阅读说明：本技术 一种(z)-4-二氟烷基-5-硫烷基-4-戊烯酮衍生物及其制备方法 ((Z) -4-difluoroalkyl-5-sulfanyl-4-pentenone derivative and preparation method thereof ) 是由 朱钢国 商甜波 周雨露 于 2019-09-26 设计创作，主要内容包括：一种(Z)-4-二氟烷基-5-硫烷基-4-戊烯酮衍生物及其制备方法,将式Ⅱ结构的炔硫醚、一溴二氟醋酸酯、面式-三(2-苯基吡啶)合铱、碱及溶剂混合,蓝光照射下形成反应体系,经后处理得到式Ⅰ结构的一种(Z)-4-二氟烷基-5-硫烷基-4-戊烯酮衍生物。本发明首次实现了自由基对非末端炔烃的加成-氢迁移-非环化的串联反应,一步实现了一种(Z)-4-二氟烷基-5-硫烷基-4-戊烯酮衍生物的立体选择性合成。该反应条件温和,底物适用范围广,反应收率良好,操作简单,对于合成含氟戊烯酮类化合物的合成提供了新途径。<Image he="168" wi="700" file="DDA0002216228640000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(A (Z) -4-difluoroalkyl-5-sulfanyl-4-pentenone derivative is prepared from alkyne thioether with structure of formula (II), monobromodifluoroacetate, iridium face-tri (2-phenylpyridine), alkali and solvent through mixing, radiating by blue light to form reaction system, and post-treating to obtain the (Z) -4-difluoroalkyl-5-sulfanyl-4-pentenone derivative with structure of formula (I). The invention realizes the series reaction of addition-hydrogen migration-non-cyclization of free radicals to non-terminal alkyne for the first time and realizes the stereoselective synthesis of the (Z) -4-difluoroalkyl-5-sulfanyl-4-pentenone derivative in one step. The method has the advantages of mild reaction conditions, wide substrate application range, good reaction yield and simple operation, and provides a new way for synthesizing the fluorine-containing pentenone compound.)

1. a (Z) -4-difluoroalkyl-5-sulfanyl-4-pentenone derivative characterized by the structure of formula I:

wherein R is₁Is one of methyl and ethyl, R₂Is one of phenyl, p-methylphenyl, p-fluorophenyl, p-chlorophenyl or p-bromophenyl, R₃Is one of hydrogen atom, methoxy or tert-butyl dimethyl siloxane group.

2. A process for producing a (Z) -4-difluoroalkyl-5-sulfanyl-4-pentenone derivative, which comprises the steps of:

mixing alkyne thioether with a structure shown in a formula II, monobromodifluoroacetate, facial-tris (2-phenylpyridine) iridium, silver carbonate and dimethyl sulfoxide under a nitrogen atmosphere, wherein the molar ratio of the alkyne thioether with the structure shown in the formula II, the monobromodifluoroacetate, the facial-tris (2-phenylpyridine) iridium to the silver carbonate is 1: 2: 0.02: 2, stirring the mixed system for 12 hours at room temperature of 25 ℃ under the irradiation of a 15W blue light lamp, carrying out post-treatment to obtain the (Z) -4-difluoroalkyl-5-sulfanyl-4-pentenone derivative with the structure shown in the formula I,

wherein R is₁Is one of methyl and ethyl, R₂Is one of phenyl, p-methylphenyl, p-fluorophenyl, p-chlorophenyl or p-bromophenyl; r₃Is one of hydrogen atom, methoxy or tert-butyl dimethyl siloxane group.

3. The method of claim 2, wherein: the post-treatment comprises quenching, extraction, washing, drying and column chromatography separation of an organic phase.

4. The production method according to claim 3, characterized in that: the quenching adopts water quenching, the extraction adopts ethyl acetate for three times, the organic phase is washed by saturated edible water, the drying adopts anhydrous sodium sulfate for drying, and the column chromatography separation adopts silica gel column chromatography for separation.

Technical Field

The invention belongs to the field of organic synthesis, and particularly relates to a (Z) -4-difluoroalkyl-5-sulfanyl-4-pentenone derivative and a preparation method thereof.

Background

The C-H bond is the simplest and most common functional group in organic compounds. The selective oxidative synthesis of hydrocarbons into oxygen-containing organic chemical products plays an extremely important role in industrial synthesis, in particular in the petrochemical industry. However, selective oxidation of hydrocarbons faces a number of problems. First, because the C-H bond activation energy of saturated hydrocarbons is high and difficult to oxidize, high temperatures and pressures or the addition of equivalent amounts of strong oxidants are generally required. Secondly, target products such as alcohols, ketones, aldehydes, acids and the like, which are mostly thermodynamically unstable intermediate compounds, are easily further deeply oxidized. These not only cause resource waste and environmental pollution, but also bring great difficulty to the separation and purification of products, which greatly increases the investment and production cost. Meanwhile, many hydrocarbons contain various carbon-hydrogen bonds, and the selective control of oxidation products is one of the key problems in the research of hydrocarbon oxidation. Therefore, the development of green and efficient oxidation reaction is also one of the hot spots studied by chemists.

The selective activation of C-H is realized, generally depending on the design of a proper guide group, and a transition metal is selected as a catalyst to obtain a target product. Another common strategy is to build the target molecular scaffold by C-H activation via free radical mechanisms. Remote C-H functionalization by radical addition of alkynes is currently achieved, however, this reaction often undergoes radical addition atom migration and cyclization to form cyclics without olefin addition products.

Pentenones are used as important organic synthesis intermediates, frequently in the synthesis of pharmaceuticals, fine chemicals and pesticides. In addition, pentenone is also widely present as an important building block in a variety of materials, drugs and pesticide molecules, and many natural and non-natural molecules with physiological or pharmacological activity contain this fragment. With the development of fluorine chemistry, more and more fluorine-containing compounds are widely applied to the fields of medicines, pesticides, materials and the like, and fluorine-containing groups (-F, -CF) are introduced into the compounds₃、-CF₂CF₃Etc.), have been receiving wide attention from chemists. Difluoromethylene (CF)₂) The compound not only has the characteristics of common fluorine-containing compounds, but also has unique chemical properties andhas medical value. Difluoromethylene is often used in the design of drugs and bioactive molecules. Therefore, a reasonable catalytic system is designed, and long-range sp initiated by the addition of difluoromethylene to internal alkyne is realized³And (Z) -olefin with a far-end functional group is synthesized in one step through carbon-hydrogen bond oxidation reaction. The process not only selectively introduces difluoromethylene into a substrate, but also realizes the oxidation of a remote C-H bond, and the synthesized pentenone compound containing difluoromethylene has important significance in theoretical research and practical application.

Disclosure of Invention

The technical problem to be solved by the invention is to provide a (Z) -4-difluoroalkyl-5-sulfanyl-4-pentenone derivative, and provide a preparation method which has mild reaction conditions, wide substrate application range, good reaction yield and simple operation, can realize the structural diversity synthesis of the (Z) -4-difluoroalkyl-5-sulfanyl-4-pentenone derivative by changing a substituent,

a (Z) -4-difluoroalkyl-5-sulfanyl-4-pentenone derivative having the structure of formula I:

wherein, in the formula I, R₁Is one of methyl and ethyl; r₂Is one of phenyl, p-methylphenyl, p-fluorophenyl, p-chlorophenyl or p-bromophenyl; r₃Is one of hydrogen atom, methoxy or tert-butyl dimethyl siloxane group.

A method for producing a (Z) -4-difluoroalkyl-5-sulfanyl-4-pentenone derivative, comprising the steps of:

under the nitrogen atmosphere, adding alkyne thioether with a structure shown in a formula II, monobromo difluoro acetate, a catalyst, alkali and a solvent, mixing, stirring the mixed system for 12 hours at room temperature of 25 ℃ under a 15W blue light lamp, and carrying out post-treatment to obtain the (Z) -4-difluoroalkyl-5-sulfanyl-4-pentenone derivative with the structure shown in the formula I:

wherein, in the formula I, R₁Is one of methyl and ethyl; r₂Is one of phenyl, p-methylphenyl, p-fluorophenyl, p-chlorophenyl or p-bromophenyl; r₃Is one of hydrogen atom, methoxy or tert-butyl dimethyl siloxane group.

The specific synthetic route involved in the reaction is shown below:

the solvent is dimethyl sulfoxide (DMSO), and the dimethyl sulfoxide is not only used as the solvent, but also used as an oxidant in the reaction. The catalyst is surface-type-tri (2-phenylpyridine) iridium, and the alkali is silver carbonate.

The optimal molar ratio of the alkyne thioether with the structure shown in the formula II, the monobromodifluoroacetate, the facial-tris (2-phenylpyridine) iridium and the silver carbonate is 1: 2: 0.02: 2.

the post-treatment comprises the following steps: quenching, extracting, washing an organic phase, drying and separating by column chromatography.

The quenching adopts water quenching, the extraction adopts ethyl acetate for three times, the organic phase is washed by saturated edible water, the drying adopts anhydrous sodium sulfate for drying, and the column chromatography separation adopts silica gel column chromatography for separation.

In the present invention, CF is generated by iridium-catalyzed monobromodifluoride₂The free radical reacts with the alkyne thioether compound, the series reaction of addition-hydrogen migration-non-cyclization of non-terminal alkyne is realized for the first time, the addition and remote C-H activation oxidation reaction of alkyne are realized in one step, and the preparation of the (Z) -4-difluoroalkyl-5-sulfanyl-4-pentenone derivative is realized.

Compared with the prior art, the invention has the following advantages:

1. the series reaction of addition-hydrogen migration-non-cyclization of free radicals to non-terminal alkynes is realized for the first time.

2. Alkyne thioether is ingeniously designed to be used as a substrate for reaction, monobromo difluorination reagent is utilized to carry out radical series reaction, and the (Z) -olefin with the remote functional group is synthesized in one step, and the reaction has high regional, three-dimensional and position selectivity.

3. Dimethyl sulfoxide not only acts as a reaction solvent, but also participates in the reaction as an oxidizing agent.

4. The reaction condition is mild, the operation is simple, the application range of the substrate is wide, the compatibility of functional groups is good, and the application prospect is good; therefore, the invention has higher theoretical innovation value and implementation value.

Detailed Description