阅读说明：本技术 一种(e)-1-芳基-4,4,4-三氟丁-2-烯-1-酮化合物的制备方法 (Preparation method of (E) -1-aryl-4, 4, 4-trifluorobutan-2-en-1-one compound ) 是由 周宇涵 李栋 吕树均 曲景平 于 2019-11-14 设计创作，主要内容包括：本发明公开了一种(E)-1-芳基-4,4,4-三氟丁-2-烯-1-酮化合物的制备方法,属于化合物制备领域。一种(E)-1-芳基-4,4,4-三氟丁-2-烯-1-酮,以通式II所述化合物为原料,在氧化剂和碱的存在下,按下述反应式进行反应,得通式I所示化合物。<Image he="294" wi="700" file="DDA0002273828490000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>本发明的方法直接使用成本低、原料广泛易得的作为氧化剂和碱,为(E)-1-芳基-4,4,4-三氟丁-2-烯-1-酮化合物的合成提供了一种方便、低成本的方法,同时避免了使用昂贵的、不稳定的三氟甲基化试剂和金属试剂。(The invention discloses a preparation method of (E) -1-aryl-4, 4, 4-trifluorobutan-2-en-1-one compounds, belonging to the field of compound preparation. The (E) -1-aryl-4, 4, 4-trifluorobutan-2-ene-1-ketone takes a compound shown in a general formula II as a raw material, and reacts according to the following reaction formula in the presence of an oxidant and alkali to obtain the compound shown in the general formula I. The method of the invention directly uses the (E) -1-aryl-4, 4, 4-trifluorobutan-2-en-1-one compound which has low cost and widely and easily obtained raw materials as an oxidant and a base, provides a convenient and low-cost method for synthesizing the (E) -1-aryl-4, 4, 4-trifluorobutan-2-en-1-one compound, and simultaneously avoids using expensive and unstable trifluoromethylation reagents and metal reagents.)

1. A process for producing (E) -1-aryl-4, 4, 4-trifluorobut-2-en-1-one compound, which comprises: taking a compound shown in a general formula II as a raw material, and reacting according to the following reaction formula in the presence of an oxidant and alkali to obtain a compound shown in a general formula I;

wherein the content of the first and second substances,

ar is selected from

r is selected from H, C1-C6 alkyl, phenyl, halogen, trifluoromethyl, trifluoromethoxy, C1-C4 alkoxy, C2-C5 ester group or cyano;

the oxidant is one of pyridine-N-oxide, 2-chloro-pyridine-N-oxide, 2-methyl-pyridine-N-oxide, 4-nitro-pyridine-N-oxide, 4-methyl-pyridine-N-oxide, 2, 6-dichloro-pyridine-N-oxide and 2, 6-dimethyl-pyridine-N-oxide;

the alkali is one of triethylamine, pyrrolidine, 1, 8-diazabicycloundec-7-ene, 4-dimethylamino pyridine, tri-N-butylamine, tetramethyl ethylenediamine, diisopropylethylamine and N, N-dimethylbenzylamine.

2. The method of claim 1, wherein: the amount of the oxidant is 1.0-2.0 times of that of the compound shown in the general formula II.

3. The method of claim 1, wherein: the amount of the alkali substance is 0.2-1.0 times of that of the compound substance shown in the general formula II.

4. The method of claim 1, wherein: the reaction can be carried out under the condition of no solvent or in a solvent, and the solvent is one of tetrahydrofuran, 1, 2-dichloroethane, dichloromethane, chloroform, toluene, N-dimethylformamide and dimethyl sulfoxide.

5. The method of claim 1, wherein: when the reaction is carried out in a solvent, the ratio of the amount of the compound substance represented by the general formula II to the volume of the solvent is 1mmol: 5-15 mL.

6. The method of claim 1, wherein: the reaction temperature is 15-25 ℃, and the reaction time is 3-6 h.

7. The method of claim 1, wherein: and R is one of H, methyl, isopropyl, phenyl, halogen, trifluoromethyl and cyano.

8. The method of claim 1, wherein: the halogen is one of fluorine, chlorine, bromine and iodine.

Technical Field

The invention relates to a preparation method of (E) -1-aryl-4, 4, 4-trifluorobutan-2-en-1-one compounds, belonging to the field of compound preparation.

Background

It is well known that the introduction of CF into organic molecules is due to the special properties of the fluorine element₃The physical, chemical and biological properties of the molecule can be significantly altered (chem. rev.2016, 116, 422). Therefore, the fluorine-containing compound has important application in the fields of medicine, agriculture, materials and the like. (E) The (E) -1-aryl-4, 4, 4-trifluorobut-2-en-1-one compound is an important reaction intermediate in organic synthesis reaction and an important building block for synthesizing a trifluoromethyl-containing compound, and can construct a novel trifluoromethyl-containing active molecule through various reactions. For example, it can be applied to michael addition reaction (org.lett.2017,19,5102), friedel-crafts reaction (chem.eur.j.2010,16,9117), diels-alder reaction (Tetrahedron 2018,74, 5232).

Currently, relatively few reports have been made on the synthesis of (E) -1-aryl-4, 4, 4-trifluorobut-2-en-1-one compounds. A common synthetic method is to obtain the compound by converting trifluoromethyl substituted propargyl alcohol (J.org.chem.2011,76,1957; org.Lett.2004,6,4073; Synlett2019,30,356). However, these methods use relatively expensive reagents and are harsh in reaction conditions, and sometimes use metal reagents, thereby greatly limiting the application of these methods.

Disclosure of Invention

The invention aims to provide a method for synthesizing (E) -1-aryl-4, 4, 4-trifluorobutan-2-en-1-one compounds (compounds shown in a general formula I) in one step, which has low cost and wide and easily obtained raw materials, directly uses 4-methylpyridine-N-oxide as an oxidant, uses triethylamine as a base, and uses trifluoromethyl substituted enol sulfonate (compounds shown in a general formula II) as a raw material, and is efficient, simple, convenient and economical.

A process for preparing (E) -1-aryl-4, 4, 4-trifluorobut-2-en-1-one compound includes such steps as reaction of the compound shown in general formula II in the presence of oxidant and alkali in solvent or in solvent under the condition of no solvent to obtain the compound shown in general formula I,

wherein the content of the first and second substances,

ar is selected from

Wherein X is selected from O, S, N (CH)₃) (ii) a n is 1,2, 3,4 and 5, and the wavy line is a connecting position;

r is selected from H, C1-C6 alkyl, phenyl, halogen, trifluoromethyl, trifluoromethoxy, C1-C4 alkoxy, C2-C5 ester group or cyano;

the oxidant is one of pyridine-N-oxide, 2-chloro-pyridine-N-oxide, 2-methyl-pyridine-N-oxide, 4-nitro-pyridine-N-oxide, 4-methyl-pyridine-N-oxide, 2, 6-dichloro-pyridine-N-oxide and 2, 6-dimethyl-pyridine-N-oxide;

the alkali is one of triethylamine, pyrrolidine, 1, 8-diazabicycloundec-7-ene, 4-dimethylamino pyridine, tri-N-butylamine, tetramethyl ethylenediamine, diisopropylethylamine and N, N-dimethylbenzylamine.

The solvent is preferably one of tetrahydrofuran, 1, 2-dichloroethane, dichloromethane, chloroform, toluene, N-dimethylformamide and dimethyl sulfoxide;

the invention can also be carried out in the absence of a solvent;

the solvent of the invention can be used in an amount meeting the reaction requirement, and the ratio of the amount of the compound substance shown in the general formula II to the volume of the solvent is preferably 1mmol (5-15) mL.

Unless otherwise indicated, the terms used herein have the following meanings.

The term "alkyl" as used herein includes straight chain and branched chain alkyl groups. Reference to a single alkyl group, such as "methyl", is intended to refer only to straight chain alkyl groups, and reference to a single branched alkyl group, such as "isopropyl", is intended to refer only to branched alkyl groups. For example, "C4 lower alkyl" includes methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, and the like. Similar rules apply to other groups used in this specification.

The term "halogen" as used herein includes fluorine, chlorine, bromine, iodine.

The C2-C5 ester group is a group with the following structure: -COOR, wherein R is C1-C4 alkyl.

The C1-C4 alkoxy group is a group having the following structure: -O-M₁Wherein M is₁Is C1-C4 alkyl, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy.

In the above scheme, the

(n-1, 2,3,4, 5) and the position of the wavy line is a connecting position, wherein (R)_nWhere n ═ 1,2, 3,4,5 means that the substitution of R on the phenyl group can be mono-or multi-substituted, and can be 1,2, 3,4 or 5 substituted. When n is 1, the substituent is monosubstituted, and the monosubstituted substituent can be 2,3 or 4; when n is 2,3,4 or 5, the substituent is multi-position substitution, wherein, n is 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, 3, 5-; n-3 is trisubstituted with the trisubstituted substitution positions being 2,3,4-, 2,3,5-, 2,3,6-, 3,4, 5-.

In the (E) -1-aryl-4, 4, 4-trifluorobut-2-en-1-one compound of the present invention, Ar is selected from the group consisting of

Wherein X is selected from O, S, N (CH)₃)；n＝1、2、3、4、5；

R is selected from one of alkyl H, C1-C6, phenyl, halogen, trifluoromethyl, trifluoromethoxy and cyano; further, R is selected from one of H, methyl, isopropyl, phenyl, halogen, trifluoromethyl and cyano;

according to the preparation method of the (E) -1-aryl-4, 4, 4-trifluorobutan-2-en-1-one compound, the amount of the oxidant is 1.0-2.0 times of that of the compound shown in the general formula II;

in the method for preparing the (E) -1-aryl-4, 4, 4-trifluorobutan-2-en-1-one compound, the amount of the alkali substance is 0.2-1.0 time of that of the compound substance shown in the general formula II;

in the method for preparing the (E) -1-aryl-4, 4, 4-trifluorobutan-2-en-1-one compound, the reaction temperature of the reaction is preferably 15-25 ℃, and the reaction time is preferably 3-6 h. A preferred technical scheme of the invention is as follows:

a preparation method of (E) -1-aryl-4, 4, 4-trifluorobutan-2-en-1-one compounds takes compounds shown in a general formula II as raw materials, and the compounds are reacted according to the following reaction formula in a solvent or under the condition of no solvent in the presence of an oxidant and alkali to obtain the compounds shown in the general formula I, wherein the reaction temperature is 25 ℃, and the reaction time is 3 h-6 h.

Wherein the content of the first and second substances,

ar is selected fromWherein X is selected from O, S, N (CH)₃)；n＝1、2、3、4、5；

R is selected from H, methyl, isopropyl, phenyl, halogen, trifluoromethyl, methoxy, carbethoxy or cyano;

the oxidant is one of pyridine-N-oxide, 2-chloro-pyridine-N-oxide, 2-methyl-pyridine-N-oxide, 4-nitro-pyridine-N-oxide, 4-methyl-pyridine-N-oxide, 2, 6-dichloro-pyridine-N-oxide and 2, 6-dimethyl-pyridine-N-oxide;

the alkali is one of triethylamine, pyrrolidine, 1, 8-diazabicycloundec-7-ene, 4-dimethylamino pyridine, tri-N-butylamine, tetramethylethylenediamine, diisopropylethylamine and N, N-dimethylbenzylamine;

the solvent is preferably one of tetrahydrofuran, 1, 2-dichloroethane, dichloromethane, chloroform, toluene, N-dimethylformamide and dimethyl sulfoxide;

the invention can also be carried out in the absence of a solvent;

specific structures of substituents of the respective raw material compounds in the above reaction formulae are listed in table 1. But is not limited to these structures.

TABLE 1

(Note: the position of the wavy line is a connection position)

Table 2 lists the structures, physical properties and properties of specific compounds 1 to 18 synthesized by the present invention¹H NMR data, but the present invention is not limited to these compounds.

TABLE 2

Of the above products¹H NMR data show that the coupling constant between CH and hydrogen on CH is 15-16, and the structure belongs to the (E) configuration.

The method directly uses cheap and commercially available pyridine-N-oxide as an oxidant, and provides a convenient and low-cost method for synthesizing the (E) -1-aryl-4, 4, 4-trifluorobutan-2-en-1-one compound. The method does not require the use of metal reagents, while avoiding the use of expensive trifluoromethylating reagents.

Detailed Description

The following non-limiting examples are presented to enable those of ordinary skill in the art to more fully understand the present invention and are not intended to limit the invention in any way.

The test methods described in the following examples are all conventional methods unless otherwise specified; the reagents and materials are commercially available, unless otherwise specified.