阅读说明：本技术 一种1,3-二取代茚类化合物的合成方法 (Synthesis method of 1, 3-disubstituted indene compounds ) 是由 成江 王志鑫 于 2020-12-03 设计创作，主要内容包括：本发明公开了一种1,3-二取代茚类化合物的合成方法,该方法在TsNHNH_2存在下和布朗斯台德酸促进下,2-(1-芳基乙烯基)苯乙酮类底物的酮羰基和烯基经分子内碳正离子环化,以制备获得各种复杂和多样的1,3-二取代茚类化合物。该方法适用于活性更低且位阻更大的酮类底物、不使用金属催化剂、仅在布朗斯台德酸促进下即可顺利进行,该方法同样也适用于醛类底物,较之现有技术已有合成方法具有更加宽泛的底物范围,尤其是该合成策略可以便捷地获得1,3-二取代茚类化合物。(The invention discloses a method for synthesizing a 1, 3-disubstituted indene compound, which is carried out at TsNHNH 2 In the presence of Bronsted acid, the keto carbonyl and alkenyl of 2- (1-aryl vinyl) acetophenone substrate are cyclized by intramolecular carbocation to prepare various complex and diversified 1, 3-disubstituted indene compounds. The method is suitable for lower activityAnd the method is also suitable for aldehyde substrates, has a wider substrate range compared with the prior synthetic method in the prior art, and particularly can conveniently obtain the 1, 3-disubstituted indene compounds by the synthetic strategy.)

1. A method for synthesizing a 1, 3-disubstituted indene compound comprises the following steps:

to a dried Schlenk closed-tube reactor equipped with a magnetic stirrer, a 2- (1-arylvinyl) acetophenone substrate represented by formula 1, TsNHNH, was sequentially added₂A Bronsted acid catalyst and an organic solvent, heating and stirring the reaction mixture for reaction, and after the reaction is completed, carrying out post-treatment to obtain a 1, 3-disubstituted indene compound shown in a formula 2;

the reaction formula is as follows:

in the above reaction formula, R₁Represents one or more substituents on the attached phenyl ring, said plurality being two, three or four, each R₁The substituents are independently of one another selected from hydrogen, halogen, C₁-C₆Alkyl radical, C₁-C₆An alkoxy group;

R₂selected from substituted or unsubstituted C₆-C₂₀Aryl, wherein the substituents in said substituted or unsubstituted are selected from halogen, C₁-C₆Alkyl radical, C₁-C₆An alkoxy group;

R₃selected from hydrogen, C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl radical, C₆-C₂₀Aryl radical, C₆-C₂₀aryl-C₁-C₆An alkyl group.

2. The method of synthesis of claim 1, wherein R is₁Represents one or more substituents on the attached phenyl ring, each R₁The substituents are independently of one another selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy;

R₂is selected from substituted or unsubstituted phenyl, wherein the substituents in the substituted or unsubstituted phenyl are selected from fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy;

R₃selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl.

3. The method of synthesis according to claim 1 or 2, wherein the compound of formula 1 is selected from the compounds of formulae 1a-1t as follows:

4. a synthesis process according to any one of claims 1 to 3, characterized in that the bronsted acid catalyst is selected from

5. The synthesis method according to any one of claims 1 to 3, wherein the organic solvent is selected from any one of methanol, ethanol, dioxane, tetrahydrofuran, 1, 2-dichloroethane and acetonitrile.

6. The method of claim 5, wherein the organic solvent is selected from methanol.

7. The synthesis method according to any one of claims 1 to 3, wherein the reaction temperature of the heating and stirring reaction is 60 to 80 ℃, and the reaction time of the reaction is 4 to 12 hours.

8. The synthesis method according to claim 7, wherein the reaction temperature of the heating and stirring reaction is 80 ℃, and the reaction time of the reaction is 6 h.

9. A synthesis process according to any one of claims 1 to 3, characterized in that the reaction is carried out in an air atmosphere or in an inert atmosphere; preferably under an inert atmosphere, which is a nitrogen atmosphere or an argon atmosphere, preferably a nitrogen atmosphere.

10. A synthesis method according to any one of claims 1 to 3, characterized in that the compound of formula 1: TsNHNH₂：The feeding molar ratio of (1): (1.05-3): (0.1 to 1); preferably, the compound of formula 1: TsNHNH₂：The feeding molar ratio of (1): 2: 0.5.

Technical Field

The application belongs to the technical field of organic synthesis, and particularly relates to a synthesis method of a 1, 3-disubstituted indene compound.

Background

In recent years, N-p-toluenesulfonylhydrazone compounds have attracted much attention in organic synthesis, and have been widely used as key building units in various transition metal catalyzed or metal-free organic reactions, and in some cases, N-p-toluenesulfonylhydrazone has proved to be an ideal diazo or carbene precursor. For example, intermolecular reactions of N-p-toluenesulfonylhydrazone with vinyl substrates can be readily prepared to obtain cyclopropane target products (see (a) j.am.chem.soc.2010,132,11179.(b) eur.j.org.chem.2012,2012,2312.(c) RSC adv.2014,4,38425.(d) j.org.chem.2015,4,1144.(e) synley 2015,26,960.(f) chem.commu.2016, 52,3677.(g) org.lett.2016, or 18,6448.(h) g.lett.2016,18,1470.(i) j.org.chem.2017,82,12746.(j) Tetrahedron lett.2017,58,3003. (58,3003.) (k) lett.2016,18,1470.).

For the type of intramolecular reaction, de Bruin et al reported the synthesis of indene compounds by the free radical route with insertion of an alkenyl C-H bond while forming a carbene intermediate under cobalt-catalyzed conditions (see J.Am.chem.Soc.2016,138, 8968.). Subsequently, Wang et al reported a rhodium (II) or copper (I) catalyzed intramolecular carbene insertion alkenyl C-H bonding to indene compounds (see Angew. chem. int. Ed.2017,56,16013.). Intramolecular reaction of keto N-p-toluenesulfonylhydrazone and alkenyl can introduce a functional group into the No. 1 position of indene, so that complex and various indene compounds can be obtained. Nevertheless, there has not been any such study or report in the past, at least because of the low degree of activation and greater steric hindrance of such substrates over aldehyde substrates. To overcome this drawback, it is necessary to provide a synthetic strategy based on different reaction mechanisms.

The base-induced reaction of N-p-toluenesulfonylhydrazone to make olefins under protic solvent conditions (Shapiro reaction) involves a carbonium ion mechanism. In fact, N-p-toluenesulfonylhydrazone is also an electrophile, acting as a carbenium ion and an alkylating agent in a series of organic reactions. Based on the chemical property studies of N-p-toluenesulfonylhydrazone, the inventors have been prompted to further develop a feasibility test for intramolecular positive ionic cyclization of keto groups and alkenyl groups. The invention discloses a method for synthesizing a polysubstituted indene compound by intramolecular reaction of an acetophenone N-p-toluenesulfonylhydrazone compound and an alkenyl under the catalysis of no metal under the presence of TsNHNH2 and the promotion of Bronsted acid. In sharp contrast to the reaction of the aforementioned aldehyde N-p-toluenesulfonylhydrazone-based substrates with alkenyl groups, the process is characterized in that: 1) the reaction substrate with lower activity is adopted, the steric hindrance of the synthesized polysubstituted indene is larger, and the complexity and the diversity of the product are improved; 2) the reaction is carried out under acidic conditions rather than basic conditions; 3) different reaction mechanisms involving carbenium ions.

Disclosure of Invention

The invention aims to overcome the defects of the prior art and provides a method for synthesizing a 1, 3-disubstituted indene compound, which is carried out at TsNHNH₂In the presence of Bronsted acid, the keto carbonyl and alkenyl of 2- (1-aryl vinyl) acetophenone substrate are cyclized by intramolecular carbocation to prepare various complex and diversified 1, 3-disubstituted indene compounds. The method is suitable for ketone substrates with lower activity and larger steric hindrance, can be smoothly carried out without using a metal catalyst and only under the promotion of Broensted acid, is also suitable for aldehyde substrates, has a wider substrate range compared with the prior synthetic method in the prior art, and particularly can conveniently obtain the 1, 3-disubstituted indene compounds by the synthetic strategy.

The invention provides a synthesis method of a 1, 3-disubstituted indene compound, which comprises the following steps:

to a dried Schlenk closed-tube reactor equipped with a magnetic stirrer, a 2- (1-arylvinyl) acetophenone substrate represented by formula 1, TsNHNH, was sequentially added₂A bronsted acid catalyst and an organic solvent. And then heating and stirring the reaction mixture for reaction, and after the reaction is completed, carrying out post-treatment to obtain the 1, 3-disubstituted indene compound shown in the formula 2.

The reaction formula is as follows:

in the above reaction formula, R₁Represents one or more substituents on the attached phenyl ring, said plurality being two, three or four, each R₁The substituents are independently of one another selected from hydrogen, halogen, C₁-C₆Alkyl radical, C₁-C₆An alkoxy group.

R₂Selected from substituted or unsubstituted C₆-C₂₀Aryl, wherein the substituents in said substituted or unsubstituted are selected from halogen, C₁-C₆Alkyl radical, C₁-C₆An alkoxy group.

R₃Selected from hydrogen, C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl radical, C₆-C₂₀Aryl radical, C₆-C₂₀aryl-C₁-C₆An alkyl group.

Preferably, R₁Represents one or more substituents on the attached phenyl ring, each R₁The substituents are independently of one another selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy.

R₂Is selected from substituted or unsubstituted phenyl, wherein the substituted or unsubstituted substituents are selected from fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy.

R₃Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl.

Most preferably, the compound of formula 1 is selected from compounds of the following formulae 1a-1 t:

the synthesis method according to the invention, wherein the Bronsted acid catalyst is selected from

According to the synthesis method of the present invention, the organic solvent is selected from any one of methanol, ethanol, dioxane, tetrahydrofuran, 1, 2-dichloroethane, and acetonitrile. Preferably, the organic solvent is selected from methanol.

According to the synthesis method of the invention, the reaction temperature of the reaction is 60-80 ℃, preferably 80 ℃. The reaction time of the reaction is 4-12h, preferably 6 h.

According to the aforementioned synthesis method of the present invention, the reaction is performed under an air atmosphere or an inert atmosphere, preferably under an inert atmosphere. The inert atmosphere is a nitrogen atmosphere or an argon atmosphere, and preferably a nitrogen atmosphere.

The aforementioned synthesis method according to the present invention, wherein the compound represented by formula 1: TsNHNH₂：The feeding molar ratio of (1): (1.05-3): (0.1 to 1); preferably, the compound of formula 1: TsNHNH₂：The feeding molar ratio of (1): 2: 0.5.

according to the synthesis method of the invention, the post-treatment operation is as follows: distilling to remove the solvent, and separating the residue by silica gel column chromatography with petroleum ether as eluting solvent to obtain the 1, 3-disubstituted indene compounds shown in the formula 2.

According to the aforementioned synthesis method of the present invention, the reaction mechanism of the reaction is shown as follows:

compared with the prior art, the method of the invention has the following beneficial effects:

1) according to the method, under the presence of TsNHNH2 and the promotion of Bronsted acid, the ketocarbonyl and alkenyl of the 2- (1-aryl vinyl) acetophenone substrate are cyclized through intramolecular carbenium ions, and various complex and various 1, 3-disubstituted indene compounds can be conveniently prepared.

2) The method is suitable for ketone substrates with lower activity and larger steric hindrance, can be smoothly carried out only under the promotion of Bronsted acid without using a metal catalyst, is also suitable for aldehyde substrates, and has a wider substrate range compared with the prior synthetic method in the prior art.

Detailed Description

The present invention will be described in further detail with reference to specific examples. Unless otherwise indicated, the procedures and procedures used are those conventional in the art, and the starting materials/reagents used are commercially available and/or prepared by known organic synthesis methods.

Examples 1-16 reaction condition optimization examples

2- (1-phenyl vinyl) acetophenone shown in formula 1a is used as a template and is placed in TsNHNH₂In the presence of the catalyst, the influence of different reaction conditions on the yield of the target indene products of the formula 2a is explored (see the reaction formula I). The results are shown in table 1:

using example 11 as an example, a typical experimental run for the reaction is as follows:

to a dried, magnetically stirred Schlenk closed tube reactor was added in sequence 2- (1-phenylvinyl) acetophenone of formula 1a (0.1mmol), TsNHNH₂(0.2mmol),(0.5equiv), and MeOH (2.0 mL). The reactor was evacuated to-0.1 MPa and then charged with N₂(1atm) repeating the above three times, stirring the reaction mixture at 80 ℃ in an oil bath for 6 hours, removing the solvent by distillation after the reaction is completed, and separating the residue by silica gel column chromatography using petroleum ether as an eluting solvent to obtain the target product of formula 2 a. (16.7mg, 81% yield) white oily liquid.¹H NMR(CDCl₃,400MHz)δ7.67-7.59(m,3H),7.55-7.47(m,3H),7.44-7.28(m,3.9H),7.25-7.14(m,0.72H),6.56(d,J＝2.0Hz,1H),6.32-6.30(m,0.18H),4.60-4.58(m,0.18H),3.68-3.61(m,1H),2.26(s,0.54H),1.45(d,J＝7.56Hz,3H).¹³C NMR(100MHz,CDCl₃)δ150.4,145.6,143.5,143.2,140.3,139.8,138.3,136.2,134.7,128.8,128.7,128.0,127.9,127.8,126.8,126.5,125.4,125.3,123.9,123.2,120.6,119.2,55.3,44.2,16.4,13.2；HRMS(EI)m/z calcd for C₁₆H₁₄ ⁺[M⁺]:206.1090；found:206.1092。

Table 1:

^areaction conditions 1a (0.1mol), TsNHNH₂(0.2mmol), solvent (2.0mL) in N₂The reaction was carried out for 6h under an atmosphere and the yield was isolated.^bThe reaction was carried out under an air atmosphere.^cTsNHNH₂(0.12mmol)。

Reaction substrate development test

Based on the optimal reaction conditions (example 11), the inventors further explored the adaptability of the optimal reaction conditions to different substituent reaction substrates, namely, a series of different 1, 3-disubstituted indene compounds were prepared by changing the structure of the reaction substrates and carrying out the reaction according to the method of example 11, and the reaction formula is as follows, and the results are as follows:

product structure characterization data are as follows:

compound 2b:

¹H NMR(CDCl₃,400MHz)δ7.68-7.59(m,3H),7.54-7.47(m,3H),7.44-7.27(m,3.9H),7.25-7.14(m,0.72H),6.64(d,J＝2.2Hz,1H),6.32-6.30(m,0.18H),4.60-4.58(m,0.18H),3.58-3.53(m,1H),2.68-2.64(m,0.36H),2.14-2.04(m,1H),1.74-1.64(m,1H),1.39-1.34(m,0.54H),1.10-1.04(m,3H)；

¹³C NMR(75MHz,CDCl₃)δ148.8,145.9,145.0,144.1,143.5,140.3,136.1,136.0,132.6,129.1,128.6,128.6,127.8,127.7,127.6,126.7,126.6,126.4,125.2,125.0,123.9,123.3,120.3,119.1,55.1,50.8,24.8,20.7,12.4,11.9；

HRMS(EI)m/z calcd for C₁₇H₁₆ ⁺[M⁺]:220.1247；found:220.1248。

compound 2c:

¹H NMR(CDCl₃,400MHz)δ7.63-7.53(m,3H),7.50-7.44(m,3H),7.42-7.36(m,1.5H),7.32-7.28(m,2H),7.25-7.19(m,2.5H),7.18-7.15(m,0.5H),7.13-7.09(m,1H),6.56(d,J＝2.0Hz,1H),6.26-6.25(m,0.5H),4.53(s,0.5H),3.54-3.52(m,1H),3.03-2.95(m,0.5H),2.48-2.39(m,1H),1.34(d,J＝7.0Hz,1.5H),1.32(d,J＝6.4Hz,1.5H),1.20(d,J＝6.8Hz,3H),0.69(d,J＝6.8Hz,3H)；

¹³C NMR(75MHz,CDCl₃)δ150.8,149.3,148.0,144.9,144.4,144.0,140.3,136.2,133.9,131.2,128.6,128.5,127.8,127.7,127.6,126.6,126.5,126.3,125.1,124.9,124.0,123.4,120.2,119.6,55.8,54.9,30.5,26.9,21.8,17.8；

HRMS(EI)m/z calcd for C₁₈H₁₈ ⁺[M⁺]:234.1403；found:234.1405.

compound 2d:

¹H NMR(CDCl₃,300MHz)δ7.66-7.59(m,3.5H),7.55-7.35(m,4.5H),7.34-7.28(m,2H),7.25-7.08(m,3.5H),6.61(d,J＝1.9Hz,1H),6.26(d,J＝1.9Hz,0.5H),4.50(d,J＝2.1Hz,0.5H),3.39(d,J＝2.0Hz,1H),1.43(s,4.5H),1.10(s,9H)；

¹³C NMR(75MHz,CDCl₃)δ153.0,150.2,146.8,144.5,144.4,143.4,140.3,136.2,135.3,131.9,128.6,128.5,128.5,127.8,127.8,127.6,126.7,126.3,126.1,125.2,124.7,124.5,124.2,122.3,120.2,60.2,54.4,34.7,33.2,29.5,28.7；

HRMS(ESI)m/z calcd for C₁₉H₂₁ ⁺[M+H⁺]:249.1638；found:249.1638。

compound 2e:

¹H NMR(CDCl₃,400MHz)δ7.70-7.67(m,3H),7.50-7.39(m,3H),7.36-7.26(m,5H),7.25-7.18(m,3H),6.66(d,J＝2.2Hz,1H),4.73(d,J＝2.2Hz,1H)；

¹³C NMR(75MHz,CDCl₃)δ149.3,144.6,143.2,139.5,136.3,135.6,128.7,128.6,128.0,127.8,127.8,126.9,126.7,125.6,124.3,120.6,55.4；

HRMS(EI)m/z calcd for C₂₁H₁₆ ⁺[M⁺]:268.1247；found:268.1248。

compound 2f:

¹H NMR(CDCl₃,400MHz)δ7.68-7.60(m,3H),7.56-7.48(m,3H),7.44-7.29(m,3.5H),7.23-7.15(m,0.4H),6.66(s,1H),6.31(s,0.1H),4.60(s,0.1H),3.63-3.59(m,1H),2.67-2.62(m,0.2H),1.67-1.47(m,3.4H),1.42-1.36(m,4H),0.98-0.94(m,3.3H)；

¹³C NMR(100MHz,CDCl₃)δ149.3,145.2,144.6,144.1,143.5,140.4,136.6,136.3,133.6,128.8,128.7,128.0,127.9,127.7,126.8,126.7,126.5,125.4,125.2,124.1,123.4,120.5,119.4,55.3,49.6,32.4,32.1,32.0,27.8,27.7,22.8,14.3；

HRMS(EI)m/z calcd for C₂₀H₂₂ ⁺[M⁺]:262.1716；found:262.1715。

compound 2g:

¹H NMR(CDCl₃,400MHz)δ7.60-7.56(m,3H),7.48-7.43(m,2H),7.40-7.27(m,9.26H),7.25-7.20(m,1.54H),7.19-7.11(m,0.72H),6.49(d,J＝1.9Hz,1H),6.23(s,0.18H),4.60(s,0.18H),3.97(s,0.36H),3.86-3.81(m,1H),3.27-3.21(m,1H),2.82-2.75(m,1H)；

¹³C NMR(100MHz,CDCl₃)δ148.3,144.2,143.6,141.6,140.5,136.0,135.8,129.3,129.1,128.8,128.7,128.6,128.5,128.0,127.9,127.8,126.9,126.8,126.5,126.4,125.5,125.2,124.1,123.7,120.7,119.8,55.3,51.0,38.4,34.5；

HRMS(EI)m/z calcd for C₂₂H₁₈ ⁺[M⁺]:282.1043；found:282.1042。

compound 2h:

¹H NMR(CDCl₃,400MHz)δ7.65-7.54(m,3H),7.53-7.44(m,3H),7.41-7.28(m,3.5H),7.25-7.10(m,1.75H),6.59(d,J＝2.8Hz,1H),6.25(s,0.25H),4.54(s,0.25H),3.52(d,J＝3.9Hz,1H),2.68-2.62(m,0.25H),2.16-1.98(m,2.5H),1.90-1.66(m,3H),1.51-1.28(m,5H),1.21-0.95(m,3H)；

¹³C NMR(100MHz,CDCl₃)δ149.9,148.0,144.6,144.1,140.4,136.3,134.8,131.6,128.7,128.7,128.0,127.9,127.7,126.8,126.6,126.4,125.2,125.0,124.1,123.6,120.3,119.6,55.6,55.1,41.0,37.1,32.6,28.5,27.1,26.9,26.7；

HRMS(EI)m/z calcd for C₂₁H₂₂ ⁺[M⁺]:274.1716；found:274.1716。

compound 2i:

¹H NMR(CDCl₃,300MHz)δ7.65-7.60(m,3H),7.58-7.44(m,3H),7.43-7.27(m,4.5H),7.21-7.11(m,1.2H),6.94-6.91(m,0.3H),6.63-6.62(m,0.3H),6.61-6.59(m,1H),4.63-4.61(m,0.3H),3.53(d,J＝2.2Hz,1H)；

¹³C NMR(75MHz,CDCl₃)δ145.2,144.8,143.9,139.8,139.3,136.2,131.5,131.0,128.7,128.6,128.1,127.8,127.7,127.6,126.8,126.8,126.2,125.3,124.9,124.1,123.9,121.2,120.3,56.5,38.2；

HRMS(EI)m/z calcd for C₁₅H₁₂ ⁺[M⁺]:192.0934；found:192.0930。

compound 2j:

¹H NMR(CDCl₃,400MHz)δ7.59-7.56(m,2H),7.49-7.44(m,4H),7.41-7.36(m,1H),7.31-7.22(m,2.2H),7.14-7.07(m,1.2H),6.52(d,J＝2.2Hz,1H),6.33-6.31(m,0.3H),4.53-4.51(m,0.3H),3.63-3.56(m,1H),2.19(s,0.9H),1.40(d,J＝7.6Hz,3H)；

¹³C NMR(100MHz,CDCl₃)δ152.1,142.8,141.6,138.4,136.4,135.6,131.4,131.2,128.84,128.8,128.0,127.8,127.7,127.0,126.6,125.2,124.8,123.7,121.4,119.6,54.9,44.1,16.2,13.0；

HRMS(EI)m/z calcd for C₁₆H₁₃Cl⁺[M⁺]:240.0700；found:240.0701。

compound 2k:

¹H NMR(CDCl₃,400MHz)δ7.61-7.58(m,2H),7.49-7.44(m,3H),7.41-7.36(m,1H),7.31-7.27(m,0.6H),7.25-7.09(m,2.3H),7.04-6.98(m,1.2H),6.88-6.82(m,0.3H),6.49(d,J＝2.0Hz,1H),6.36-6.34(m,0.3H),4.52(s,0.3H),3.62-3.55(m,1H),2.19(s,0.9H),1.40(d,J＝7.6Hz,3H)；

¹³C NMR(100MHz,CDCl₃)δ161.8(d,J_C-F＝242.0Hz),152.6,152.5,142.8,139.8,139.0,138.9,137.7,137.6,136.8,135.9,128.8,128.7,127.9,127.8,127.7,126.9,124.7(d,J_C-F＝8.9Hz),121.2(d,J_C-F＝8.7Hz),113.2(d,J_C-F＝22.5Hz),111.8(d,J_C-F＝22.7Hz),110.9(d,J_C-F＝22.9Hz),106.5(d,J_C-F＝23.2Hz),54.7,44.1,16.4,13.0；

HRMS(EI)m/z calcd for C₁₆H₁₃F⁺[M⁺]:224.0996；found:224.0997。

compound 2l:

¹H NMR(CDCl₃,400MHz)δ7.66-7.62(m,2H),7.50-7.37(m,4H),7.32-7.27(m,2H),7.25-7.21(m,1H),7.17-7.10(m,4H),6.94-6.88(m,2H),6.77-6.73(m,1H),6.44(d,J＝1.8Hz,1H),6.33-6.31(m,1H),4.55-4.52(m,1H),3.89(s,3H),3.88(s,3H),3.63-3.56(m,1H),2.23(s,3H),1.42(d,J＝7.6Hz,3H)；

¹³C NMR(100MHz,CDCl₃)δ159.4,158.4,152.4,147.2,143.0,141.1,140.6,139.5,136.3,136.2,136.1,128.7,128.7,127.9,127.7,127.7,126.7,124.4,121.0,111.7,110.7,109.9,105.3,55.8,55.7,54.6,44.1,16.7,13.2；

HRMS(EI)m/z calcd for C₁₇H₁₆O⁺[M⁺]:236.1196；found:236.1202。

compound 2m:

¹H NMR(CDCl₃,400MHz)δ7.58-7.55(m,2H),7.51-7.44(m,3H),7.41-7.36(m,2H),7.30-7.27(m,0.6H),7.25-7.18(m,1.6H),7.11-7.08(m,0.4H),6.56(d,J＝2.1Hz,1H),6.27-6.25(m,0.2H),4.53-4.51(m,0.2H),3.62-3.54(m,1H),2.19(s,0.6H),1.38(d,J＝7.6Hz,3H)；

¹³C NMR(75MHz,CDCl₃)δ150.4,148.4,144.8,142.7,139.6,139.1,135.3,134.9,132.4,131.3,128.7,128.7,127.9,127.7,127.6,126.9,126.8,125.0,124.2,123.9,120.7,119.9,55.0,43.8,16.1,13.0；

HRMS(EI)m/z calcd for C₁₆H₁₃Cl⁺[M⁺]:240.0700；found:240.0699。

compound 2n:

¹H NMR(CDCl₃,400MHz)δ7.59-7.56(m,2H),7.49-7.44(m,2H),7.42-7.37(m,2H),7.31-7.27(m,0.36H),7.25-7.22(m,1.36H),7.12-7.09(m,0.36H),7.03-6.92(m,1.36H),6.60(d,J＝2.0Hz,1H),6.25-6.23(m,0.18H),4.53-4.51(m,0.18H),3.62-3.54(m,1H),2.20(s,0.54H),1.39(d,J＝7.6Hz,3H)；

¹³C NMR(100MHz,CDCl₃)δ162.5(d,J_C-F＝240.0Hz),151.0,150.9,145.7,145.1,145.0,143.0,142.9,140.1,139.6,139.1,135.6,134.3,128.8,128.0,127.9,127.7,127.0,123.8(d,J_C-F＝9.2Hz),119.8(d,J_C-F＝8.7Hz),113.5(d,J_C-F＝22.5Hz),111.8(d,J_C-F＝22.8Hz),111.7(d,J_C-F＝23.3Hz),107.8(d,J_C-F＝23.8Hz),55.2,43.7,16.4,13.2；

HRMS(EI)m/z calcd for C₁₆H₁₃F⁺[M⁺]:224.0996；found:224.0994。

compound 2o:

¹H NMR(CDCl₃,300MHz)δ7.60-7.55(m,2H),7.44-7.35(m,3H),7.33-7.26(m,0.9H),7.25-7.18(m,2.3H),7.15-7.11(m,1H),7.01-6.94(m,0.9H),6.88-6.82(m,0.3H),6.41(d,J＝2.1Hz,1H),6.26-6.24(m,0.3H),4.74-4.72(m,0.3H),3.68-3.59(m,1H),2.20(s,0.9H),1.39(d,J＝7.6Hz,3H)；

¹³C NMR(75MHz,CDCl₃)δ156.8(d,J_C-F＝248.5Hz),153.7,153.6,141.9,141.8,139.5,139.4,138.1,136.3,135.6,129.1(d,J_C-F＝7.1Hz),128.5,128.2(d,J_C-F＝3.6Hz),127.9,127.6,127.5,126.8,126.7,118.9(d,J_C-F＝3.2Hz),115.2(d,J_C-F＝2.9Hz),114.1(d,J_C-F＝21.7Hz),112.7(d,J_C-F＝20.7Hz),52.8,44.6,16.3,13.0；

HRMS(EI)m/z calcd for C₁₆H₁₃F⁺[M⁺]:224.0996；found:224.0997。

compound 2p:

¹H NMR(CDCl₃,300MHz)δ7.69-7.64(m,2H),7.54-7.48(m,2H),7.46-7.40(m,3H),7.35-7.26(m,0.6H),6.57-6.54(m,1H),6.26-6.23(m,0.15H),4.57-4.55(m,0.15H),3.66-3.59(m,1H),2.48-2.45(m,3H),2.39-2.37(m,0.45H),2.27-2.24(m,0.45H),1.46-1.41(m,3H)；

¹³C NMR(100MHz,CDCl₃)δ147.6,143.4,138.6,136.3,136.2,135.1,133.7,128.7,128.1,127.9,127.7,127.5,126.8,126.0,124.8,122.9,121.3,118.9,55.1,43.9,21.8,16.6,13.2；

HRMS(EI)m/z calcd for C₁₇H₁₆ ⁺[M⁺]:220.1247；found:220.1247。

compound 2q:

¹H NMR(CDCl₃,300MHz)δ7.60-7.49(m,4H),7.35-7.27(m,4.6H),7.25-7.15(m,0.6H),7.11-7.01(m,1.2H),6.51(d,J＝1.8Hz,1H),6.28-6.26(m,0.3H),4.54(d,J＝3.1Hz,0.3H),3.64-3.57(m,1H),2.44(s,3H),2.33(s,0.9H),2.23(s,0.9H),1.42(d,J＝7.6Hz,3H)；

¹³C NMR(100MHz,CDCl₃)δ150.4,149.0,145.6,143.3,139.6,137.7,137.5,136.3,134.9,133.2,129.4,129.4,127.8,127.7,126.7,126.5,125.3,125.1,123.8,123.1,120.6,119.2,54.9,44.1,21.5,21.2,16.4,13.1；

HRMS(EI)m/z calcd for C₁₇H₁₆ ⁺[M⁺]:220.1247；found:220.1247。

compound 2r:

¹H NMR(CDCl₃,300MHz)δ7.58-7.50(m,4H),7.46-7.43(m,2H),7.37-7.28(m,2.36H),7.26-7.19(m,0.72H),7.07-7.04(m,0.36H),6.54(d,J＝2.2Hz,1H),6.25-6.23(m,0.18H),4.53-4.51(m,0.18H),3.66-3.58(m,1H),2.24(s,0.54H),1.42(d,J＝7.6Hz,3H)；

¹³C NMR(100MHz,CDCl₃)δ150.3,142.8,142.4,138.7,134.6,134.2,133.5,129.3,129.2,128.9,128.9,127.0,126.6,125.5,125.5,123.8,123.3,120.3,119.3,54.5,44.3,16.3,13.2；

HRMS(EI)m/z calcd for C₁₆H₁₃Cl⁺[M⁺]:240.0700；found:240.0707。

compound 2s:

¹H NMR(CDCl₃,300MHz)δ7.63-7.49(m,4H),7.42-7.28(m,4.36H),7.26-7.19(m,0.72H),7.10-7.03(m,0.36H),6.56(d,J＝2.2Hz,1H),6.25-6.23(m,0.18H),4.53-4.51(m,0.18H),3.66-3.59(m,1H),2.24(s,0.54H),1.42(d,J＝7.6Hz,3H)；

¹³C NMR(100MHz,CDCl₃)δ145.5,137.8,137.5,134.4,133.2,129.9,129.1,125.2,123.2,123.1,123.0,122.3,122.3,121.9,121.5,121.2,120.8,120.7,119.1,118.5,115.6,114.6,45.0,39.5,11.5,8.4；

HRMS(EI)m/z calcd for C₁₆H₁₃Cl⁺[M⁺]:240.0700；found:240.0700。

compound 2t:

¹H NMR(CDCl₃,300MHz)δ7.53-7.47(m,2H),7.43-7.39(m,1H),7.35-7.30(m,2H),7.28-7.25(m,2H),7.20-7.15(m,1H),6.53(d,J＝2.0Hz,1H),3.72-3.63(m,1H),1.43(d,J＝7.6Hz,3H)；

¹³C NMR(75MHz,CDCl₃)δ149.2,143.5,140.9,140.4,135.0,133.3,131.0,129.9,128.8,126.6,126.2,125.1,122.8,120.8,44.5,16.1；

HRMS(EI)m/z calcd for C₁₆H₁₃Cl⁺[M⁺]:240.0700；found:240.0702。

the embodiments described above are only preferred embodiments of the inventors determined after extensive experimental screening and are not exhaustive of the possible implementations of the invention. Any obvious modifications to the present invention, which do not depart from the synthetic route of the present invention, should be construed as being included within the scope of the present invention as set forth in the appended claims.