阅读说明：本技术 一种脂肪族胺选择性硫化的方法 (Method for selective vulcanization of aliphatic amine ) 是由 杨明瑜 秦玉曼 韩雨洁 李松蓉 魏俊发 于 2019-11-25 设计创作，主要内容包括：本发明公开了一种脂肪族胺选择性硫化的方法,将脂肪族胺在铜催化下通过1,5-位的氢迁移与二硫化物反应,实现了脂肪族胺的位点选择性硫化。本发明方法可以使一级、二级和三级C-H键高效地转换为C<Sub>SP</Sub><Sup>3</Sup>-S键。同时,生物活性化合物的后期修饰也证明了这种方法的合成效用。本发明制备方法简单,反应条件温和,适用于不同的胺和二硫化物,原子利用率高,符合绿色化学的要求,为C<Sub>SP</Sub><Sup>3</Sup>-S键的构建提供了一种更为直接有效的方法,同时也为现代有机合成、天然产物和医药提供有力的合成手段。(The invention discloses a method for selective vulcanization of aliphatic amine, which realizes site selective vulcanization of aliphatic amine by carrying out 1, 5-site hydrogen migration and disulfide reaction on the aliphatic amine under the catalysis of copper. The method can efficiently convert the primary, secondary and tertiary C-H bonds into C SP 3 -an S bond. At the same time, the late modification of the biologically active compoundsThe synthetic utility of this approach was demonstrated. The preparation method is simple, has mild reaction conditions, is suitable for different amines and disulfides, has high atom utilization rate, meets the requirement of green chemistry, and is C SP 3 The construction of the-S bond provides a more direct and effective method, and simultaneously provides a powerful synthetic means for modern organic synthesis, natural products and medicines.)

1. A method for selective vulcanization of aliphatic amines, characterized by: adding a compound shown in a formula I or a formula I 'and a disulfide shown in a formula II, a copper catalyst, a nitrogen-containing ligand, an inorganic base and a metal simple substance into an organic solvent, and reacting at 25-50 ℃ under the illumination condition with the wavelength of 390-760 nm to obtain a vulcanized product shown in a formula III or a formula III';

in formulae I and III, R¹Represents a substituent at position α or β of N, which is hydrogen, C₁～C₆Alkyl, phenyl, monohalophenyl, polyhalophenyl, nitro-substituted phenyl, C₁～C₆Alkoxy-substituted phenyl, C₁～C₆Any one of alkyl substituted phenyl and dimethyl, R²Represents hydrogen, C₁～C₃Any one of alkyl radicals, R³Represents hydrogen, C₁～C₈Alkyl radical, CH₂COOCH₃、Any one of them, Ts represents

2. The method of claim 1 for the selective vulcanization of aliphatic amines, wherein: the copper catalyst is any one of copper trifluoromethanesulfonate, copper acetylacetonate, copper hexafluoroacetylacetonate, cuprous iodide and copper bromide.

3. The method of claim 1 for the selective vulcanization of aliphatic amines, wherein: the nitrogen-containing ligand is any one of 5-nitro-1, 10-phenanthroline, bipyridine, 4, 7-dichloro-1 and 10-phenanthroline.

4. The method of claim 1 for the selective vulcanization of aliphatic amines, wherein: the inorganic base is any one of sodium dihydrogen phosphate, potassium phosphate, sodium bicarbonate and disodium hydrogen phosphate.

5. The method of claim 1 for the selective vulcanization of aliphatic amines, wherein: the metal simple substance is any one of zinc powder, indium powder, manganese powder, cerium powder, aluminum powder and copper powder.

6. The method of claim 1 for the selective vulcanization of aliphatic amines, wherein: the organic solvent is any one of chlorobenzene, dichloromethane, 1, 2-dichloroethane, tetrahydrofuran and N, N-dimethylformamide.

7. The method of claim 1 for the selective vulcanization of aliphatic amines, wherein: the molar ratio of the compound of formula I or the compound of formula I' to the disulfide of formula II, the copper catalyst, the nitrogen-containing ligand, the inorganic base and the metal simple substance is 1 (1.0-1.5): 0.05-0.15): 1.0-1.5): 1.5-2.0.

8. The method of claim 1 for the selective vulcanization of aliphatic amines, wherein: reacting for 8-10 hours at 35-45 ℃ under the illumination condition with the wavelength of 390-760 nm.

Technical Field

The invention relates to a method for selectively vulcanizing aliphatic amine.

Background

C_SP ³the-S bond plays a key role in modern organic synthesis, natural products and medicine. For example, butoconazole is an imidazole antifungal drug used in gynecology, nelfinavir is an antiretroviral drug used in the treatment of Human Immunodeficiency Virus (HIV), and clinical trials have shown that C is introduced_SP ³the-S moiety may improve its biological activity. The medicines have physiological activities of resisting tumor, resisting inflammation, regulating immunity, etc. Amino acids play an important role in the life activities of living organisms as the most basic structural units of proteins, and C can be found in natural amino acids such as cysteine_SP ³-S-bonds, which promote the metabolic processes of body-related proteins. Thus, for compounds containing C_SP ³The compound of-S adopts a high-efficiency and high-selectivity method to directly assemble C_SP ³the-S bond is particularly important.

Structure C_SP ³The textbook route to the-S bond is the nucleophilic substitution of alkyl halides with metal sulfates. Similar to other types of nucleophilic substitution reactions, this approach is sensitive to steric effects. With the development of transition metal catalysis, C is more effectively realized through transition metal catalysis cross coupling of organic halide/olefin and mercaptan/thioether_SP ³Construction of the S bond. Dong team has recently effectively constructed C by catalytic hydro-sulfurization of olefins_SP ³An S bond, wherein metal rhodium is used as a catalyst, and the hydrosulfurization reaction of 1, 3-diene is expanded to obtain sulfides with high regiocontrollability, such as allyl or homoallyl (X. -H. Yang, R.T. Davison, S. -Z. Nie, F.A. Cruz, T.M.McGinnis and V.M.Dong, J.Am.chem.Soc.,2019,141,3006.). However, this reaction requires pre-functionalization of the substrate and regioselectivity is highly dependent on the substrate structure. From this point of view, C_SP ³Direct sulfurization of-S is clearly an ideal transformation.

Disclosure of Invention

The invention aims to provide a method for selectively vulcanizing aliphatic amine, which is simple to operate, mild in reaction conditions and high in efficiency.

Aiming at the purposes, the technical scheme adopted by the invention is as follows: adding a compound shown in a formula I or a formula I 'and a disulfide shown in a formula II, a copper catalyst, a nitrogen-containing ligand, an inorganic base and a metal simple substance into an organic solvent, and reacting at 25-50 ℃ under the illumination condition with the wavelength of 390-760 nm to obtain a vulcanization product shown in a formula III or a formula III'.

In formulae I and III, R¹Represents a substituent at position α or β of N, which is hydrogen, C₁～C₆Alkyl, phenyl, monohalophenyl, polyhalophenyl, nitro-substituted phenyl, C₁～C₆Alkoxy-substituted phenyl, C₁～C₆Any one of alkyl substituted phenyl and dimethyl, R²Represents hydrogen, C₁～C₃Any one of alkyl radicals, R³Represents hydrogen, C₁～C₈Alkyl radical, CH₂COOCH₃、

Any one of them, Ts represents

In the formulae II and III, R represents phenyl, monohalophenyl, polyhalophenyl, nitro-substituted phenyl, C₁～C₆Alkoxy-substituted phenyl, C₁～C₆Any one of alkyl substituted phenyl, naphthyl, benzyl and acetoxyl; in the formulas I 'and III', n is an integer of 1-3.

In the method, the copper catalyst is any one of copper trifluoromethanesulfonate, copper acetylacetonate, copper hexafluoroacetylacetonate, cuprous iodide and copper bromide.

In the above method, the nitrogen-containing ligand is any one of 5-nitro-1, 10-phenanthroline, bipyridine, 4, 7-dichloro-1, 10-phenanthroline.

In the above method, the inorganic base is any one of sodium dihydrogen phosphate, potassium phosphate, sodium bicarbonate and disodium hydrogen phosphate.

In the method, the metal simple substance is any one of zinc powder, indium powder, manganese powder, cerium powder, aluminum powder and copper powder.

In the method, the organic solvent is any one of chlorobenzene, dichloromethane, 1, 2-dichloroethane, tetrahydrofuran and N, N-dimethylformamide.

In the above method, the molar ratio of the compound of formula I or the compound of formula I' to the disulfide of formula II, the copper catalyst, the nitrogen-containing ligand, the inorganic base and the metal simple substance is preferably 1 (1.0-1.5): (0.05-0.15): 1.0-1.5): 1.5-2.0.

In the above method, the reaction is preferably carried out at 35 to 45 ℃ for 8 to 10 hours under an illumination condition with a wavelength of 390 to 760 nm.

The invention has the following beneficial effects:

according to the invention, the sulfonyl protected N-F compound realizes the delta position vulcanization reaction of aliphatic amine in the presence of a copper catalyst, a nitrogen-containing ligand, inorganic base and a metal simple substance. Through a series of substrate extension experiments, the inventor finds that when disulfide molecules have electron-donating groups such as alkoxy, acetoxyl and the like, the reaction yield is high, and NO is contained₂When the electron groups are equiflat, the target product can be obtained. The target product can be obtained with a good yield no matter whether the reaction site is primary carbon, secondary carbon or tertiary carbon. When the center of the reaction site is provided with groups such as amido, ester, siloxy and the like, the target product can be obtained, and the good adaptability of the reaction system is reflected.

According to the invention, the site selective sulfuration of the aliphatic amine is realized by the reaction of 1, 5-site hydrogen migration and disulfide of the aliphatic amine under the catalysis of copper. The method can convert C-H bonds of primary, secondary and tertiary stages into C efficiently_SP ³-an S bond. At the same time, late modifications of the biologically active compounds also demonstrate the synthetic utility of this approach. The preparation method of the inventionSimple, mild reaction condition, suitability for different amines and disulfides, high atom utilization rate, and meeting the requirement of green chemistry, namely C_SP ³The construction of the-S bond provides a more direct and effective method, and simultaneously provides a powerful synthetic means for modern organic synthesis, natural products and medicines.

Detailed Description

The present invention will be described in further detail with reference to examples, but the scope of the present invention is not limited to the examples.