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CN-122013209-A - Hydroxy substituted alkane compound and method for synthesizing hydroxy substituted alkane compound by electrochemical reduction coupling

CN122013209ACN 122013209 ACN122013209 ACN 122013209ACN-122013209-A

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a hydroxy-substituted alkane compound and a method for synthesizing the hydroxy-substituted alkane compound by electrochemical reduction coupling. The hydroxy-substituted alkane compound comprises an alpha-trifluoromethyl alcohol compound and a ketone carbonyl derivative hydroxy alkylate, wherein the structural general formula of the alpha-trifluoromethyl alcohol compound is CF 3 -C(OH)(R 1 )-CH(R 5 )-R 2 , the structural general formula of the ketone carbonyl derivative hydroxy alkylate is that R 3 -C(OH)(R 4 )-CH(R 5 )-R 2 ,R 1 is aryl, heteroaryl or C1-C4 alkyl, R 2 is aryl, condensed ring group and alkenyl, R 3 is cyano or C1-C4 alkoxycarbonyl, R 4 is phenyl or C1-C4 alkyl, and R 5 is H or C1-C4 alkyl. The hydroxy-substituted alkane compound and the synthesis method provided by the invention have the advantages of mild reaction conditions and simple operation.

Inventors

  • LI YINUO
  • WU SIYI
  • SHI YIFEI
  • LI YINGNA
  • BAI MENGJIAO
  • WANG XIN
  • YOU JIAXING

Assignees

  • 山东金科力电源科技有限公司
  • 山东师范大学

Dates

Publication Date
20260512
Application Date
20260414

Claims (10)

  1. 1. The hydroxy-substituted alkane compound is characterized by comprising an alpha-trifluoromethyl alcohol compound and a ketocarbonyl derivative hydroxy alkylate, wherein the structural general formula of the alpha-trifluoromethyl alcohol compound is CF 3 -C(OH)(R 1 )-CH(R 5 )-R 2 , the structural general formula of the ketocarbonyl derivative hydroxy alkylate is R 3 -C(OH)(R 4 )-CH(R 5 )-R 2 , R 1 is aryl, heteroaryl or C1-C4 alkyl, R 2 is aryl, condensed ring group and alkenyl, R 3 is cyano or C1-C4 alkoxycarbonyl, R 4 is phenyl or C1-C4 alkyl, and R 5 is H or C1-C4 alkyl.
  2. 2. The hydroxy-substituted alkane compound according to claim 1, wherein the aryl group is phenyl, C1-C4 alkyl-substituted phenyl, C1-C4 alkoxy-substituted phenyl, halophenyl, cyano-substituted phenyl, naphthyl, phenanthryl, [1,1' -biphenyl ] -4-yl, the heteroaryl group is furyl, thienyl or benzothienyl, the condensed ring group is 9H-fluorenyl, and the alkenyl group is allyl or cinnamyl.
  3. 3. A method for synthesizing the hydroxy-substituted alkane compound according to claim 1 or 2 by electrochemical reduction coupling is characterized by comprising the following steps of taking carbonyl compounds and alkyl halides as reactants, introducing current into an undivided electrolytic cell for electrolytic reaction in the presence of an organic solvent and electrolyte, and separating and purifying to obtain the hydroxy-substituted alkane compound.
  4. 4. The method for synthesizing the hydroxy-substituted alkane compound by electrochemical reduction coupling according to claim 3, wherein the carbonyl compound comprises a trifluoromethyl ketone compound, a benzoyl cyanide and an oxo-carboxylic ester, the structural formula of the trifluoromethyl ketone compound is CF 3 -CO-R 1 , the benzoyl cyanide is benzoyl cyanide, and the oxo-carboxylic ester is ethyl 2-oxo-propionate.
  5. 5. The method for synthesizing a hydroxy-substituted alkane compound according to claim 4, wherein the alkyl halide has a structural formula of R 2 -CH(R 5 -X, wherein X is halogen.
  6. 6. The method for synthesizing a hydroxy-substituted alkane compound by electrochemical reduction coupling according to claim 3, wherein the electrolyte is a quaternary ammonium salt or a lithium salt.
  7. 7. The method for synthesizing a hydroxy-substituted alkane compound by electrochemical reduction coupling according to claim 6, wherein the organic solvent is one or more of acetonitrile, N-dimethylacetamide and N, N-dimethylformamide.
  8. 8. The method for synthesizing the hydroxy-substituted alkane compound by electrochemical reduction coupling according to claim 3, wherein the molar ratio of the carbonyl compound to the alkyl halide is 1:2-3 based on the molar amount of the carbonyl compound.
  9. 9. The method for synthesizing the hydroxyl-substituted alkane compound by electrochemical reduction coupling according to claim 3 is characterized in that an anode of the electrolytic reaction is a tin electrode, a cathode of the electrolytic reaction is a copper electrode, the electrolytic reaction is carried out under constant current, and the current is 5-15 mA.
  10. 10. The method for synthesizing the hydroxy-substituted alkane compound by electrochemical reduction coupling according to claim 9, which is characterized in that the specific operation of separation and purification is that the reaction solution is poured into water, extracted by ethyl acetate, the organic phases are combined, washed by saturated saline solution, dried by anhydrous magnesium sulfate, filtered and concentrated, and the residue is purified by silica gel column chromatography to obtain the hydroxy-substituted alkane compound.

Description

Hydroxy substituted alkane compound and method for synthesizing hydroxy substituted alkane compound by electrochemical reduction coupling Technical Field The invention belongs to the technical field of organic synthesis, and particularly relates to a hydroxy-substituted alkane compound and a method for synthesizing the hydroxy-substituted alkane compound by electrochemical reduction coupling. Background In the fields of organic synthesis, pharmaceutical chemistry and material science, hydroxyl-containing alkane compounds are important organic synthesis building blocks, wherein alpha-trifluoromethyl alcohol can obviously enhance the lipid solubility, metabolic stability and bioavailability of medicines due to unique electronic, spatial and hydrophobic characteristics of trifluoromethyl (-CF 3), and can widely exist in medicines such as flutter, lansoprazole and the like, and meanwhile, other hydroxyl-substituted alkane derivatives (such as cyano-substituted and ester-substituted hydroxyalkanes) are also key intermediates in the fields of fine chemical industry and agricultural chemicals, and have irreplaceable values in the fields of medicine research and development, material synthesis and the like. The conventional method for preparing the hydroxy-substituted alkane compound at present mainly comprises ionic reaction, including addition of nucleophilic reagent to carbonyl compound, alkylation of organic metal reagent to ketone compound and the like, and the method has definite path, but has the limitations of harsh reaction conditions, excessive reagent, more byproducts, low atom economy, complex operation, high cost, possible environmental pollution and the like. In recent years, a photo-redox catalytic free radical coupling strategy is gradually applied to the synthesis of the compounds. For example, patent CN108774121a discloses a method for preparing α -aryl- β -trifluoromethyl ketones by visible light catalysis, the product of which can be further converted into α -trifluoromethyl alcohol derivatives. However, the method needs noble metal catalyst or special photosensitizer, which increases the cost and difficulty of product separation and limits the large-scale application. The biocatalysis reduction method is also used for synthesizing chiral hydroxyalkanes (especially chiral alpha-trifluoromethyl alcohols), such as the preparation of chiral alpha-trifluoromethyl alcohols by imine reductase AtRedAm in patent CN121538277A, which can solve the difficult problem of chiral isomer separation, but has the problems of difficult catalyst preparation, narrow substrate applicability, slow reaction rate, poor enzyme stability and the like. In the German International edition of application chemistry (Angew. Chem. Int. Ed. 2025, 64 (4): e202415218, DOI 10.1002/anie. 202415218) ("International edition of application chemistry, 2025.64 (4) 2025, volume 64, 4 th, article No. e202415218, DOI 10.1002/anie. 202415218), it is reported that a trifluoromethyl thiophene salt is used as a trifluoromethyl source, CF 3 radicals are generated by electrochemical reduction, after addition to unactivated olefins, carbanions are generated by secondary cathodic reduction, and then the reaction is terminated by solvent protonation, mgBr 2 is used as a sacrificial reducing agent, high selectivity is realized by combining with cyclic voltammetry, and the functional group tolerance is excellent. Although the existing synthesis method is more and the organic synthesis has remarkable progress in the trifluoromethylation reaction, the electrochemical synthesis of hydroxy-substituted alkane compounds still has the defects of less direct synthesis method, partial special sacrificial reagent or electrolyte, high cost and operation complexity, narrow substrate applicability, difficult compatibility with redox sensitive heterocyclic compounds, and still has the advantages of improving the reaction efficiency, yield and selectivity and difficult meeting the requirements of large-scale industrial production and drug research and development. Disclosure of Invention The invention aims to overcome the defects in the prior art, and provides a hydroxy-substituted alkane compound and a method for synthesizing the hydroxy-substituted alkane compound by electrochemical reduction coupling, which have the advantages of mild reaction conditions, simple operation, environmental friendliness and good functional group compatibility, can simultaneously synthesize an alpha-trifluoromethyl alcohol compound and a ketone carbonyl derivative hydroxy alkylate, and fill the blank in the prior art. Hydroxy-substituted alkane compound The hydroxy-substituted alkane compound comprises an alpha-trifluoromethyl alcohol compound and a ketone carbonyl derivative hydroxy alkylate, and has the following structural formula: 1. the structural general formula of the alpha-trifluoromethyl alcohol compound is CF 3-C(OH)(R1)-CH(R 5)-R2; 2. the structural general formula of the k