, in the presence of additives, at room temperature Alcohol or corresponding aldehyde is oxidized to corresponding carboxylic acid or ketone compound, the reaction formula is as follows:
  • R can be an alkyl group, an aryl group, an alkene group, an alkynyl group, etc.; preferably, the alkyl group is a straight or branched chain alkane with 3 to 15 carbons, which is compatible with functional groups such as alkoxy and halogen.
  • R 1 is a C1-C15 linear or branched alkane, or an unsaturated hydrocarbon containing a benzene ring or alkene or alkyne
  • R 2 is a C1-C15 linear or branched alkane or a benzene ring or alkene or alkyne Unsaturated hydrocarbons such as hydrocarbons.
  • the steps are: adding nitrate, 4-hydroxy-2,2,6,6-tetramethylpiperidine oxide and additives into a three-necked flask, pumping air (pure oxygen or air), and then adding alcohol to In the reaction system, the reaction is stirred at room temperature for 10-72 hours; concentrated, flash column chromatography (or direct distillation and steaming) to obtain carboxylic acid compounds.
  • ferric nitrate nonahydrate (405.8mg, 1.0mmol), 4-hydroxy-2,2,6,6-tetramethylpiperidine oxide (171.4mg, 1.0mmol), potassium chloride (75.7mg , 1.0mmol), 1a (1.4353g, 10.0mmol) and dichloromethane (2mL), ventilate (pure oxygen) three times, stir at room temperature (25°C) for 33 hours, and obtain 41% of 2a (with dibromomethane as internal Standard, nuclear magnetic yield), 27% of 3a (using dibromomethane as internal standard, nuclear magnetic yield).
  • the solvent has a significant influence on the reaction: 3,5,5-trimethyl-1-hexanol (isononyl alcohol, 1a) is used as the reaction substrate, and the yields in different solvents are significantly different (No. 1-4, The above examples 1-4); using acetonitrile as a solvent, the target compound (2a) can be obtained with a yield of 83% in only 12 hours; adding one equivalent of acetonitrile to 1,2-dichloroethane and toluene produces The rate is significantly increased, showing that acetonitrile has a promoting effect on the reaction (Sequence No. 5 and 6, Examples 5 and 6 above).
  • the reaction process of the present invention is: the primary alcohol is first oxidized to the corresponding aldehyde under the catalysis of nonahydrate ferric nitrate/4-hydroxy-2,2,6,6-tetramethylpiperidine oxide/potassium chloride (3 ), accompanied by the formation of esters (4) and acetals (5) (stage 1); as the reaction proceeds, aldehydes and acetals are gradually converted into corresponding carboxylic acids (2) (stage 2)
  • the solvent involved in the present invention can be acetonitrile, 1,2-dichloroethane, 1,1-dichloroethane, 1,2-dichloropropane, 1,3-dichloropropane, dichloromethane, nitro One or a mixture of methane, benzene, toluene, ethyl acetate, and tetrahydrofuran.
  • acetonitrile is used as the solvent (additive) to achieve the best effect.
  • the molar ratio of alcohol or corresponding aldehyde/acetonitrile is 1:1 to 6; preferably, the molar ratio of alcohol or corresponding aldehyde/acetonitrile is 1:3 .

Abstract

Disclosed is a new method for synthesizing carboxylic acid or ketone compounds from an alcohol or corresponding aldehyde using oxygen or oxygen in the air as an oxidant. Under the catalysis of a nitrate/4-hydroxy-2,2,6,6-tetramethylpiperidine oxide and under the action of additives, an alcohol or corresponding aldehyde is oxidized to a corresponding carboxylic acid or ketone compound. When an additional inorganic chloride is added, the reaction is accelerated. The invention has advantages such as a low catalyst price, easy operation, a high yield, rich substrate diversity, mild reaction conditions, and being environmentally friendly. The invention is not only suitable for laboratory synthesis but also suitable for industrial synthesis of carboxylic acid or ketone compounds.

Description

一种以氧气或空气中的氧气作为氧化剂从醇或醛合成羧酸或酮类化合物的方法A method for synthesizing carboxylic acid or ketone compounds from alcohol or aldehyde using oxygen or oxygen in the air as oxidant 技术领域Technical field
本发明涉及一种化学合成方法，具体地说，是一种以氧气或空气中的氧气作为氧化剂从醇或醛合成羧酸或酮类化合物的新方法，即在硝酸盐、4-羟基-2,2,6,6-四甲基哌啶氧化物存在的条件下将醇或醛氧化为相应的羧酸或酮类化合物。The present invention relates to a chemical synthesis method. Specifically, it is a new method for synthesizing carboxylic acid or ketone compounds from alcohols or aldehydes using oxygen or oxygen in the air as an oxidant. ,2,6,6-Tetramethylpiperidine oxide is used to oxidize alcohol or aldehyde to the corresponding carboxylic acid or ketone compound.
背景技术Background technique
羧酸是一类基础的化工原料，在化学工业中具有举足轻重的重要地位。氧化反应是羧酸类化合物的主要合成路径，传统氧化方法(重金属氧化物)带来的环境负担往往成为工业生产中不可逾越的障碍，因此基于空气氧化的合成方法受到人们越来越多的关注。近年来，人们在廉价金属催化的醇的空气氧化反应领域开展了一些工作，发展了一些基于廉价金属催化剂的空气氧化体系实现从醇到羧酸的一步转化(Tetrahedron Lett.,1995,36,6923-6926；Chem.Commun.,2004,244-245；J.Org.Chem.,2007,72,7030-7033；Applied Catalysis A:General,2012,423-424,52-58；Chem.Commun.,2015,51,4799-4802；J.Am.Chem.Soc.,2016,138,8344-8347；Synthesis,2018,50,1629-1639；Chin.J.Chem.,2018,36,15-19.)，但由于各种原因不适用于工业规模生产。由于2,2,6,6-四甲基哌啶氧化物的价格较高，在工业规模时其成本占比太高。相较而言，4-羟基-2,2,6,6-四甲基哌啶氧化物及其低廉，但其催化活性很低。Carboxylic acid is a kind of basic chemical raw material and has a pivotal and important position in the chemical industry. Oxidation reaction is the main synthesis route of carboxylic acid compounds. The environmental burden brought by traditional oxidation methods (heavy metal oxides) is often an insurmountable obstacle in industrial production. Therefore, air oxidation-based synthesis methods have attracted more and more attention. . In recent years, people have carried out some work in the air oxidation reaction of alcohols catalyzed by cheap metals, and developed some air oxidation systems based on cheap metal catalysts to achieve one-step conversion from alcohol to carboxylic acid (Tetrahedron Lett., 1995, 36, 6923) -6926; Chem. Commun., 2004, 244-245; J. Org. Chem., 2007, 72, 7030-7033; Applied Catalysis A: General, 2012, 423-424, 52-58; Chem. Commun., 2015,51,4799-4802; J.Am.Chem.Soc.,2016,138,8344-8347; Synthesis,2018,50,1629-1639; Chin.J.Chem.,2018,36,15-19. ), but it is not suitable for industrial-scale production for various reasons. Due to the high price of 2,2,6,6-tetramethylpiperidine oxide, its cost ratio is too high on an industrial scale. In comparison, 4-hydroxy-2,2,6,6-tetramethylpiperidine oxide is extremely cheap, but its catalytic activity is very low.
发明内容Summary of the invention
为了克服上述现有技术存在的缺陷，本发明研究并发展了一种基于硝酸盐/4-羟基-2,2,6,6-四甲基哌啶氧化物的以氧气或空气中氧气为氧化剂的从醇或醛合成羧酸或酮类化合物的催化氧化体系。In order to overcome the above-mentioned shortcomings of the prior art, the present invention has researched and developed a nitrate/4-hydroxy-2,2,6,6-tetramethylpiperidine oxide based on oxygen or oxygen in the air as the oxidant A catalytic oxidation system for the synthesis of carboxylic acids or ketones from alcohols or aldehydes.
本发明目的是提供一种简单、高效、快捷且更加经济的基于硝酸盐/4-羟基-2,2,6,6-四甲基哌啶氧化物催化氧化羧酸或酮类化合物的合成新方法。The purpose of the present invention is to provide a simple, efficient, fast and more economical synthesis novel based on nitrate/4-hydroxy-2,2,6,6-tetramethylpiperidine oxide catalytic oxidation carboxylic acid or ketone compound method.
本发明是通过以下技术方案来实现的：The present invention is realized through the following technical solutions:
本发明公开了一种以氧气或空气中的氧气作为氧化剂从醇或相应的醛合成羧酸或酮类化合物的新方法，在硝酸盐/4-羟基-2,2,6,6-四甲基哌啶氧化物催化下，并在添加剂的作用下，将反应底物醇或相应的醛氧化为相应的羧酸或酮类化合物，其反应式如下：The present invention discloses a new method for synthesizing carboxylic acid or ketone compound from alcohol or corresponding aldehyde with oxygen or oxygen in the air as oxidant. It is used in nitrate/4-hydroxy-2,2,6,6-tetramethyl Under the catalysis of piperidine oxide and the action of additives, the reaction substrate alcohol or the corresponding aldehyde is oxidized to the corresponding carboxylic acid or ketone compound. The reaction formula is as follows:
Figure PCTCN2020102499-appb-000001
Figure PCTCN2020102499-appb-000001
本发明所述方法具体包括以下步骤：将硝酸盐、4-羟基-2,2,6,6-四甲基哌啶氧化物及添加 剂加入到容器中，抽换气，然后将反应底物醇或相应的醛一次加入或滴加到反应体系中，搅拌反应；浓缩，快速柱层析或直接蒸馏蒸出，得羧酸或酮类化合物。The method of the present invention specifically includes the following steps: adding nitrate, 4-hydroxy-2,2,6,6-tetramethylpiperidine oxide and additives into a container, ventilating, and then removing the reaction substrate alcohol Or the corresponding aldehyde is added to the reaction system at a time or dropwise, and the reaction is stirred; concentrated, fast column chromatography or direct distillation and steaming to obtain carboxylic acid or ketone compound.
本发明中，所述的醇是伯醇RCH 2OH或仲醇R 1CHOHR 2。 In the present invention, the alcohol is primary alcohol RCH 2 OH or secondary alcohol R 1 CHOHR 2 .
其中，R为C3-C15的直链或支链烷烃，或含苯环或烯烃或炔烃的不饱和烃，底物兼容烷氧基、卤素等官能团；反应底物或是前述伯醇所对应的醛。Among them, R is C3-C15 linear or branched alkanes, or unsaturated hydrocarbons containing benzene rings or alkenes or alkynes, and the substrate is compatible with functional groups such as alkoxy and halogen; the reaction substrate or the corresponding primary alcohol Of aldehydes.
优选地，所述的伯醇是一元伯醇或是二元伯醇，所述二元伯醇为碳数大于6的二元伯醇。Preferably, the primary alcohol is a primary monohydric alcohol or a primary dihydric alcohol, and the primary dihydric alcohol is a primary dihydric alcohol with a carbon number greater than 6.
其中，R 1为C1-C15的直链或支链烷烃，或含苯环或烯烃或炔烃的不饱和烃等；R 2为C1-C15的直链或支链烷烃，或含苯环或烯烃或炔烃的不饱和烃等。 Among them, R 1 is C1-C15 linear or branched alkanes, or unsaturated hydrocarbons containing benzene rings or alkenes or alkynes; R 2 is C1-C15 linear or branched alkanes, or containing benzene rings or Unsaturated hydrocarbons such as alkenes or alkynes.
优选地，所述的仲醇为二级脂肪醇、苄醇、烯丙醇或炔丙醇等。Preferably, the secondary alcohol is a secondary fatty alcohol, benzyl alcohol, allyl alcohol or propargyl alcohol.
本发明中，所述的添加剂是1,2-二氯乙烷、1,1-二氯乙烷、1,2-二氯丙烷、1,3-二氯丙烷、二氯甲烷、硝基甲烷、苯、甲苯、乙腈、乙酸乙酯、四氢呋喃等中一种或几种；优选地，为乙腈。In the present invention, the additives are 1,2-dichloroethane, 1,1-dichloroethane, 1,2-dichloropropane, 1,3-dichloropropane, dichloromethane, nitromethane One or more of benzene, toluene, acetonitrile, ethyl acetate, tetrahydrofuran, etc.; preferably, acetonitrile.
本发明中，所述硝酸盐为九水合硝酸铁、三水合硝酸铜中的一种或混合；优选地，为九水合硝酸铁。In the present invention, the nitrate is one or a mixture of iron nitrate nonahydrate and copper nitrate trihydrate; preferably, it is iron nitrate nonahydrate.
本发明中，所述的醇或相应的醛、硝酸盐、4-羟基-2,2,6,6-四甲基哌啶氧化物的摩尔比为100：(1～10)：(1～10)；优选地，为100：5：5。In the present invention, the molar ratio of the alcohol or the corresponding aldehyde, nitrate, 4-hydroxy-2,2,6,6-tetramethylpiperidine oxide is 100: (1-10): (1~ 10); Preferably, it is 100:5:5.
本发明中，所述的醇或相应的醛、添加剂的摩尔比为1：(1～6)；优选地，为1：3。In the present invention, the molar ratio of the alcohol or the corresponding aldehyde and the additive is 1:(1-6); preferably, it is 1:3.
本发明中，当额外添加无机氯化物时，反应被加速，所述的无机氯化物包括氯化锂、氯化钠、氯化钾、氯化铷、氯化铯等中的一种或几种；优选地，为氯化钾。In the present invention, when additional inorganic chloride is added, the reaction is accelerated. The inorganic chloride includes one or more of lithium chloride, sodium chloride, potassium chloride, rubidium chloride, cesium chloride, etc. ; Preferably, it is potassium chloride.
其中，所述的醇或相应的醛、无机氯化物的摩尔比为100:(1～10)；优选地，为100:5。Wherein, the molar ratio of the alcohol or corresponding aldehyde and inorganic chloride is 100:(1-10); preferably, it is 100:5.
本发明中，所述抽换气的气体是纯氧气或空气中的氧气。In the present invention, the gas for pumping is pure oxygen or oxygen in the air.
本发明中，所述反应的温度为室温～50℃；优选地，为室温。In the present invention, the reaction temperature is room temperature to 50°C; preferably, it is room temperature.
本发明具有反应条件温和、易操作、产率较高、底物的多样性丰富、环境友好等优点。除此之外，与以九水合硝酸铁、2,2,6,6-四甲基氮氧化合物、氯化钾催化体系(麻生明姜兴国，一种氧气氧化醇或醛制备酸的方法，申请号：201610141434.2，2016.03.11)相比本发明具有以下优势：1)催化剂价格及其低廉，生产成本大幅度降低；2)添加剂如乙腈对本反应具有显著促进作用；3)溶剂用量大幅度降低；4)无需添加氯化物反应即可进行。本发明不仅适用于实验室合成也适用于工业上合成羧酸类化合物。The invention has the advantages of mild reaction conditions, easy operation, high yield, rich substrate diversity, environmental friendliness and the like. In addition, with the nonahydrate ferric nitrate, 2,2,6,6-tetramethyl nitroxide, potassium chloride catalytic system (Aso Ming Jiang Xingguo, a method of oxygen oxidation of alcohol or aldehyde to produce acid, Application number: 201610141434.2, 2016.03.11) Compared with the present invention, it has the following advantages: 1) The price of the catalyst is extremely low, and the production cost is greatly reduced; 2) Additives such as acetonitrile can significantly promote the reaction; 3) The amount of solvent is greatly reduced ; 4) The reaction can be carried out without adding chloride. The invention is not only suitable for laboratory synthesis but also suitable for industrial synthesis of carboxylic acid compounds.
附图说明Description of the drawings
图1为氯化物的添加与否对异壬醇氧化反应的影响的曲线图。Figure 1 is a graph showing the effect of chloride addition on the oxidation reaction of isononanol.
具体实施方式detailed description
本发明合成羧酸或酮类化合物的方法，是在硝酸盐/4-羟基-2,2,6,6-四甲基哌啶氧化物催化下，在添加剂存在的条件下，室温下可将醇或相应的醛氧化为相应的羧酸或酮类化合物，其反应式如下：The method for synthesizing carboxylic acid or ketone compound of the present invention is catalyzed by nitrate/4-hydroxy-2,2,6,6-tetramethylpiperidine oxide, in the presence of additives, at room temperature Alcohol or corresponding aldehyde is oxidized to corresponding carboxylic acid or ketone compound, the reaction formula is as follows:
Figure PCTCN2020102499-appb-000002
Figure PCTCN2020102499-appb-000002
其中，R可以是烷基，芳基，烯烃，炔基等；优选地，烷基为3～15个碳的直链或支链烷烃，可兼容烷氧基、卤素等官能团。Among them, R can be an alkyl group, an aryl group, an alkene group, an alkynyl group, etc.; preferably, the alkyl group is a straight or branched chain alkane with 3 to 15 carbons, which is compatible with functional groups such as alkoxy and halogen.
R 1为C1-C15的直链或支链烷烃，或含苯环或烯烃或炔烃的不饱和烃等；R 2为C1-C15的直链或支链烷烃或含苯环或烯烃或炔烃的不饱和烃等。 R 1 is a C1-C15 linear or branched alkane, or an unsaturated hydrocarbon containing a benzene ring or alkene or alkyne; R 2 is a C1-C15 linear or branched alkane or a benzene ring or alkene or alkyne Unsaturated hydrocarbons such as hydrocarbons.
其步骤是：将硝酸盐、4-羟基-2,2,6,6-四甲基哌啶氧化物及添加剂加入到三口瓶中，抽换气(纯氧或空气)，然后将醇加到反应体系中，室温下搅拌反应10-72小时；浓缩，快速柱层析(或直接蒸馏蒸出)，得羧酸类化合物。The steps are: adding nitrate, 4-hydroxy-2,2,6,6-tetramethylpiperidine oxide and additives into a three-necked flask, pumping air (pure oxygen or air), and then adding alcohol to In the reaction system, the reaction is stirred at room temperature for 10-72 hours; concentrated, flash column chromatography (or direct distillation and steaming) to obtain carboxylic acid compounds.
下面通过具体实施例对本发明的技术方案作进一步地说明：The technical solution of the present invention will be further explained by specific embodiments below:
实施例1Example 1
Figure PCTCN2020102499-appb-000003
Figure PCTCN2020102499-appb-000003
向三口瓶中加入九水合硝酸铁(401.8mg,1.0mmol)，4-羟基-2,2,6,6-四甲基哌啶氧化物(172.4mg,1.0mmol)，氯化钾(75.9mg,1.0mmol)，1a(1.4381g,10.0mmol)和1,2-二氯乙烷(2mL)，抽换气(纯氧)三次，室温下(25℃)搅拌33小时，得49％的2a(以二溴甲烷为内标，核磁产率)，39％的3a(以二溴甲烷为内标，核磁产率)。Add ferric nitrate nonahydrate (401.8mg, 1.0mmol), 4-hydroxy-2,2,6,6-tetramethylpiperidine oxide (172.4mg, 1.0mmol), potassium chloride (75.9mg ,1.0mmol), 1a (1.4381g, 10.0mmol) and 1,2-dichloroethane (2mL), ventilate (pure oxygen) three times, stir at room temperature (25℃) for 33 hours, obtain 49% of 2a (Using dibromomethane as internal standard, nuclear magnetic yield), 39% of 3a (using dibromomethane as internal standard, nuclear magnetic yield).
实施例2Example 2
Figure PCTCN2020102499-appb-000004
Figure PCTCN2020102499-appb-000004
向三口瓶中加入九水合硝酸铁(405.8mg,1.0mmol),4-羟基-2,2,6,6-四甲基哌啶氧化物(171.4mg,1.0mmol)，氯化钾(75.7mg,1.0mmol)，1a(1.4353g,10.0mmol)和二氯甲烷(2mL)，换气(纯氧)三次，室温下(25℃)搅拌33小时，得41％的2a(以二溴甲烷为内标，核磁产率)，27％的3a(以二溴甲烷为内标，核磁产率)。To the three-necked flask was added ferric nitrate nonahydrate (405.8mg, 1.0mmol), 4-hydroxy-2,2,6,6-tetramethylpiperidine oxide (171.4mg, 1.0mmol), potassium chloride (75.7mg , 1.0mmol), 1a (1.4353g, 10.0mmol) and dichloromethane (2mL), ventilate (pure oxygen) three times, stir at room temperature (25℃) for 33 hours, and obtain 41% of 2a (with dibromomethane as internal Standard, nuclear magnetic yield), 27% of 3a (using dibromomethane as internal standard, nuclear magnetic yield).
实施例3Example 3
Figure PCTCN2020102499-appb-000005
Figure PCTCN2020102499-appb-000005
向三口瓶中加入九水合硝酸铁(403.5mg,1.0mmol),4-羟基-2,2,6,6-四甲基哌啶氧化物(171.6mg,1.0mmol)，氯化钾(75.0mg,1.0mmol)，1a(1.4359g,10.0mmol)和甲苯(2mL)，换气(纯氧)三次，室温下(25℃)搅拌24小时，得25％的2a(以二溴甲烷为内标，核磁产率)，63％的3a(以二溴甲烷为内标，核磁产率)。Add ferric nitrate nonahydrate (403.5mg, 1.0mmol), 4-hydroxy-2,2,6,6-tetramethylpiperidine oxide (171.6mg, 1.0mmol), potassium chloride (75.0mg ,1.0mmol), 1a (1.4359g, 10.0mmol) and toluene (2mL), ventilate (pure oxygen) three times, stir at room temperature (25℃) for 24 hours, and obtain 25% of 2a (using dibromomethane as internal standard, NMR yield), 63% of 3a (using dibromomethane as internal standard, NMR yield).
实施例4Example 4
Figure PCTCN2020102499-appb-000006
Figure PCTCN2020102499-appb-000006
向三口瓶中加入九水合硝酸铁(405.0mg,1.0mmol)，4-羟基-2,2,6,6-四甲基哌啶氧化物(172.2mg,1.0mmol)，氯化钾(75.0mg,1.0mmol)，1a(1.4442g,10.0mmol)和乙腈(2mL)，换气(纯氧)三次，室温下(25℃)搅拌12小时，快速柱层析(石油醚/乙酸乙酯＝10/1)，得2a(1.4387g,产率:83％,纯度:91％)。Add ferric nitrate nonahydrate (405.0mg, 1.0mmol), 4-hydroxy-2,2,6,6-tetramethylpiperidine oxide (172.2mg, 1.0mmol), potassium chloride (75.0mg , 1.0mmol), 1a (1.4442g, 10.0mmol) and acetonitrile (2mL), ventilate (pure oxygen) three times, stir at room temperature (25℃) for 12 hours, flash column chromatography (petroleum ether/ethyl acetate=10 /1) to obtain 2a (1.4387g, yield: 83%, purity: 91%).
实施例5Example 5
Figure PCTCN2020102499-appb-000007
Figure PCTCN2020102499-appb-000007
向三口瓶中加入九水合硝酸铁(404.7mg,1.0mmol),4-羟基-2,2,6,6-四甲基哌啶氧化物(171.6mg,1.0mmol)，氯化钾(74.8mg,1.0mmol)，1a(1.4438g,10.0mmol)，乙腈(413.8mg,10.0mmol)和1,2-二氯乙烷(2mL)，换气(纯氧)三次，室温下(25℃)搅拌24小时，得58％的2a(以二溴甲烷为内标，核磁产率)，26％的3a(以二溴甲烷为内标，核磁产率)。Add ferric nitrate nonahydrate (404.7mg, 1.0mmol), 4-hydroxy-2,2,6,6-tetramethylpiperidine oxide (171.6mg, 1.0mmol), potassium chloride (74.8mg , 1.0mmol), 1a (1.4438g, 10.0mmol), acetonitrile (413.8mg, 10.0mmol) and 1,2-dichloroethane (2mL), ventilation (pure oxygen) three times, stirring at room temperature (25℃) In 24 hours, 58% of 2a (using dibromomethane as internal standard, nuclear magnetic yield) and 26% of 3a (using dibromomethane as internal standard, nuclear magnetic yield) were obtained.
实施例6Example 6
Figure PCTCN2020102499-appb-000008
Figure PCTCN2020102499-appb-000008
向三口瓶中加入九水合硝酸铁(404.4mg,1.0mmol),4-羟基-2,2,6,6-四甲基哌啶氧化物(172.8mg,1.0mmol)，氯化钾(75.8mg,1.0mmol)，1a(1.4550g,10.0mmol)，乙腈(409.6mg,10.0mmol)和甲苯(2mL)，换气(纯氧)三次，室温下(25℃)搅拌24小时，得44％的2a(以二溴甲烷为内标，核磁产率)，46％的3a(以二溴甲烷为内标，核磁产率)。Add ferric nitrate nonahydrate (404.4mg, 1.0mmol), 4-hydroxy-2,2,6,6-tetramethylpiperidine oxide (172.8mg, 1.0mmol), potassium chloride (75.8mg , 1.0mmol), 1a (1.4550g, 10.0mmol), acetonitrile (409.6mg, 10.0mmol) and toluene (2mL), ventilate (pure oxygen) three times, stir at room temperature (25℃) for 24 hours to obtain 44% 2a (using dibromomethane as internal standard, nuclear magnetic yield), 46% of 3a (using dibromomethane as internal standard, nuclear magnetic yield).
实施例7Example 7
Figure PCTCN2020102499-appb-000009
Figure PCTCN2020102499-appb-000009
向三口瓶中加入九水合硝酸铁(403.7mg,1.0mmol)，4-羟基-2,2,6,6-四甲基哌啶氧化物(172.0mg,1.0mmol)，氯化钾(75.1mg,1.0mmol)，1a(1.4357g,10.0mmol)和乙腈(1.2280g,30mmol)，换气(纯氧)三次，室温下(25℃)搅拌10小时，快速柱层析(石油醚/乙酸乙酯＝10/1)，得2a(1.3316g,85％)。Add ferric nitrate nonahydrate (403.7mg, 1.0mmol), 4-hydroxy-2,2,6,6-tetramethylpiperidine oxide (172.0mg, 1.0mmol), potassium chloride (75.1mg , 1.0mmol), 1a (1.4357g, 10.0mmol) and acetonitrile (1.2280g, 30mmol), ventilate (pure oxygen) three times, stir at room temperature (25℃) for 10 hours, flash column chromatography (petroleum ether/ethyl acetate) Ester = 10/1) to give 2a (1.3316 g, 85%).
实施例8Example 8
Figure PCTCN2020102499-appb-000010
Figure PCTCN2020102499-appb-000010
向三口瓶中加入九水合硝酸铁(404.4mg,1.0mmol)，4-羟基-2,2,6,6-四甲基哌啶氧化物(172.6mg,1.0mmol)，氯化钾(74.8mg,1.0mmol)，1a(1.4338g,10.0mmol)和乙腈(0.8320g,20mmol)，换气(纯氧)三次，室温下(25℃)搅拌24小时，快速柱层析(石油醚/乙酸乙酯＝10/1)，得2a(1.2883g，82％)。Add ferric nitrate nonahydrate (404.4mg, 1.0mmol), 4-hydroxy-2,2,6,6-tetramethylpiperidine oxide (172.6mg, 1.0mmol), potassium chloride (74.8mg , 1.0mmol), 1a (1.4338g, 10.0mmol) and acetonitrile (0.8320g, 20mmol), ventilation (pure oxygen) three times, stirring at room temperature (25℃) for 24 hours, flash column chromatography (petroleum ether/ethyl acetate Ester = 10/1) to give 2a (1.2883g, 82%).
实施例9Example 9
Figure PCTCN2020102499-appb-000011
Figure PCTCN2020102499-appb-000011
向三口瓶中加入九水合硝酸铁(403.0mg,1.0mmol)，4-羟基-2,2,6,6-四甲基哌啶氧化物(172.4mg,1.0mmol)，氯化钾(75.4mg,1.0mmol)，1a(1.4442g,10.0mmol)和乙腈(0.4060g,10mmol)，换气(纯氧)三次，室温下(25℃)搅拌24小时，快速柱层析(石油醚/乙酸乙酯＝10/1)，得2a(1.1226g,71％)。Add ferric nitrate nonahydrate (403.0mg, 1.0mmol), 4-hydroxy-2,2,6,6-tetramethylpiperidine oxide (172.4mg, 1.0mmol), potassium chloride (75.4mg , 1.0mmol), 1a (1.4442g, 10.0mmol) and acetonitrile (0.4060g, 10mmol), ventilate (pure oxygen) three times, stir at room temperature (25℃) for 24 hours, flash column chromatography (petroleum ether/ethyl acetate) Ester = 10/1) to give 2a (1.1226 g, 71%).
实施例10Example 10
Figure PCTCN2020102499-appb-000012
Figure PCTCN2020102499-appb-000012
向三口瓶中加入九水合硝酸铁(402.9mg,1.0mmol)，4-羟基-2,2,6,6-四甲基哌啶氧化物(171.2mg,1.0mmol)，氯化钾(74.8mg,1.0mmol)，1a(1.4403g,10.0mmol)和乙腈(0.2113g,5mmol)，换气(纯氧)三次，室温下(25℃)搅拌24小时，得49％的2a(以二溴甲烷为内标，核磁产率)，26％的3a(以二溴甲烷为内标，核磁产率)。Add ferric nitrate nonahydrate (402.9mg, 1.0mmol), 4-hydroxy-2,2,6,6-tetramethylpiperidine oxide (171.2mg, 1.0mmol), potassium chloride (74.8mg , 1.0mmol), 1a (1.4403g, 10.0mmol) and acetonitrile (0.2113g, 5mmol), ventilated (pure oxygen) three times, stirred at room temperature (25 ℃) for 24 hours, 49% of 2a (using dibromomethane as Internal standard, nuclear magnetic yield), 26% of 3a (using dibromomethane as internal standard, nuclear magnetic yield).
实施例11Example 11
Figure PCTCN2020102499-appb-000013
Figure PCTCN2020102499-appb-000013
向三口瓶中加入九水合硝酸铁(201.5mg,0.5mmol)，4-羟基-2,2,6,6-四甲基哌啶氧化物(85.8mg,0.5mmol)，氯化钾(37.2mg,0.5mmol)，1a(1.4389g,10.0mmol)和乙腈(1.2408g,30mmol)，换气(纯氧)三次，室温下(25℃)搅拌24小时，过短硅胶柱(二氯甲烷：20mL×3)，浓缩，快速柱层析(石油醚/乙酸乙酯＝50/1～5/1)，得产物2a(1.2455g,79％):产物为液体。Add iron nitrate nonahydrate (201.5mg, 0.5mmol), 4-hydroxy-2,2,6,6-tetramethylpiperidine oxide (85.8mg, 0.5mmol), potassium chloride (37.2mg , 0.5mmol), 1a (1.4389g, 10.0mmol) and acetonitrile (1.2408g, 30mmol), ventilate (pure oxygen) three times, stir at room temperature (25℃) for 24 hours, too short silica gel column (dichloromethane: 20mL ×3), concentration, and flash column chromatography (petroleum ether/ethyl acetate=50/1～5/1) to obtain product 2a (1.2455g, 79%): the product is liquid.
实施例12Example 12
Figure PCTCN2020102499-appb-000014
Figure PCTCN2020102499-appb-000014
向三口瓶中加入九水合硝酸铁(202.6mg,0.5mmol)，4-羟基-2,2,6,6-四甲基哌啶氧化物(86.6mg,0.5mmol)，氯化钾(37.2mg,0.5mmol)和乙腈(1.2321g,30mmol)，换气(纯氧)三次，室温(25℃)搅拌下滴加1a(1.3806g,9.6mmol)(5小时内滴完)，室温下继续搅拌反应19小时，过短硅胶柱(二氯甲烷：20mL×3)，浓缩，快速柱层析(石油醚/乙酸乙酯＝50/1～5/1)，得产物2a(1.2899g,85％):产物为液体。Add iron nitrate nonahydrate (202.6mg, 0.5mmol), 4-hydroxy-2,2,6,6-tetramethylpiperidine oxide (86.6mg, 0.5mmol), potassium chloride (37.2mg , 0.5mmol) and acetonitrile (1.2321g, 30mmol), ventilate (pure oxygen) three times, add 1a (1.3806g, 9.6mmol) dropwise under stirring at room temperature (25°C) (dropped within 5 hours), continue stirring at room temperature Reaction for 19 hours, short silica gel column (dichloromethane: 20mL×3), concentration, and flash column chromatography (petroleum ether/ethyl acetate=50/1～5/1) to obtain product 2a (1.2899g, 85%) ): The product is liquid.
实施例13Example 13
Figure PCTCN2020102499-appb-000015
Figure PCTCN2020102499-appb-000015
向三口瓶中加入九水合硝酸铁(201.2mg,0.5mmol)，4-羟基-2,2,6,6-四甲基哌啶氧化物(86.4mg,0.5mmol)，1a(1.4546g,10.0mmol)和乙腈(1.2237g,30mmol)，换气(纯氧)三次，室温下(25℃)搅拌24小时，快速柱层析(石油醚/乙酸乙酯＝50/1～10/1)，得2a(1.1226g,70％)。Add ferric nitrate nonahydrate (201.2mg, 0.5mmol), 4-hydroxy-2,2,6,6-tetramethylpiperidine oxide (86.4mg, 0.5mmol), 1a (1.4546g, 10.0 mmol) and acetonitrile (1.2237g, 30mmol), ventilation (pure oxygen) three times, stirring at room temperature (25°C) for 24 hours, flash column chromatography (petroleum ether/ethyl acetate=50/1～10/1), Obtained 2a (1.1226g, 70%).
1H NMR(300MHz,CDCl 3):δ＝10.86(br d,1H),2.37(dd,J 1＝14.7Hz,J 2＝6.0Hz,1H),2.18(dd,J 1＝14.7Hz,J 2＝8.1Hz,1H),2.11-1.98(m,1H),1.27(dd,J 1＝14.1Hz,J 2＝4.2Hz,1H),1.18(dd,J 1＝14.1Hz,J 2＝6.0Hz,1H),1.01(d,J＝6.3Hz,3H),0.91(s,3H)； 13C NMR(75MHz,CDCl 3):δ＝179.9,50.5,43.7,31.0,29.9,26.8,22.6；IR(neat,cm -1)＝2958,1713,1469,1411,1366,1286,1247,1219,1171,1079；MS(EI):m/z(％)143[M-H,5.37],57(100). 1 H NMR (300MHz, CDCl 3 ): δ = 10.86 (br d, 1H), 2.37 (dd, J 1 =14.7 Hz, J 2 ＝ 6.0 Hz, 1H), 2.18 (dd, J 1 =14.7 Hz, J 2 ＝8.1Hz,1H),2.11-1.98(m,1H),1.27(dd,J 1 ＝14.1Hz,J 2 ＝4.2Hz,1H), 1.18(dd,J 1 ＝14.1Hz,J 2 ＝6.0 Hz, 1H), 1.01 (d, J = 6.3 Hz, 3H), 0.91 (s, 3H); 13 C NMR (75MHz, CDCl 3 ): δ = 179.9, 50.5, 43.7, 31.0, 29.9, 26.8, 22.6; IR(neat,cm -1 )=2958,1713,1469,1411,1366,1286,1247,1219,1171,1079; MS(EI): m/z(%)143[MH,5.37],57(100 ).
实施例14Example 14
Figure PCTCN2020102499-appb-000016
Figure PCTCN2020102499-appb-000016
向三口瓶中加入三水合硝酸铜(121.2mg,0.5mmol)，4-羟基-2,2,6,6-四甲基哌啶氧化物(85.3mg,0.5mmol)和乙腈(1.2300g,30mmol)，换气(纯氧)三次，室温(25℃)搅拌下滴加1a(1.4055g,9.7mmol)(5小时内滴完)，室温下继续搅拌反应67小时，过短硅胶柱(二氯甲烷：20mL×3)，以二溴甲烷为内标，得3a 47％(核磁产率)，快速柱层析(石油醚/乙酸乙酯＝50/1～5/1)，得2a(0.6677g,43％)。Add copper nitrate trihydrate (121.2mg, 0.5mmol), 4-hydroxy-2,2,6,6-tetramethylpiperidine oxide (85.3mg, 0.5mmol) and acetonitrile (1.2300g, 30mmol) to a three-necked flask ), ventilate (pure oxygen) three times, add 1a (1.4055g, 9.7mmol) dropwise under stirring at room temperature (25°C) (dropped within 5 hours), continue to stir and react at room temperature for 67 hours, too short a silica gel column (dichloro Methane: 20mL×3), with dibromomethane as the internal standard, 3a 47% (nuclear magnetic yield), flash column chromatography (petroleum ether/ethyl acetate=50/1～5/1), 2a (0.6677g) ,43%).
实施例15Example 15
Figure PCTCN2020102499-appb-000017
Figure PCTCN2020102499-appb-000017
向三口瓶中加入九水合硝酸铁(40.1mg,0.1mmol)，4-羟基-2,2,6,6-四甲基哌啶氧化物(17.4mg,0.1mmol)，1a(1.4345g,10.0mmol)和乙腈(1.2500g,30mmol)，换气(纯氧)三次，室温(25℃)搅拌下72小时，过短硅胶柱(二氯甲烷：20mL×3)，以二溴甲烷为内标，得3a12％(核磁产率)，原料1a回收59％。Add ferric nitrate nonahydrate (40.1mg, 0.1mmol), 4-hydroxy-2,2,6,6-tetramethylpiperidine oxide (17.4mg, 0.1mmol), 1a (1.4345g, 10.0 mmol) and acetonitrile (1.2500g, 30mmol), ventilation (pure oxygen) three times, stirring at room temperature (25℃) for 72 hours, too short silica gel column (dichloromethane: 20mL×3), using dibromomethane as internal standard, 3a12% (nuclear magnetic yield) was obtained, and 59% of raw material 1a was recovered.
实施例16Example 16
Figure PCTCN2020102499-appb-000018
Figure PCTCN2020102499-appb-000018
向三口瓶中加入九水合硝酸铁(202.7mg,0.5mmol)，4-羟基-2,2,6,6-四甲基哌啶氧化物(84.8mg,0.5mmol)，1a(1.4434g,10.0mmol)和乙腈(1.2309g,30mmol)，换气(纯氧)三次，50℃搅拌下18小时，快速柱层析(石油醚/乙酸乙酯＝50/1～5/1)，得2a(1.1539g,73％)。Add iron nitrate nonahydrate (202.7mg, 0.5mmol), 4-hydroxy-2,2,6,6-tetramethylpiperidine oxide (84.8mg, 0.5mmol), 1a (1.4434g, 10.0 mmol) and acetonitrile (1.2309g, 30mmol), ventilation (pure oxygen) three times, stirring at 50°C for 18 hours, flash column chromatography (petroleum ether/ethyl acetate=50/1～5/1) to obtain 2a( 1.1539g, 73%).
实施例17Example 17
Figure PCTCN2020102499-appb-000019
Figure PCTCN2020102499-appb-000019
向三口瓶中加入九水合硝酸铁(199.6mg,0.5mmol)，4-羟基-2,2,6,6-四甲基哌啶氧化物(85.0mg,0.5mmol)，月桂醇1b(1.8620g,10.0mmol)和乙腈(1.2431g,30mmol)，换气(纯氧)三次，室温下(25℃)搅拌48小时，过短硅胶柱(二氯甲烷：20mL×3)，以二溴甲烷为内标，得2b 70％(核磁产率)。Add ferric nitrate nonahydrate (199.6mg, 0.5mmol), 4-hydroxy-2,2,6,6-tetramethylpiperidine oxide (85.0mg, 0.5mmol), lauryl alcohol 1b (1.8620g) to the three-necked flask , 10.0mmol) and acetonitrile (1.2431g, 30mmol), ventilation (pure oxygen) three times, stirring at room temperature (25℃) for 48 hours, too short silica gel column (dichloromethane: 20mL×3), with dibromomethane as the inner Mark, get 2b 70% (NMR yield).
实施例18Example 18
Figure PCTCN2020102499-appb-000020
Figure PCTCN2020102499-appb-000020
向三口瓶中加入九水合硝酸铁(202.4mg,0.5mmol)，4-羟基-2,2,6,6-四甲基哌啶氧化物 (85.7mg,0.5mmol)，氯化钾(37.7mg,0.5mmol)，月桂醇1b(1.8583g,10.0mmol)和乙腈(1.6404g,40mmol)，换气(纯氧)三次，室温下(25℃)搅拌24小时，过短硅胶柱(二氯甲烷：20mL×3；乙酸乙酯：60mL)，浓缩，快速柱层析(石油醚/乙酸乙酯＝50/1～5/1)，得产物2b(1.7469g,87％):产物为固体，43.2-44.3℃(正己烷/乙酸乙酯＝4/1)。To the three-necked flask was added ferric nitrate nonahydrate (202.4mg, 0.5mmol), 4-hydroxy-2,2,6,6-tetramethylpiperidine oxide (85.7mg, 0.5mmol), potassium chloride (37.7mg , 0.5mmol), lauryl alcohol 1b (1.8583g, 10.0mmol) and acetonitrile (1.6404g, 40mmol), ventilation (pure oxygen) three times, stirring at room temperature (25℃) for 24 hours, too short silica gel column (dichloromethane) ：20mL×3; ethyl acetate: 60mL), concentrate, and flash column chromatography (petroleum ether/ethyl acetate=50/1～5/1) to obtain product 2b (1.7469g, 87%): the product is solid. 43.2-44.3°C (n-hexane/ethyl acetate=4/1).
1H NMR(300MHz,CDCl 3)δ11.45(brs,1H,COOH),2.35(t,J＝7.5Hz,2H,CH 2),1.63(quint,J＝7.1Hz,2H,CH 2),1.40-1.18(m,16H,8×CH 2),0.88(t,J＝6.6Hz,3H,CH 3)； 13C NMR(75MHz,CDCl 3)δ180.7,34.1,31.9,29.6,29.4,29.3,29.2,29.0,24.7,22.7,14.1；IR(KBr,cm -1):2917,2849,1694,1470,1430,1411,1351,1328,1303,1249,1220,1193,1084；MS(EI)m/z(％):200(M +,9.43),73(100). 1 H NMR(300MHz,CDCl 3 )δ11.45(brs,1H,COOH), 2.35(t,J=7.5Hz,2H,CH 2 ), 1.63(quint,J=7.1Hz,2H,CH 2 ), 1.40-1.18(m,16H,8×CH 2 ),0.88(t,J=6.6Hz,3H,CH 3 ); 13 C NMR(75MHz,CDCl 3 )δ180.7,34.1,31.9,29.6,29.4, 29.3,29.2,29.0,24.7,22.7,14.1; IR(KBr,cm -1 ): 2917,2849,1694,1470,1430,1411,1351,1328,1303,1249,1220,1193,1084; MS(EI )m/z(%):200(M + ,9.43),73(100).
实施例19Example 19
Figure PCTCN2020102499-appb-000021
Figure PCTCN2020102499-appb-000021
向三口瓶中加入九水合硝酸铁(202.1mg,0.5mmol)，4-羟基-2,2,6,6-四甲基哌啶氧化物(86.1mg,0.5mmol)和乙腈(1.2302g,30mmol)，换气(纯氧)三次，室温(25℃)搅拌下滴加正己醇1c(0.9821g,10.0mmol)(5小时内滴完)，室温下继续搅拌反应10小时，过短硅胶柱(二氯甲烷：20mL×3)，浓缩，快速柱层析(石油醚/乙酸乙酯＝10/1～5/1)，得产物2c(0.8786g,79％):产物为液体。Add ferric nitrate nonahydrate (202.1mg, 0.5mmol), 4-hydroxy-2,2,6,6-tetramethylpiperidine oxide (86.1mg, 0.5mmol) and acetonitrile (1.2302g, 30mmol) to a three-necked flask ), ventilate (pure oxygen) three times, add n-hexanol 1c (0.9821g, 10.0mmol) dropwise under stirring at room temperature (25°C) (dropped within 5 hours), continue to stir and react for 10 hours at room temperature, the silica gel column is too short ( Dichloromethane: 20mL×3), concentrated, and flash column chromatography (petroleum ether/ethyl acetate=10/1～5/1), product 2c (0.8786g, 79%) is obtained: the product is liquid.
1H NMR(300MHz,CDCl 3)δ10.85(brs,1H,COOH),2.35(t,J＝7.5Hz,2H,CH 2),1.63(quint,J＝7.2Hz,2H,CH 2),1.40-1.28(m,4H,2×CH 2),0.90(t,J＝6.6Hz,3H,CH 3)； 13C NMR(75MHz,CDCl 3)δ180.4,34.0,31.2,24.3,22.3,13.8；IR(neat,cm -1):2960,2934,2875,1712,1463,1414,1293,1247,1213,1107；MS(EI)m/z(％):117(M+H,100),99(100). 1 H NMR(300MHz,CDCl 3 )δ10.85(brs,1H,COOH), 2.35(t,J=7.5Hz,2H,CH 2 ), 1.63(quint,J=7.2Hz,2H,CH 2 ), 1.40-1.28(m,4H,2×CH 2 ),0.90(t,J=6.6Hz,3H,CH 3 ); 13 C NMR(75MHz,CDCl 3 )δ180.4,34.0,31.2,24.3,22.3, 13.8; IR (neat, cm -1 ): 2960, 2934, 2875, 1712, 1463, 1414, 1293, 1247, 1213, 1107; MS (EI) m/z (%): 117 (M+H, 100) , 99(100).
实施例20Example 20
Figure PCTCN2020102499-appb-000022
Figure PCTCN2020102499-appb-000022
向三口瓶中加入九水合硝酸铁(202.0mg,0.5mmol)，4-羟基-2,2,6,6-四甲基哌啶氧化物(85.7mg,0.5mmol)，氯化钾(37.2mg,0.5mmol)和乙腈(1.2328g,30mmol)，换气(纯氧)三次，室温(25℃)搅拌下滴加正丁醇1d(0.7358g,10.0mmol)(5小时内滴加完毕)，室温下继续搅拌反应17小时，过短硅胶柱(二氯甲烷：20mL×3)，浓缩，快速柱层析(石油醚/乙酸 乙酯＝10/1～3/1)，得产物2d(核磁产率:80％；分离产率:55％):产物为液体。Add iron nitrate nonahydrate (202.0mg, 0.5mmol), 4-hydroxy-2,2,6,6-tetramethylpiperidine oxide (85.7mg, 0.5mmol), potassium chloride (37.2mg , 0.5mmol) and acetonitrile (1.2328g, 30mmol), ventilate (pure oxygen) three times, add n-butanol 1d (0.7358g, 10.0mmol) dropwise under stirring at room temperature (25°C) (the addition is complete within 5 hours), Continue to stir and react for 17 hours at room temperature. Short silica gel column (dichloromethane: 20mL×3), concentrate, and flash column chromatography (petroleum ether/ethyl acetate=10/1～3/1) to obtain product 2d (NMR Yield: 80%; Isolated yield: 55%): The product is liquid.
实施例21Example 21
Figure PCTCN2020102499-appb-000023
Figure PCTCN2020102499-appb-000023
向三口瓶中加入九水合硝酸铁(202.0mg,0.5mmol)，4-羟基-2,2,6,6-四甲基哌啶氧化物(86.5mg,0.5mmol)，正丁醛3d(0.721g,10.0mmol)和乙腈(1.2249g,30mmol)，换气(纯氧)三次，室温下搅拌反应22小时，原料3d完全转化。Add ferric nitrate nonahydrate (202.0mg, 0.5mmol), 4-hydroxy-2,2,6,6-tetramethylpiperidine oxide (86.5mg, 0.5mmol), n-butyraldehyde 3d (0.721 g, 10.0mmol) and acetonitrile (1.2249g, 30mmol), ventilated (pure oxygen) three times, stirred and reacted at room temperature for 22 hours, the raw material 3d was completely converted.
1H NMR(300MHz,CDCl 3)δ2.34(t,J＝7.5Hz,2H,CH 2),1.70-1.60(m,2H,CH 2),0.98(t,J＝7.5Hz,3H,CH 3)； 13C NMR(75MHz,CDCl 3)δ180.4,35.9,18.1,13.5；IR(neat,cm -1):2969,2879,2666,1713,1461,1414,1283,1220,1096；MS(EI)m/z(％):88(M +,2.75),60(100). 1 H NMR(300MHz,CDCl 3 )δ2.34(t,J=7.5Hz,2H,CH 2 ),1.70-1.60(m,2H,CH 2 ),0.98(t,J=7.5Hz,3H,CH 3 ); 13 C NMR (75MHz, CDCl 3 ) δ180.4, 35.9, 18.1, 13.5; IR (neat, cm -1 ): 2969, 2879, 2666, 1713, 1461, 1414, 1283, 1220, 1096; MS (EI)m/z(%):88(M + ,2.75),60(100).
实施例22Example 22
Figure PCTCN2020102499-appb-000024
Figure PCTCN2020102499-appb-000024
向三口瓶中加入九水合硝酸铁(201.6mg,0.5mmol)，4-羟基-2,2,6,6-四甲基哌啶氧化物(85.5mg,0.5mmol)和乙腈(1.2524g,30mmol)，换气(纯氧)三次，室温(25℃)搅拌下滴加6-氯己醇1e(1.2999g,9.5mmol)(5小时内滴完)，室温下继续搅拌19小时，过短硅胶柱(二氯甲烷：20mL×3)，以二溴甲烷为内标，得产物2e 83％(核磁产率)。Add ferric nitrate nonahydrate (201.6mg, 0.5mmol), 4-hydroxy-2,2,6,6-tetramethylpiperidine oxide (85.5mg, 0.5mmol) and acetonitrile (1.2524g, 30mmol) to the three-necked flask ), ventilate (pure oxygen) three times, add 6-chlorohexanol 1e (1.2999g, 9.5mmol) dropwise under stirring at room temperature (25°C) (dropped within 5 hours), continue stirring at room temperature for 19 hours, too short silica gel Column (dichloromethane: 20mL×3), with dibromomethane as the internal standard, the product 2e 83% (nuclear magnetic yield) was obtained.
实施例23Example 23
Figure PCTCN2020102499-appb-000025
Figure PCTCN2020102499-appb-000025
向三口瓶中加入九水合硝酸铁(201.0mg,0.5mmol)，4-羟基-2,2,6,6-四甲基哌啶氧化物(86.0mg,0.5mmol)，氯化钾(37.0mg,0.5mmol)，6-氯己醇1e(1.3747g,10.0mmol)和乙腈(1.2693g,30mmol)，换气(纯氧)三次，室温下(25℃)搅拌12小时，过短硅胶柱(二氯甲烷：20mL×3)，浓缩，快速柱层析(石油醚/乙酸乙酯＝10/1～3/1)，得产物2e(1.1037g,73％):产物为液体。Add ferric nitrate nonahydrate (201.0mg, 0.5mmol), 4-hydroxy-2,2,6,6-tetramethylpiperidine oxide (86.0mg, 0.5mmol), potassium chloride (37.0mg , 0.5mmol), 6-chlorohexanol 1e (1.3747g, 10.0mmol) and acetonitrile (1.2693g, 30mmol), ventilate (pure oxygen) three times, stir at room temperature (25℃) for 12 hours, too short silica gel column ( Dichloromethane: 20mL×3), concentrated, and flash column chromatography (petroleum ether/ethyl acetate=10/1～3/1) to obtain product 2e (1.1037g, 73%): the product is liquid.
实施例24Example 24
Figure PCTCN2020102499-appb-000026
Figure PCTCN2020102499-appb-000026
向三口瓶中加入九水合硝酸铁(202.1mg,0.5mmol)，4-羟基-2,2,6,6-四甲基哌啶氧化物(86.3mg,0.5mmol)，氯化钾(37.6mg,0.5mmol)和乙腈(1.2524g,30mmol)，换气(纯氧)三次，室温(25℃)搅拌下滴加6-氯己醇1e(1.2855g,10.0mmol)(5小时内滴完)，室温下继续搅拌13小时，过短硅胶柱(二氯甲烷：20mL×3)，浓缩，快速柱层析(石油醚/乙酸乙酯＝10/1～3/1)，得产物2e(1.0895g,77％):产物为液体。Add ferric nitrate nonahydrate (202.1mg, 0.5mmol), 4-hydroxy-2,2,6,6-tetramethylpiperidine oxide (86.3mg, 0.5mmol), potassium chloride (37.6mg , 0.5mmol) and acetonitrile (1.2524g, 30mmol), ventilate (pure oxygen) three times, add 6-chlorohexanol 1e (1.2855g, 10.0mmol) dropwise under stirring at room temperature (25°C) (drip within 5 hours) , Continue to stir for 13 hours at room temperature, short silica gel column (dichloromethane: 20mL×3), concentrate, and flash column chromatography (petroleum ether/ethyl acetate=10/1～3/1) to obtain product 2e (1.0895 g, 77%): The product is liquid.
1H NMR(300MHz,CDCl 3)δ3.54(t,J＝6.6Hz,2H,CH 2),2.38(t,J＝7.2Hz,2H,CH 2),1.80(quint,J＝7.2Hz,2H,CH 2),1.67(quint,J＝8.1Hz,2H,CH 2),1.58-1.48(m,2H,CH 2)； 13C NMR(75MHz,CDCl 3)δ180.0,44.7,33.8,32.1,26.2,23.9；IR(neat,cm -1):2943,2869,2676,1713,1541,1414,1277,1238,1133,1056；MS(EI)m/z(％):153(M( 37Cl)+H,3.34),151(M( 35Cl)+H,9.76),73(100). 1 H NMR (300MHz, CDCl 3 ) δ 3.54 (t, J = 6.6 Hz, 2H, CH 2 ), 2.38 (t, J = 7.2 Hz, 2H, CH 2 ), 1.80 (quint, J = 7.2 Hz, 2H, CH 2 ), 1.67 (quint, J = 8.1 Hz, 2H, CH 2 ), 1.58-1.48 (m, 2H, CH 2 ); 13 C NMR (75MHz, CDCl 3 ) δ 180.0, 44.7, 33.8, 32.1,26.2,23.9; IR(neat,cm -1 ):2943,2869,2676,1713,1541,1414,1277,1238,1133,1056; MS(EI)m/z(%):153(M( 37 Cl) + H, 3.34), 151 (M ( 35 Cl) + H, 9.76), 73 (100).
实施例25Example 25
Figure PCTCN2020102499-appb-000027
Figure PCTCN2020102499-appb-000027
向三口瓶中加入九水合硝酸铁(201.6mg,0.5mmol)，4-羟基-2,2,6,6-四甲基哌啶氧化物(85.9mg,0.5mmol)和乙腈(1.2254g,30mmol)，换气(纯氧)三次，室温(25℃)搅拌下滴加5-己炔醇1f(0.9745g,10.0mmol)(5小时内滴完)，室温下继续反应27小时，过短硅胶柱(二氯甲烷：20mL×3)，以二溴甲烷为内标，得产物2f71％(核磁产率)。Add ferric nitrate nonahydrate (201.6mg, 0.5mmol), 4-hydroxy-2,2,6,6-tetramethylpiperidine oxide (85.9mg, 0.5mmol) and acetonitrile (1.2254g, 30mmol) into a three-necked flask ), ventilate (pure oxygen) three times, add 5-hexynol 1f (0.9745g, 10.0mmol) dropwise under stirring at room temperature (25°C) (dropped within 5 hours), continue to react at room temperature for 27 hours, too short silica gel Column (dichloromethane: 20 mL×3), with dibromomethane as the internal standard, to obtain the product 2f 71% (nuclear magnetic yield).
实施例26Example 26
Figure PCTCN2020102499-appb-000028
Figure PCTCN2020102499-appb-000028
向三口瓶中加入九水合硝酸铁(202.2mg,0.5mmol)，4-羟基-2,2,6,6-四甲基哌啶氧化物(86.2mg,0.5mmol)，氯化钾(36.8mg,0.5mmol)，5-己炔醇1f(0.9799g,10.0mmol)和乙腈(1.2323g,30mmol)，换气(纯氧)三次，室温下(25℃)搅拌16小时，过短硅胶柱(二氯 甲烷：20mL×3)，浓缩，快速柱层析(石油醚/乙酸乙酯＝5/1～3/1)，得产物2f(0.7204g,64％):产物为液体。Add iron nitrate nonahydrate (202.2mg, 0.5mmol), 4-hydroxy-2,2,6,6-tetramethylpiperidine oxide (86.2mg, 0.5mmol), potassium chloride (36.8mg , 0.5mmol), 5-hexynol 1f (0.9799g, 10.0mmol) and acetonitrile (1.2323g, 30mmol), ventilation (pure oxygen) three times, stirring at room temperature (25℃) for 16 hours, too short silica gel column ( Dichloromethane: 20mL×3), concentrated, and flash column chromatography (petroleum ether/ethyl acetate=5/1～3/1) to obtain product 2f (0.7204g, 64%): the product is liquid.
实施例27Example 27
Figure PCTCN2020102499-appb-000029
Figure PCTCN2020102499-appb-000029
向三口瓶中加入九水合硝酸铁(202.4mg,0.5mmol)，4-羟基-2,2,6,6-四甲基哌啶氧化物(86.4mg,0.5mmol)，氯化钾(36.8mg,0.5mmol)和乙腈(1.2263g,30mmol)，换气(纯氧)三次，室温(25℃)搅拌下滴加5-己炔醇1f(0.9570g,9.7mmol)(5小时内滴完)，室温下继续反应15小时，过短硅胶柱(二氯甲烷：20mL×3)，浓缩，快速柱层析(石油醚/乙酸乙酯＝5/1～3/1)，得产物2f(0.7987g,73％):产物为液体。Add iron nitrate nonahydrate (202.4mg, 0.5mmol), 4-hydroxy-2,2,6,6-tetramethylpiperidine oxide (86.4mg, 0.5mmol), potassium chloride (36.8mg , 0.5mmol) and acetonitrile (1.2263g, 30mmol), ventilate (pure oxygen) three times, add 5-hexynol 1f (0.9570g, 9.7mmol) dropwise under stirring at room temperature (25°C) (dropped in 5 hours) , Continue the reaction at room temperature for 15 hours, short a silica gel column (dichloromethane: 20mL×3), concentrate, and flash column chromatography (petroleum ether/ethyl acetate=5/1～3/1) to obtain the product 2f (0.7987) g, 73%): The product is liquid.
1H NMR(300MHz,CDCl 3):δ2.52(t,J＝7.5Hz,2H,CH 2),2.29(td,J＝6.9,2.4Hz,2H,CH 2),1.99(t,J＝2.7Hz,1H,CH),1.86(quant,J＝7.2Hz,2H,CH 2)； 13C NMR(75MHz,CDCl 3)δ179.7,83.0,69.3,32.5,23.2,17.7；IR(neat,cm -1)＝3297,2946,2118,1714,1434,1245,1206,1158,1052；MS(EI):m/z(％)111[M-H,4.72],70(100). 1 H NMR (300MHz, CDCl 3 ): δ2.52 (t, J = 7.5 Hz, 2H, CH 2 ), 2.29 (td, J = 6.9, 2.4 Hz, 2H, CH 2 ), 1.99 (t, J = 2.7Hz, 1H, CH), 1.86 (quant, J = 7.2Hz, 2H, CH 2 ); 13 C NMR (75MHz, CDCl 3 ) δ 179.7, 83.0, 69.3, 32.5, 23.2, 17.7; IR (neat, cm -1 )=3297,2946,2118,1714,1434,1245,1206,1158,1052; MS(EI): m/z(%)111[MH,4.72],70(100).
实施例28Example 28
Figure PCTCN2020102499-appb-000030
Figure PCTCN2020102499-appb-000030
向三口瓶中加入九水合硝酸铁(202.5mg,0.5mmol)，4-羟基-2,2,6,6-四甲基哌啶氧化物(85.7mg,0.5mmol)，3,4-二甲氧基苯乙醇1g(1.8209g,10.0mmol)和乙腈(1.2270g,30mmol)，换气(纯氧)三次，室温下(25℃)搅拌24小时，过短硅胶柱(乙酸乙酯：20mL×3)，浓缩，快速柱层析(石油醚/乙酸乙酯＝5/1～1/1)，得产物2g(1.2351g,63％):产物为固体，95.0-96.3℃(正己烷/乙酸乙酯＝4/1)。Add ferric nitrate nonahydrate (202.5mg, 0.5mmol), 4-hydroxy-2,2,6,6-tetramethylpiperidine oxide (85.7mg, 0.5mmol), 3,4-dimethyl into the three-necked flask 1g (1.8209g, 10.0mmol) of oxyphenethyl alcohol and acetonitrile (1.2270g, 30mmol), ventilate (pure oxygen) three times, stir at room temperature (25°C) for 24 hours, short silica gel column (ethyl acetate: 20mL× 3) Concentrate and flash column chromatography (petroleum ether/ethyl acetate=5/1～1/1) to obtain the product 2g (1.2351g, 63%): the product is a solid, 95.0-96.3℃ (n-hexane/acetic acid Ethyl ester = 4/1).
1H NMR(300MHz,CDCl 3)δ6.85-6.79(m,3H,Ar-H),3.88(s,3H,CH 3),3.87(s,3H,CH 3),3.60(s,2H,CH 2)； 13C NMR(75MHz,CDCl 3)δ177.9,149.0,148.4,125.7,121.6,112.5,111.3,55.9,40.6；IR(KBr,cm -1):3005,2963,2942,2839,2650,1717,1646,1608,1593,1515,1468,1447,1423,1396,1340,1263,1242,1190,1149,1037,1018；MS(EI)m/z(％):196(M +,93.46),151(100). 1 H NMR (300MHz, CDCl 3 ) δ6.85-6.79 (m, 3H, Ar-H), 3.88 (s, 3H, CH 3 ), 3.87 (s, 3H, CH 3 ), 3.60 (s, 2H, CH 2 ); 13 C NMR (75MHz, CDCl 3 ) δ 177.9, 149.0, 148.4, 125.7, 121.6, 112.5, 111.3, 55.9, 40.6; IR (KBr, cm -1 ): 3005, 2963, 2942, 2839, 2650, 1717,1646,1608,1593,1515,1468,1447,1423,1396,1340,1263,1242,1190,1149,1037,1018; MS(EI)m/z(%):196(M + ,93.46) , 151(100).
实施例29Example 29
Figure PCTCN2020102499-appb-000031
Figure PCTCN2020102499-appb-000031
向三口瓶中加入九水合硝酸铁(202.4mg,0.5mmol)，4-羟基-2,2,6,6-四甲基哌啶氧化物(86.6mg,0.5mmol)，氯化钾(37.5mg,0.5mmol)，壬二醇1h(1.5997g,10.0mmol)和乙腈(1.2545g,30mmol)，换气(纯氧)三次，室温下(25℃)搅拌48小时，将反应液以氢氧化钠溶液碱化，乙酸乙酯萃取(20mL*3)，水相以浓盐酸酸化，静置析出，过滤，水洗得产物2h(1.3233g,70％):产物为固体，105.1-106.9℃(正己烷/乙酸乙酯＝4/1)。Add ferric nitrate nonahydrate (202.4mg, 0.5mmol), 4-hydroxy-2,2,6,6-tetramethylpiperidine oxide (86.6mg, 0.5mmol), potassium chloride (37.5mg , 0.5mmol), nonanediol 1h (1.5997g, 10.0mmol) and acetonitrile (1.2545g, 30mmol), ventilate (pure oxygen) three times, stir at room temperature (25°C) for 48 hours, and mix the reaction solution with sodium hydroxide The solution is alkalized, extracted with ethyl acetate (20mL*3), the aqueous phase is acidified with concentrated hydrochloric acid, standing for precipitation, filtered, and washed with water to obtain the product 2h (1.3233g, 70%): the product is a solid, 105.1-106.9℃ (n-hexane /Ethyl acetate=4/1).
1H NMR(300MHz,DMSO-d 6):δ＝11.98(br d,2H),2.18(d,J＝7.5Hz,4H),1.53-1.40(m,4H),1.30-1.18(m,6H)； 13C NMR(75MHz,DMSO-d 6):δ＝175.5,34.6,29.43,29.39,25.4；IR(KBr,cm -1)＝3028,2934,2849,1701,1467,1437,1410,1344,1309,1268,1252,1230,1208,1196,1129,10978,1051,930；MS(EI):m/z(％)189[M+H,35.43],171(100). 1 H NMR (300MHz, DMSO-d 6 ): δ = 11.98 (br d, 2H), 2.18 (d, J = 7.5 Hz, 4H), 1.53-1.40 (m, 4H), 1.30-1.18 (m, 6H) ); 13 C NMR (75MHz, DMSO-d 6 ): δ = 175.5, 34.6, 29.43, 29.39, 25.4; IR (KBr, cm -1 ) = 3028, 2934, 2849, 1701, 1467, 1437, 1410, 1344 ,1309,1268,1252,1230,1208,1196,1129,10978,1051,930; MS(EI): m/z(%)189[M+H,35.43],171(100).
实施例30Example 30
Figure PCTCN2020102499-appb-000032
Figure PCTCN2020102499-appb-000032
向三口瓶中加入九水合硝酸铁(201.9mg,0.5mmol)，4-羟基-2,2,6,6-四甲基哌啶氧化物(86.5mg,0.5mmol)，苯乙醇1i(1.2249g,10.0mmol)和乙腈(1.2348g,30mmol)，换气(纯氧)三次，室温下搅拌15小时，过短硅胶柱(乙酸乙酯：20mL×3)，浓缩，快速柱层析(石油醚/乙酸乙酯＝10)，得产物2i(1.0705g,89％):产物为液体。Add ferric nitrate nonahydrate (201.9mg, 0.5mmol), 4-hydroxy-2,2,6,6-tetramethylpiperidine oxide (86.5mg, 0.5mmol), phenethyl alcohol 1i (1.2249g) to the three-necked flask , 10.0mmol) and acetonitrile (1.2348g, 30mmol), ventilation (pure oxygen) three times, stirring at room temperature for 15 hours, too short silica gel column (ethyl acetate: 20mL×3), concentration, flash column chromatography (petroleum ether /Ethyl acetate=10) to obtain product 2i (1.0705g, 89%): the product is liquid.
1H NMR(300MHz,CDCl 3)δ7.96(d,J＝7.2Hz,2H,Ar-H),7.55(t,J＝7.2Hz,1H,Ar-H),7.44(t,J＝7.5Hz,2H,Ar-H),2.59(s,3H,CH 3)； 13C NMR(75MHz,CDCl 3)δ198.0,137.1,133.0,128.5,128.2,26.5. 1 H NMR(300MHz,CDCl 3 )δ7.96(d,J=7.2Hz,2H,Ar-H),7.55(t,J=7.2Hz,1H,Ar-H),7.44(t,J=7.5 Hz, 2H, Ar-H), 2.59 (s, 3H, CH 3 ); 13 C NMR (75MHz, CDCl 3 ) δ 198.0, 137.1, 133.0, 128.5, 128.2, 26.5.
实施例31Example 31
Figure PCTCN2020102499-appb-000033
Figure PCTCN2020102499-appb-000033
向三口瓶中加入九水合硝酸铁(201.9mg,0.5mmol)，4-羟基-2,2,6,6-四甲基哌啶氧化物 (85.9mg,0.5mmol)，1-辛烯-3-醇1j(1.2789g,10.0mmol)和乙腈(1.2507g,30mmol)，换气(纯氧)三次，室温下搅拌11小时，过短硅胶柱(乙酸乙酯：20mL×3)，浓缩，快速柱层析(石油醚/乙酸乙酯＝10)，得产物2j(0.7349g,58％):产物为液体。Add ferric nitrate nonahydrate (201.9mg, 0.5mmol), 4-hydroxy-2,2,6,6-tetramethylpiperidine oxide (85.9mg, 0.5mmol), 1-octene-3 to the three-necked flask -Alcohol 1j (1.2789g, 10.0mmol) and acetonitrile (1.2507g, 30mmol), ventilation (pure oxygen) three times, stirring at room temperature for 11 hours, too short silica gel column (ethyl acetate: 20mL×3), concentration, fast Column chromatography (petroleum ether/ethyl acetate=10), the product 2j (0.7349 g, 58%) is obtained: the product is liquid.
1H NMR(300MHz,CDCl 3):δ＝6.38(dd,J 1＝17.7Hz,J 2＝10.2Hz,1H),6.21(d,J＝17.4Hz,1H),5.80(d,J＝10.2Hz,1H),2.57(t,J＝7.5Hz,2H),1.70-1.56(m,2H),1.40-1.22(m,4H),0.90(t,J＝6.6Hz,3H)； 13C NMR(75MHz,CDCl 3):δ＝201.0,136.6,127.7,39.6,31.4,23.7,22.4,13.8. 1 H NMR (300MHz, CDCl 3 ): δ = 6.38 (dd, J 1 =17.7 Hz, J 2 =10.2 Hz, 1H), 6.21 (d, J = 17.4 Hz, 1H), 5.80 (d, J = 10.2 Hz,1H), 2.57(t,J=7.5Hz,2H),1.70-1.56(m,2H),1.40-1.22(m,4H),0.90(t,J=6.6Hz,3H); 13 C NMR (75MHz, CDCl 3 ): δ=201.0, 136.6, 127.7, 39.6, 31.4, 23.7, 22.4, 13.8.
实施例32基于纯氧的1mol规模的异壬酸(2a)的合成Example 32 Synthesis of 1mol scale isononanoic acid (2a) based on pure oxygen
Figure PCTCN2020102499-appb-000034
Figure PCTCN2020102499-appb-000034
向三口瓶中加入九水合硝酸铁(40.4612g,0.1mol),4-羟基-2,2,6,6-四甲基哌啶氧化物(17.2267g,0.1mol)，氯化钾(7.5055g,0.1mol)，异壬醇1a(175mL,1.0mol)和乙腈(156mL,3.0mol)，换气(纯氧)三次，室温下搅拌23小时(控制温度不高于45℃)，常压蒸馏回收乙腈，减压蒸馏(106℃/3.5mmHg)得产物2a(118.5825g；Yield:75％；Purity:93％):产物为液体。Add ferric nitrate nonahydrate (40.4612g, 0.1mol), 4-hydroxy-2,2,6,6-tetramethylpiperidine oxide (17.2267g, 0.1mol), potassium chloride (7.5055g) to the three-necked flask , 0.1mol), isononanol 1a (175mL, 1.0mol) and acetonitrile (156mL, 3.0mol), ventilation (pure oxygen) three times, stirring at room temperature for 23 hours (control temperature not higher than 45℃), atmospheric distillation The acetonitrile was recovered and distilled under reduced pressure (106°C/3.5mmHg) to obtain product 2a (118.5825g; Yield: 75%; Purity: 93%): the product was liquid.
实施例33基于空气流的1mol规模的异壬酸(2a)的合成Example 33 Synthesis of 1 mol scale isononanoic acid (2a) based on air flow
Figure PCTCN2020102499-appb-000035
Figure PCTCN2020102499-appb-000035
向三口瓶中加入九水合硝酸铁(40.4190g,0.1mol)，4-羟基-2,2,6,6-四甲基哌啶氧化物(17.2080g,0.1mol)，氯化钾(7.4590g,0.1mol)，异壬醇1a(175mL,1.0mol)和乙腈(156mL,3.0mol)，换气(纯氧)三次，室温下搅拌72小时(控制温度不高于50℃)，常压蒸馏回收乙腈，减压蒸馏(110℃/7.0mmHg)得产物2a(134.3592g,Yield:82％；Purity:98％):产物为液体。Add ferric nitrate nonahydrate (40.4190g, 0.1mol), 4-hydroxy-2,2,6,6-tetramethylpiperidine oxide (17.2080g, 0.1mol), potassium chloride (7.4590g) into a three-necked flask , 0.1mol), isononanol 1a (175mL, 1.0mol) and acetonitrile (156mL, 3.0mol), ventilate (pure oxygen) three times, stir at room temperature for 72 hours (control temperature not higher than 50℃), distillation at atmospheric pressure The acetonitrile was recovered and distilled under reduced pressure (110°C/7.0mmHg) to obtain product 2a (134.3592g, Yield: 82%; Purity: 98%): the product was liquid.
通过具体实施例来分析本发明的相应有益效果：The corresponding beneficial effects of the present invention are analyzed through specific examples:
1)溶剂对本反应的影响显著：以3,5,5-三甲基-1-己醇(异壬醇，1a)为反应底物，在不同的溶剂中产率差异显著(序号1-4,以上实施例1-4)；以乙腈为溶剂，仅需12小时即可以 83％的产率得到目标化合物(2a)；向1,2-二氯乙烷和甲苯中添加一当量的乙腈，产率显著提升，显示乙腈对本反应具有促进作用(序号5和6,以上实施例5,6)。1) The solvent has a significant influence on the reaction: 3,5,5-trimethyl-1-hexanol (isononyl alcohol, 1a) is used as the reaction substrate, and the yields in different solvents are significantly different (No. 1-4, The above examples 1-4); using acetonitrile as a solvent, the target compound (2a) can be obtained with a yield of 83% in only 12 hours; adding one equivalent of acetonitrile to 1,2-dichloroethane and toluene produces The rate is significantly increased, showing that acetonitrile has a promoting effect on the reaction (Sequence No. 5 and 6, Examples 5 and 6 above).
Figure PCTCN2020102499-appb-000036
Figure PCTCN2020102499-appb-000036
2)乙腈添加量对反应的影响：添加0.5-4当量的乙腈，反应均可进行；优选地，添加量为2-4当量时，可以82-85％的产率可到相应的异壬酸(以上实施例4,7-10)。2) The effect of the amount of acetonitrile added on the reaction: adding 0.5-4 equivalents of acetonitrile, the reaction can be carried out; preferably, when the added amount is 2-4 equivalents, the corresponding isononanoic acid can be obtained with a yield of 82-85% (Example 4, 7-10 above).
Figure PCTCN2020102499-appb-000037
Figure PCTCN2020102499-appb-000037
3)加料方式对反应的影响：不同加料方式可影响反应副产物(酯，4a)的生成，当以滴加的方式投料时，副产物4a的生成显著降低(以上实施例11,12)。3) The influence of the feeding method on the reaction: different feeding methods can affect the generation of reaction by-products (ester, 4a). When feeding in a dropwise manner, the generation of by-product 4a is significantly reduced (Examples 11, 12 above).
Figure PCTCN2020102499-appb-000038
Figure PCTCN2020102499-appb-000038
4)氯化物对反应的影响：当添加氯化物时，反应可在一定程度上被加速(特别是从醇到醛的氧化过程)(见图1)。添加氯化物后，醛的生成在4小时后即可达到峰值；与之相对应的，不加氯化物时醛的生成则在8小时达到峰值(以上实施例13)。4) The effect of chloride on the reaction: When chloride is added, the reaction can be accelerated to a certain extent (especially the oxidation process from alcohol to aldehyde) (see Figure 1). After chloride is added, the generation of aldehydes can reach the peak after 4 hours; correspondingly, the generation of aldehydes without chlorides will reach the peak in 8 hours (Example 13 above).
Figure PCTCN2020102499-appb-000039
Figure PCTCN2020102499-appb-000039
本发明的反应历程是：伯醇在九水合硝酸铁/4-羟基-2,2,6,6-四甲基哌啶氧化物/氯化钾催化下，先被氧化为相应的醛(3)，同时伴随酯(4)以及缩醛(5)的生成(阶段1)；随着反应的进行，醛和缩醛逐渐转化为相应的羧酸(2)(阶段2)The reaction process of the present invention is: the primary alcohol is first oxidized to the corresponding aldehyde under the catalysis of nonahydrate ferric nitrate/4-hydroxy-2,2,6,6-tetramethylpiperidine oxide/potassium chloride (3 ), accompanied by the formation of esters (4) and acetals (5) (stage 1); as the reaction proceeds, aldehydes and acetals are gradually converted into corresponding carboxylic acids (2) (stage 2)
Figure PCTCN2020102499-appb-000040
Figure PCTCN2020102499-appb-000040
因此，自然地，从醛(3)出发，在九水合硝酸铁/4-羟基-2,2,6,6-四甲基哌啶氧化物催化下，也可实现羧酸(2)的合成(以上实施例17)。Therefore, naturally, starting from aldehyde (3), under the catalysis of nonahydrate ferric nitrate/4-hydroxy-2,2,6,6-tetramethylpiperidine oxide, the synthesis of carboxylic acid (2) can also be achieved (Example 17 above).
Figure PCTCN2020102499-appb-000041
Figure PCTCN2020102499-appb-000041
除此之外，对于多羟基体系，本方法也是适用的(以上实施例29)：In addition, for polyhydroxyl systems, this method is also applicable (Example 29 above):
Figure PCTCN2020102499-appb-000042
Figure PCTCN2020102499-appb-000042
本发明所涉及的溶剂可以是乙腈、1,2-二氯乙烷、1,1-二氯乙烷、1,2-二氯丙烷、1,3-二氯丙烷、二氯甲烷、硝基甲烷、苯、甲苯、乙酸乙酯、四氢呋喃的一种或混合。优选地，采用乙腈为溶剂(添加剂)可取得最佳效果，醇或相应的醛/乙腈的摩尔比为：1:1～6；优选地，醇或相应的醛/乙腈的摩尔比1:3。The solvent involved in the present invention can be acetonitrile, 1,2-dichloroethane, 1,1-dichloroethane, 1,2-dichloropropane, 1,3-dichloropropane, dichloromethane, nitro One or a mixture of methane, benzene, toluene, ethyl acetate, and tetrahydrofuran. Preferably, acetonitrile is used as the solvent (additive) to achieve the best effect. The molar ratio of alcohol or corresponding aldehyde/acetonitrile is 1:1 to 6; preferably, the molar ratio of alcohol or corresponding aldehyde/acetonitrile is 1:3 .
最后，还需要注意的是，以上列举的仅是本发明的几个具体实施例。显然，本发明不限于以上实施例，还可以有许多变形。本领域的普通技术人员能从本发明公开的内容直接导出或联想到的所有变形，均应认为是本发明的保护范围。Finally, it should be noted that the above-listed are only a few specific embodiments of the present invention. Obviously, the present invention is not limited to the above embodiments, and many variations are possible. All modifications that can be directly derived or imagined by a person of ordinary skill in the art from the disclosure of the present invention should be considered as the protection scope of the present invention.

Claims (11)

  1. 一种以氧气或空气中的氧气作为氧化剂从醇或相应的醛合成羧酸或酮类化合物的方法，其特征在于，在硝酸盐/4-羟基-2,2,6,6-四甲基哌啶氧化物的催化下，并在添加剂的作用下，将反应底物醇或相应的醛氧化为相应的羧酸或酮类化合物，其反应式如下：A method for synthesizing carboxylic acids or ketones from alcohols or corresponding aldehydes using oxygen or oxygen in the air as an oxidant, characterized in that the nitrate/4-hydroxy-2,2,6,6-tetramethyl Under the catalysis of piperidine oxide and the action of additives, the reaction substrate alcohol or the corresponding aldehyde is oxidized to the corresponding carboxylic acid or ketone compound. The reaction formula is as follows:
    Figure PCTCN2020102499-appb-100001
    Figure PCTCN2020102499-appb-100001
  2. 根据权利要求1所述的方法，其特征在于，所述方法具体包括以下步骤：将硝酸盐、4-羟基-2,2,6,6-四甲基哌啶氧化物及添加剂加入到容器中，抽换气，然后将反应底物醇或相应的醛一次加入或滴加到反应体系中，搅拌反应；浓缩，快速柱层析或直接蒸馏蒸出，得羧酸类化合物。The method according to claim 1, wherein the method specifically comprises the following steps: adding nitrate, 4-hydroxy-2,2,6,6-tetramethylpiperidine oxide and additives into a container , Ventilate, and then add the reaction substrate alcohol or the corresponding aldehyde to the reaction system at one time or dropwise, stir the reaction; concentrate, flash column chromatography or direct distillation and steam to obtain carboxylic acid compounds.
  3. 根据权利要求1或2所述的方法，其特征在于，所述醇是伯醇RCH 2OH或仲醇R 1CHOHR 2；其中，R为C3-C15的直链或支链烷烃，或含苯环或烯烃或炔烃的不饱和烃；所述反应底物兼容烷氧基、卤素官能团；R 1为C1-C15的直链或支链烷烃，或含苯环或烯烃或炔烃的不饱和烃；R 2为C1-C15的直链或支链烷烃，或含苯环或烯烃或炔烃的不饱和烃。 The method according to claim 1 or 2, wherein the alcohol is a primary alcohol RCH 2 OH or a secondary alcohol R 1 CHOHR 2 ; wherein R is a C3-C15 linear or branched alkane, or contains benzene Unsaturated hydrocarbons of cyclic or alkenes or alkynes; the reaction substrate is compatible with alkoxy and halogen functional groups; R 1 is C1-C15 linear or branched alkanes, or unsaturated hydrocarbons containing benzene rings or alkenes or alkynes Hydrocarbon; R 2 is a C1-C15 linear or branched alkane, or an unsaturated hydrocarbon containing a benzene ring or alkene or alkyne.
  4. 根据权利要求3所述的方法，其特征在于，所述伯醇是一元伯醇或是二元伯醇；其中，所述二元伯醇为碳数大于6的二元伯醇；所述仲醇为二级脂肪醇、苄醇、烯丙醇或炔丙醇。The method of claim 3, wherein the primary alcohol is a primary monohydric alcohol or a primary dihydric alcohol; wherein the primary dihydric alcohol is a primary dihydric alcohol with a carbon number greater than 6; the secondary The alcohol is a secondary fatty alcohol, benzyl alcohol, allyl alcohol or propargyl alcohol.
  5. 根据权利要求1或2所述的方法，其特征在于，所述添加剂是1,2-二氯乙烷、1,1-二氯乙烷、1,2-二氯丙烷、1,3-二氯丙烷、二氯甲烷、硝基甲烷、苯、甲苯、乙腈、乙酸乙酯、四氢呋喃中的一种或几种。The method according to claim 1 or 2, wherein the additive is 1,2-dichloroethane, 1,1-dichloroethane, 1,2-dichloropropane, 1,3-dichloroethane One or more of chloropropane, dichloromethane, nitromethane, benzene, toluene, acetonitrile, ethyl acetate, and tetrahydrofuran.
  6. 根据权利要求1或2所述的方法，其特征在于，所述硝酸盐为九水合硝酸铁、三水合硝酸铜中的一种或混合。The method according to claim 1 or 2, wherein the nitrate is one or a mixture of ferric nitrate nonahydrate and copper nitrate trihydrate.
  7. 根据权利要求1或2所述的方法，其特征在于，所述醇或相应的醛、硝酸盐、4-羟基-2,2,6,6-四甲基哌啶氧化物的摩尔比为100：(1～10)：(1～10)。The method according to claim 1 or 2, wherein the molar ratio of the alcohol or the corresponding aldehyde, nitrate, 4-hydroxy-2,2,6,6-tetramethylpiperidine oxide is 100 : (1～10): (1～10).
  8. 根据权利要求1或2所述的方法，其特征在于，所述醇或相应的醛、添加剂的摩尔比为1：(1～6)。The method according to claim 1 or 2, characterized in that the molar ratio of the alcohol or the corresponding aldehyde and the additive is 1: (1-6).
  9. 根据权利要求1或2所述的方法，其特征在于，所述反应的温度为室温～50℃。The method of claim 1 or 2, wherein the reaction temperature is room temperature to 50°C.
  10. 根据权利要求1或2所述的方法，其特征在于，当额外添加无机氯化物时，反应被加速，所述无机氯化物包括氯化锂、氯化钠、氯化钾、氯化铷、氯化铯中的一种或几种。The method of claim 1 or 2, wherein the reaction is accelerated when an inorganic chloride is additionally added, the inorganic chloride includes lithium chloride, sodium chloride, potassium chloride, rubidium chloride, chlorine One or more of cesium.
  11. 根据权利要求2所述的方法，其特征在于，所述抽换气的气体为纯氧气或空气中的氧气。The method according to claim 2, wherein the gas to be pumped and ventilated is pure oxygen or oxygen in the air.
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