WO2021169359A1

WO2021169359A1 - Benzodihydrofuro heterocyclic compound and preparation method therefor

Info

Publication number: WO2021169359A1
Application number: PCT/CN2020/124999
Authority: WO
Inventors: 伍婉卿; 周菲; 江焕峰
Original assignee: 华南理工大学
Priority date: 2020-02-29
Filing date: 2020-10-30
Publication date: 2021-09-02
Also published as: CN111205279B; CN111205279A

Abstract

The present invention relates to the technical field of organic synthesis. Discloses are a multi-substituted benzodihydrofuro heterocyclic compound and a preparation method therefor and an application thereof. A palladium salt catalyst, an oxidant, an additive, and alkali are added into a reactor, and then aa and bb are added to dissolve in an organic solvent, and stir at 50-70ºC for reaction, and the reaction product is separated and purified to obtain a multi-substituted benzodihydrofuro heterocyclic compound. The reaction formula of the preparation method is as shown in formula (I). According to the method of the present invention, simple and easy-to-obtain alkynone oxime ether and o-iodophenyl alkenyl ether are used as reaction materials to synthesize a series of multi-substituted benzodihydrofuro heterocyclic compounds. The method has the characteristics of simple and easy-to-obtain raw materials, convenient operation, mild conditions, high step economy, wide substrate applicability, and good functional group tolerance.

Description

A benzodihydrofuro heterocyclic compound and preparation method thereof

Technical field

The invention belongs to the technical field of organic synthesis, and in particular relates to a chromatic dihydrofuro heterocyclic compound and a preparation method thereof.

Background technique

Heterocyclic compounds are an important part of many natural products, functional material molecules, agrochemicals and medicines. Among them, benzodihydrofuroheterocyclic derivatives are particularly interesting due to their outstanding biological activities. For example, (a) Prucalopride is a high-affinity 5-HT4 receptor agonist; (b) CellCept is inosine monophosphate Dehydrogenase (IMPDH) inhibitor; (c) liliflol A and (d) cedralin A are selective COX-2 inhibitors. The structural formulas are as follows:

Therefore, it is very necessary to explore the method of efficiently synthesizing benzodihydrofuroheterocyclic compounds. In recent years, scientists have developed the following representative transition metal-catalyzed synthesis methods to construct this heterocyclic compound: (1) transition metal-catalyzed nucleophilic substitution; (2) transition metal-catalyzed hydroalkoxy (3) Transition metal-catalyzed transfer insertion cyclization; (4) Intramolecular Heck cyclization catalyzed by metal palladium. (Feng,J.; Zhang,J.ACS.Catal.,2016,6,6651; Omer,A.Ther.Adv.Gastroenter.2017,10,877; Radadiya,A.; Shah,A.Eur.J.Med. Chem. 2015, 97, 356; Coy, ED; Cuca, LE; Sefkow, M. Bioorg. Med. Chem. Lett. 2009, 19, 6922; Zhu, J.; Price, BA; Zhao, SX; Skonezny, PMTetrahedron. Lett. 2000, 41, 4011; Pelly, SC; Govender, S.; Fernandes, MA; Schmalz, H.-G.; Koning, CBJOrg. Chem. 2007, 72, 2857; Saito, H.; Oishi, H .; Kitagaki, S.; Nakamura, S.; Anada, M.; Hashimoto, S. Org. Lett. 2002, 4, 3887; Trost, BM; Thiel, OR; Tsui, H.-CJAm. Chem. Soc .2003, 125, 13155).

Although these strategies are diverse, there are still some limitations, such as harsh reaction conditions, high reaction temperature, and limited substrate range. This makes the conversion efficiency of the reaction low, does not have broad application prospects, and does not conform to the development concept of green chemistry. It can be seen that there is still room for improvement and improvement in the synthesis of benzodihydrofuran compounds. Therefore, it is of great significance to explore the development of novel and efficient synthesis methods.

Palladium-catalyzed intermolecular olefinic cross-coupling reaction is one of the effective strategies to achieve heterocyclic synthesis. In recent years, research has mainly focused on acrylates, allyl bromide, allyl alcohol, etc., and electron-rich olefin ethers Has received very little attention. (She, Z.; Niu, D.; Chen, L.; Gunawan, MA; Shanja, X.; Hersh, WH; Chen, YJOrg. Chem. 2012, 77, 3627; Li, C.; Li, J .; Zhou,F.; Li,C.; Wu,WJOrg.Chem.2019,84,11958; Wu,W.; Li,C.; Zhou,F.; Li,J.; Xu,X.; Jiang,H.Adv.Synth.Catal.2019,361,3813). Therefore, it is necessary to develop a palladium-catalyzed cross-coupling reaction of alkynone oxime ether and o-iodophenyl alkenyl ether to provide a convenient and efficient new synthetic strategy for the construction of chromatic dihydrofuro heterocyclic derivatives.

Summary of the invention

In order to overcome the shortcomings of the prior art, the purpose of the present invention is to provide a chromo-dihydrofuro heterocyclic compound and a preparation method thereof.

The primary object of the present invention is to provide a method for preparing chromatic dihydrofuro heterocyclic compounds.

Another object of the present invention is to provide a polysubstituted chromatic dihydrofuro heterocyclic compound prepared by the above method.

The purpose of the present invention is achieved through the following technical solutions.

The structure of a multi-substituted benzodihydrofuro heterocyclic compound provided by the present invention is as follows:

Wherein, R ^{1 is} selected from at least one of phenyl, 4-methylphenyl, 4-chlorophenyl, naphthalene ring, and 3-methoxyphenyl;

R ^{2 is} selected from at least one of 4-methoxyphenyl, 3-methylphenyl, 4-propyl-1,1'-biphenyl, thiophene, and n-heptyl;

R ^{3 is} selected from 4-methylphenyl.

The present invention provides a method for preparing multi-substituted benzodihydrofuro heterocyclic compounds, the reaction formula of which is as follows:

R ^{3 is} selected from 4-methylphenyl.

The preparation method of polysubstituted benzodihydrofuro heterocyclic compounds provided by the present invention includes the following steps:

Add palladium salt catalyst, oxidant, additives and alkali into the reactor, and then add

Dissolved in an organic solvent, stirred and reacted to obtain a reaction liquid, and after separation and purification of the reaction liquid, the polysubstituted chromatic dihydrofuro heterocyclic compound was obtained.

Further, the palladium salt catalyst is palladium acetate; the molar ratio of the added amount of the palladium salt catalyst to the reaction substrate is (0.10-0.20):1; the reaction substrate includes

and

Further, the oxidant is copper chloride; the molar ratio of the added amount of the oxidant to the reaction substrate is (2.0-3.0):1; the reaction substrate includes

and

Further, the additive is tetrabutylammonium bromide; the molar ratio of the added amount of the additive to the reaction substrate is (0.5～1.0):1; the reaction substrate includes

and

Further, the base is potassium carbonate; the molar ratio of the amount of base added to the reaction substrate is (1.5 to 2.0):1; the reaction substrate includes

and

Further, the organic solvent is tetrahydrofuran; the temperature of the stirring reaction is 50-70° C., and the time of the stirring reaction is 10-16 h.

Further, the separation and purification includes: cooling the reaction solution to room temperature, extracting with ethyl acetate, combining the organic phases, drying with anhydrous sodium sulfate, filtering, and distilling under reduced pressure to remove the solvent to obtain a crude product, which is purified by thin layer chromatography The multi-substituted chromatic dihydrofuro heterocyclic compound is obtained.

Further, the thin layer chromatography purification is thin layer chromatography using a mixed solvent of petroleum ether and ethyl acetate as a developing solvent, and the volume ratio of the petroleum ether to ethyl acetate is (50-200):1.

The reaction principle of the present invention is based on alkynone oxime ether and o-iodophenyl alkenyl ether as raw materials. Under the combined action of palladium, oxidant, additive and alkali, the aryl palladium intermediate obtained by oxidizing palladium is activated for the second The molecular olefins undergo migration and insertion, followed by oxidative addition, and finally undergo qualitative decomposition to synthesize polysubstituted chromatic dihydrofuro heterocyclic compounds in one step.

Compared with the prior art, the present invention has the following advantages and beneficial effects:

(1) The synthetic method provided by the present invention uses simple and easy-to-obtain alkynone oxime ether and o-iodophenyl alkenyl ether as the reaction raw materials to synthesize a series of polysubstituted chromatic dihydrofuro heterocyclic compounds. The method has raw materials Simple and easy to obtain, convenient operation, mild conditions, high step economy, wide substrate applicability, good tolerance of functional groups, etc.;

(2) The synthesis method of the present invention is novel and efficient, and its potential application value in industry has been preliminarily proved through a large-scale experiment, so it is expected to be further applied to actual industrial production.

Description of the drawings

Figure 1 and Figure 2 are respectively the hydrogen spectrum and carbon spectrum of the target product obtained in Example 1;

Figures 3 and 4 are respectively the hydrogen spectrum and carbon spectrum of the target product obtained in Example 2;

5 and 6 are the hydrogen spectrum and carbon spectrum of the target product obtained in Example 3, respectively;

7 and 8 are the hydrogen spectrum and carbon spectrum of the target product obtained in Example 4, respectively;

9 and 10 are respectively the hydrogen spectrum and carbon spectrum of the target product obtained in Example 5;

11 and 12 are respectively the hydrogen spectrum and the carbon spectrum of the target product obtained in Example 6;

13 and 14 are respectively the hydrogen spectrum and carbon spectrum of the target product obtained in Example 7;

15 and 16 are respectively the hydrogen spectrum and the carbon spectrum of the target product obtained in Example 8;

17 and 18 are the hydrogen spectrum and carbon spectrum of the target product obtained in Example 9 respectively;

19 and 20 are respectively the hydrogen spectrum and carbon spectrum of the target product obtained in Example 10;

21 and 22 are the hydrogen spectrum and carbon spectrum of the target product obtained in Example 11, respectively.

Detailed ways

The specific implementation of the present invention will be further described below in conjunction with examples, but the implementation and protection of the present invention are not limited to this. It should be pointed out that if there are processes that are not specifically described in detail below, those skilled in the art can implement or understand with reference to the prior art. If the manufacturer of the reagent or instrument is not indicated, it shall be regarded as a conventional product that can be purchased on the market.

The structural formula of the alkynone oxime ether used in the following examples is

It is prepared by the following method: add PdCl ₂ (PPh ₃ ) ₂ (0.5 mol%), CuI (2 mol%), terminal alkynes (1.0 equivalent), triethylamine, acid chloride (1.5 equivalent), and add 25mL Shrek in sequence The tube was evacuated and filled with nitrogen, and the operation was repeated 3-4 times. The reaction system was reacted at room temperature for 12 hours. At the end of the reaction, saturated ammonium chloride solution was added to quench the reaction, the organic phase was extracted, and the column was concentrated to obtain alkynone. The obtained alkynone was dissolved in methanol, methoxyamine hydrochloride (2.0 equivalent), pyridine (1mL/3.5mmol), anhydrous sodium sulfate (2.0 equivalent) were added, and the reaction system was stirred at room temperature for 12 hours. Saturated ammonium chloride solution is added, the organic phase is extracted with ethyl acetate, the organic phase is dried and concentrated, and separated by column to obtain the alkynone oxime ether substrate.

The structural formula of o-iodophenyl alkenyl ether used in the following examples is

It is prepared by the following method: add o-iodophenol (1.0 equivalent) and acetone to a 50ml round bottom flask, slowly add 1,2-dibromoethane (5.0 equivalent), and finally add potassium carbonate (2.0 equivalent), at room temperature Stir for 14 hours, reflux and stir for 6 hours. After the reaction is completed, the aqueous phase is quenched, the organic phase is extracted, and the product is separated by concentrating through a column. The obtained product was dissolved in dimethyl sulfoxide, potassium tert-butoxide (1.5 equivalent) was added, and the reaction was carried out at room temperature for 24 hours. At the end of the reaction, the aqueous phase was added to quench the reaction, the organic phase was extracted, and the column was concentrated to obtain o-iodobenzene. Alkenyl ether substrates.

Example 1

In the reaction tube, first add 0.03 mmol of palladium acetate, 0.5 mmol of copper chloride, 0.2 mmol of tetrabutylammonium bromide, 0.4 mmol of potassium carbonate, and finally add alkynone oxime ether (R ¹ =R ² = Ph) and 0.4 millimoles of 1-iodo-2-(vinyloxy)benzene were dissolved in 2.5 ml of tetrahydrofuran solvent, and the reaction was stirred at 60 degrees Celsius at 700 rpm for 12 hours, and the stirring was stopped. Add 5 mL of water, extract 3 times with ethyl acetate, combine the organic phases and dry with 0.5 g of anhydrous sodium sulfate, filter, concentrate under reduced pressure, and then separate and purify by thin layer chromatography to obtain the target product. The thin layer chromatography used The developing agent is a petroleum ether:ethyl acetate mixed solvent with a volume ratio of 150:1, and the yield is 81%.

The hydrogen spectrum and carbon spectrum of the product obtained in this example are shown in Fig. 1 and Fig. 2 respectively; the structural characterization data are shown as follows:

¹ H NMR (500MHz, CDCl ₃ ) δ 7.74 (d, J = 7.0 Hz, 2H), 7.65 (d, J = 7.4 Hz, 2H), 7.53-7.43 (m, 3H), 7.39 (t, J = 7.2Hz, 1H), 7.33 (t, J = 7.3 Hz, 2H), 7.17 (t, J = 7.7 Hz, 1H), 6.96 (d, J = 7.2 Hz, 1H), 6.85 (m, 2H), 5.85 (t, J=10.1Hz, 1H), 3.13(m, 2H);

¹³ C NMR(125MHz, CDCl ₃ )δ169.6, 163.7, 158.7, 130.5, 129.6, 129.0, 128.9, 128.8, 128.5, 128.4, 128.3, 127.5, 126.8, 124.5, 120.8, 112.8, 109.5, 75.5, 34.7;

IR(KBr)ν _max 3359,3056,2926,1604,1460,1230,1017,910,726,496cm ^-1 ;

HRMS (ESI) Calcd for Chemical Formula: C ₂₃ H ₁₈ NO ₂ , [M+H] ⁺ : 340.1332, found 340.1331.

Inferred from the above data, the following structure is obtained:

Example 2

In the reaction tube, first add 0.03 mmol of palladium acetate, 0.5 mmol of copper chloride, 0.2 mmol of tetrabutylammonium bromide, 0.4 mmol of potassium carbonate, and finally add alkynone oxime ether (R ¹ = 4-methyl Phenyl phenyl, R ² =Ph) and 0.4 millimoles of 1-iodo-2-(vinyloxy)benzene were dissolved in 2.5 ml of tetrahydrofuran solvent, and the reaction was stirred at 60 degrees Celsius at 700 rpm for 12 hours, and the stirring was stopped. Add 5 mL of water, extract 3 times with ethyl acetate, combine the organic phases and dry with 0.5 g of anhydrous sodium sulfate, filter, concentrate under reduced pressure, and then separate and purify by thin layer chromatography to obtain the target product. The thin layer chromatography used The developing agent is a petroleum ether:ethyl acetate mixed solvent with a volume ratio of 150:1, and the yield is 80%.

The hydrogen spectrum and carbon spectrum of the product obtained in this example are shown in Figure 3 and Figure 4, respectively; the structural characterization data are shown below:

¹ H NMR (500MHz, CDCl ₃ ) δ7.73 (d, J = 7.0Hz, 2H), 7.56 (d, J = 7.7Hz, 2H), 7.46 (m, 3H), 7.17 (m, 3H), 6.98 (d, J = 7.2Hz, 1H), 6.86 (m, 2H), 5.84 (t, J = 10.1Hz, 1H), 3.52-2.94 (m, 2H), 2.36 (s, 3H);

¹³ C NMR (125MHz, CDCl ₃ ) δ 169.5, 163.6, 158.7, 139.7, 130.4, 129.2, 128.8, 128.7, 128.4, 128.3, 127.5, 126.9, 126.0, 124.6, 120.8, 112.5, 109.5, 75.6, 34.6, 21.3;

IR(KBr)ν _max 3432,3050,2931,1613,1461,1327,1228,1021,913,827,744,592,503cm ^-1 ;

HRMS (ESI) Calcd for Chemical Formula: C ₂₄ H ₂₀ NO ₂ , [M+H] ⁺ : 354.1489, found 354.1484.

Inferred from the above data, the following structure is obtained:

Example 3

In the reaction tube, first add 0.03 mmol of palladium acetate, 0.5 mmol of copper chloride, 0.2 mmol of tetrabutylammonium bromide, 0.4 mmol of potassium carbonate, and finally add alkynone oxime ether (R ¹ = 4-chloro Phenyl group, R ² =Ph) and 0.4 millimoles of 1-iodo-2-(vinyloxy)benzene were dissolved in 2.5 ml of tetrahydrofuran solvent, and the reaction was stirred at 60 degrees Celsius at 700 rpm for 12 hours, and the stirring was stopped. Add 5 mL of water, extract 3 times with ethyl acetate, combine the organic phases and dry with 0.5 g of anhydrous sodium sulfate, filter, concentrate under reduced pressure, and then separate and purify by thin layer chromatography to obtain the target product. The thin layer chromatography used The developing agent is a mixed solvent of petroleum ether: ethyl acetate with a volume ratio of 100:1, and the yield is 84%.

The hydrogen spectrum and carbon spectrum of the product obtained in this example are shown in Figure 5 and Figure 6, respectively; the structural characterization data are shown below:

¹ H NMR(400MHz, CDCl ₃ )δ7.75(d,J=6.8Hz,2H), 7.61(d,J=8.0Hz,2H), 7.50(d,J=6.6Hz,3H), 7.31(d ,J=8.0Hz,2H),7.21(t,J=7.6Hz,1H),7.01(d,J=7.2Hz,1H),6.89(t,J=6.4Hz,2H),5.86(t,J =10.0Hz, 1H), 3.23 (m, 1H), 3.08 (m, 1H);

¹³ C NMR (100MHz, CDCl ₃ ) δ 169.8, 162.6, 158.6, 135.9, 130.6, 130.2, 128.9, 128.7, 128.5, 128.4, 127.5, 127.2, 126.6, 124.6, 121.0, 112.8, 109.5, 75.3, 34.8;

IR(KBr)ν _max 3057,2930,1597,1460,1328,1229,1092,1012,917,833,747,510cm ^-1 ;

HRMS (ESI) Calcd for Chemical Formula: C ₂₃ H ₁₆ ClNNaO ₂ , [M+Na] ⁺ : 396.0762, found 396.0762.

Inferred from the above data, the following structure is obtained:

Example 4

In the reaction tube, first add 0.03 millimoles of palladium acetate, 0.5 millimoles of copper chloride, 0.2 millimoles of tetrabutylammonium bromide, 0.4 millimoles of potassium carbonate, and finally add acetylenone oxime ether (R ¹ = naphthalene ring, R ² =Ph) and 0.4 millimoles of 1-iodo-2-(vinyloxy)benzene were dissolved in 2.5 ml of tetrahydrofuran solvent, and the reaction was stirred at 60 degrees Celsius at 700 rpm for 12 hours, and the stirring was stopped. Add 5 mL of water, extract 3 times with ethyl acetate, combine the organic phases and dry with 0.5 g of anhydrous sodium sulfate, filter, concentrate under reduced pressure, and then separate and purify by thin layer chromatography to obtain the target product. The thin layer chromatography used The developing agent is a petroleum ether:ethyl acetate mixed solvent with a volume ratio of 100:1, and the yield is 72%.

The hydrogen spectrum and carbon spectrum of the product obtained in this example are shown in Fig. 7 and Fig. 8 respectively; the structural characterization data are shown as follows:

¹ H NMR(400MHz,CDCl ₃ )δ8.16(s,1H),7.82(m,5H),7.52(m,5H),7.49–7.38(m,1H),7.24(t,J=7.8Hz, 1H), 6.95 (q, J = 8.0 Hz, 2H), 6.84 (t, J = 7.4 Hz, 1H), 5.97 (t, J = 10.0 Hz, 1H), 3.41-2.96 (m, 2H);

¹³ C NMR (100MHz, CDCl ₃ ) δ 169.9, 163.5, 158.7, 133.6, 132.9, 130.5, 129.0, 128.9, 128.5, 128.4, 128.3, 127.5, 127.4, 126.9, 126.3, 125.7, 124.7, 120.9, 112.7, 109.6, 75.6 ,34.7;

IR(KBr)ν _max 3411,3223,3053,2938,2251,1594,1460,1228,917,750,579, 480cm ^-1 ;

HRMS(ESI) Calcd for Chemical Formula: C ₂₇ H ₁₉ NNaO ₂ , [M+Na] ⁺ : 412.1308, found 412.1313.

Inferred from the above data, the following structure is obtained:

Example 5

In the reaction tube, first add 0.03 mmol of palladium acetate, 0.5 mmol of copper chloride, 0.2 mmol of tetrabutylammonium bromide, 0.4 mmol of potassium carbonate, and finally add alkynone oxime ether (R ¹ = 3-methyl Oxyphenyl, R ² = Ph) and 0.4 millimoles of 1-iodo-2-(vinyloxy)benzene were dissolved in 2.5 ml of tetrahydrofuran solvent, and the reaction was stirred at 60 degrees Celsius at 700 rpm for 12 hours, and the stirring was stopped. Add 5 mL of water, extract 3 times with ethyl acetate, combine the organic phases and dry with 0.5 g of anhydrous sodium sulfate, filter, concentrate under reduced pressure, and then separate and purify by thin layer chromatography to obtain the target product. The thin layer chromatography used The developing agent is a petroleum ether:ethyl acetate mixed solvent with a volume ratio of 80:1, and the yield is 78%.

The hydrogen spectrum and carbon spectrum of the product obtained in this example are shown in Figure 9 and Figure 10, respectively; the structural characterization data are shown below:

¹ H NMR (400MHz, CDCl ₃ ) δ 7.80 (d, J = 6.6 Hz, 2H), 7.51 (d, J = 5.2 Hz, 3H), 7.31 (m, 2H), 7.21 (m, 2H), 7.01 (m, 2H), 6.90 (m, 2H), 5.91 (t, J = 10.2 Hz, 1H), 3.58 (s, 3H), 3.19 (d, J = 10.2 Hz, 2H);

¹³ C NMR (100MHz, CDCl ₃ ) δ 169.8, 163.4, 159.5, 158.6, 130.4, 130.2, 129.6, 128.8, 128.3, 128.2, 127.3, 126.9, 124.6, 121.1, 120.9, 116.6, 113.1, 112.2, 109.5, 75.5, 54.8 ,34.4;

IR(KBr)ν _max 3488,3059,2937,2840,1594,1467,1309,1232,1163,1034,903,750,694,528,451cm ^-1 ;

HRMS (ESI) Calcd for Chemical Formula: C ₂₄ H ₂₀ NO ₃ , [M+H] ⁺ : 370.1438, found 370.1445.

Inferred from the above data, the following structure is obtained:

Example 6

In the reaction tube, first add 0.03 mmol of palladium acetate, 0.5 mmol of copper chloride, 0.2 mmol of tetrabutylammonium bromide, 0.4 mmol of potassium carbonate, and finally add alkynone oxime ether (R ¹ = Ph, R ² = 4-methoxyphenyl) and 0.4 millimoles of 1-iodo-2-(vinyloxy)benzene were dissolved in 2.5 ml of tetrahydrofuran solvent, and the reaction was stirred at 60 degrees Celsius at 700 rpm for 12 hours, and the stirring was stopped. Add 5 mL of water, extract 3 times with ethyl acetate, combine the organic phases and dry with 0.5 g of anhydrous sodium sulfate, filter, concentrate under reduced pressure, and then separate and purify by thin layer chromatography to obtain the target product. The thin layer chromatography used The developing agent is a mixed solvent of petroleum ether: ethyl acetate with a volume ratio of 100:1, and the yield is 74%.

The hydrogen spectrum and carbon spectrum of the product obtained in this example are shown in Figure 11 and Figure 12, respectively; the structural characterization data are as follows:

¹ H NMR(400MHz, CDCl ₃ )δ7.79–7.57(m,4H), 7.48–7.28(m,3H), 7.18(t,J=7.8Hz,1H), 6.97(t,J=7.6Hz, 3H), 6.85(m,2H), 5.82(t,J=10..2Hz,1H), 3.84(s,3H), 3.27–2.90(m,2H);

¹³ C NMR (100MHz, CDCl ₃ ) δ 169.6, 163.6, 161.3, 158.7, 129.9, 129.5, 129.1, 128.8, 128.5, 128.3, 126.9, 124.6, 120.7, 120.0, 114.2, 111.6, 109.5, 75.7, 55.3, 34.5;

IR(KBr)ν _max 3591,3442,3228,2935,2838,2248,1622,1459,1248,1170,1100,1026,910,835,529,449cm ^-1 ;

HRMS(ESI) Calcd for Chemical Formula: C ₂₄ H ₂₀ NO ₃ , [M+H] ⁺ : 370.1438, found 370.1441.

Inferred from the above data, the following structure is obtained:

Example 7

In the reaction tube, first add 0.03 mmol of palladium acetate, 0.5 mmol of copper chloride, 0.2 mmol of tetrabutylammonium bromide, 0.4 mmol of potassium carbonate, and finally add alkynone oxime ether (R ¹ = Ph, R ² = 3-methylphenyl) and 0.4 millimoles of 1-iodo-2-(vinyloxy)benzene were dissolved in 2.5 ml of tetrahydrofuran solvent, and the reaction was stirred at 60 degrees Celsius at 700 rpm for 12 hours, and the stirring was stopped. Add 5 mL of water, extract 3 times with ethyl acetate, combine the organic phases and dry with 0.5 g of anhydrous sodium sulfate, filter, concentrate under reduced pressure, and then separate and purify by thin layer chromatography to obtain the target product. The thin layer chromatography used The developing agent is a petroleum ether:ethyl acetate mixed solvent with a volume ratio of 150:1, and the yield is 75%.

The hydrogen spectrum and carbon spectrum of the product obtained in this example are shown in Figure 13 and Figure 14 respectively; the structural characterization data are shown below:

¹ H NMR(400MHz,CDCl ₃ )δ7.66(d,J=7.6Hz,2H), 7.54(d,J=7.6Hz,1H), 7.50(s,1H), 7.37(m,4H), 7.28 (s, 1H), 7.18 (t, J = 7.8 Hz, 1H), 6.97 (d, J = 7.2 Hz, 1H), 6.86 (m, 2H), 5.84 (t, J = 10.0 Hz, 1H), 3.19 (m,1H),3.09(m,1H),2.26(s,3H);

¹³ C NMR (100MHz, CDCl ₃ ) δ 169.8, 163.7, 158.8, 138.7, 131.2, 129.6, 129.1, 129.0, 128.9, 128.7, 128.6, 128.4, 127.5, 127.0, 125.4, 124.5, 120.8, 112.8, 109.6, 75.4, 34.8 ,21.2;

IR(KBr)ν _max 3557,3468,3188,3036,2930,2852,2717,2546,2428,1622,1464,1317,1229,1091,908,749,582,483cm ^-1 ;

HRMS (ESI) Calcd for Chemical Formula: C ₂₄ H ₂₀ NO ₂ , [M+H] ⁺ : 354.1489, found 354.1486.

Inferred from the above data, the following structure is obtained:

Example 8

In the reaction tube, first add 0.03 mmol of palladium acetate, 0.5 mmol of copper chloride, 0.2 mmol of tetrabutylammonium bromide, 0.4 mmol of potassium carbonate, and finally add alkynone oxime ether (R ¹ = Ph, R ² = 4-propyl-1,1'-biphenyl) and 0.4 millimoles of 1-iodo-2-(vinyloxy)benzene are dissolved in 2.5 ml of tetrahydrofuran solvent, and the reaction is stirred at a speed of 700 rpm at 60 degrees Celsius. Stop stirring for 12 hours. Add 5 mL of water, extract 3 times with ethyl acetate, combine the organic phases and dry with 0.5 g of anhydrous sodium sulfate, filter, concentrate under reduced pressure, and then separate and purify by thin layer chromatography to obtain the target product. The thin layer chromatography used The developing agent is a mixed solvent of petroleum ether: ethyl acetate with a volume ratio of 100:1, and the yield is 81%.

The hydrogen spectrum and carbon spectrum of the product obtained in this example are shown in Figure 15 and Figure 16, respectively; the structural characterization data are shown below:

¹ H NMR(400MHz, CDCl ₃ )δ7.81(d,J=8.4Hz,2H), 7.68(d,J=7.8Hz,4H), 7.55(d,J=8.0Hz,2H), 7.38(m , 3H), 7.29 (d, J = 8.0 Hz, 2H), 7.20 (t, J = 7.6 Hz, 1H), 6.99 (d, J = 6.8 Hz, 1H), 6.95-6.79 (m, 2H), 5.90 (t,J＝10.0Hz,1H),3.34–2.98(m,2H),2.66(t,J＝7.6Hz,2H),1.72(m,2H),1.00(t,J＝7.6Hz,3H) ；

¹³ C NMR (100MHz, CDCl ₃ ) δ 169.4, 163.7, 158.7, 143.2, 142.7, 137.2, 129.6, 129.0, 128.9, 128.7, 128.5, 128.3, 127.2, 126.9, 126.8, 125.9, 124.6, 120.8, 112.7, 109.5, 75.5 ,37.6,34.7,24.4,13.8;

IR(KBr)ν _max 3485,3387,3049,2935,1610,1489,1319,1229,1097,1016,916,826,741,515cm ^-1 ;

HRMS(ESI) Calcd for Chemical Formula: C ₃₂ H ₂₇ NNaO ₂ , [M+Na] ⁺ : 480.1934, found 480.1933.

Inferred from the above data, the following structure is obtained:

Example 9

In the reaction tube, first add 0.03 mmol of palladium acetate, 0.5 mmol of copper chloride, 0.2 mmol of tetrabutylammonium bromide, 0.4 mmol of potassium carbonate, and finally add alkynone oxime ether (R ¹ = Ph, R ² = thiophene) and 0.4 millimoles of 1-iodo-2-(vinyloxy)benzene were dissolved in 2.5 ml of tetrahydrofuran solvent, and the reaction was stirred at 60 degrees Celsius at 700 rpm for 12 hours, and the stirring was stopped. Add 5 mL of water, extract 3 times with ethyl acetate, combine the organic phases and dry with 0.5 g of anhydrous sodium sulfate, filter, concentrate under reduced pressure, and then separate and purify by thin layer chromatography to obtain the target product. The thin layer chromatography used The developing agent is a petroleum ether:ethyl acetate mixed solvent with a volume ratio of 150:1, and the yield is 70%.

The hydrogen spectrum and carbon spectrum of the product obtained in this example are shown in Figure 17 and Figure 18, respectively; the structural characterization data are shown below:

¹ H NMR (400MHz, CDCl ₃ ) δ 7.75 (d, J = 1.8 Hz, 1H), 7.62 (d, J = 6.8 Hz, 2H), 7.48 (d, J = 5.0 Hz, 1H), 7.44-7.30 (m, 4H), 7.19 (t, J = 7.6 Hz, 1H), 7.03 (d, J = 7.2 Hz, 1H), 6.87 (t, J = 6.4 Hz, 2H), 5.86 (t, J = 10.4 Hz ,1H),3.31–2.96(m,2H);

¹³ C NMR(100MHz, CDCl ₃ )δ165.3, 163.5, 158.7, 129.6, 128.9, 128.8, 128.6, 128.4, 128.2, 126.9, 126.8, 126.7, 126.6, 124.6, 121.0, 112.1, 109.6, 75.5, 34.8;

IR(KBr)ν _max 3560,3093,2931,1706,1601,1460,1349,1227,900,742cm ^-1 ;

HRMS (ESI) Calcd for Chemical Formula: C ₂₁ H ₁₅ NNaO ₂ S, [M+Na] ⁺ : 368.0716, found 368.0718.

Inferred from the above data, the following structure is obtained:

Example 10

In the reaction tube, first add 0.03 mmol of palladium acetate, 0.5 mmol of copper chloride, 0.2 mmol of tetrabutylammonium bromide, 0.4 mmol of potassium carbonate, and finally add alkynone oxime ether (R ¹ = Ph, R ² = n-heptyl) and 0.4 millimoles of 1-iodo-2-(vinyloxy)benzene were dissolved in 2.5 ml of tetrahydrofuran solvent, and the reaction was stirred at 60 degrees Celsius at 700 rpm for 12 hours, and the stirring was stopped. Add 5 mL of water, extract 3 times with ethyl acetate, combine the organic phases and dry with 0.5 g of anhydrous sodium sulfate, filter, concentrate under reduced pressure, and then separate and purify by thin layer chromatography to obtain the target product. The thin layer chromatography used The developing agent is a mixed solvent of petroleum ether: ethyl acetate with a volume ratio of 200:1, and the yield is 52%.

The hydrogen spectrum and carbon spectrum of the product obtained in this example are shown in Figure 19 and Figure 20, respectively; the structural characterization data are as follows:

¹ H NMR (400MHz, CDCl ₃ ) δ 7.58 (d, J = 7.0 Hz, 2H), 7.43-7.31 (m, 3H), 7.16 (t, J = 7.6 Hz, 1H), 7.09 (d, J = 7.6Hz,1H), 6.93–6.75(m,2H), 5.73(t,J=9.6Hz,1H), 3.40(m,1H), 3.12(m,1H), 2.79(m,2H), 1.69( m,2H),1.40–1.15(m,8H),0.88(t,J=6.6Hz,3H);

¹³ C NMR (100MHz, CDCl ₃ ) δ 172.1, 162.2, 158.9, 129.4, 129.1, 128.6, 128.5, 128.3, 126.2, 124.6, 120.8, 113.4, 109.3, 75.4, 36.5, 31.6, 29.1,28.7, 28.0, 26.4, 22.5 ,14.0;

IR(KBr)ν _max 3281,3056,2933,2862,1693,1600,1462,1334,1231,914,749,524cm ^-1 ;

HRMS(ESI) Calcd for Chemical Formula: C ₂₄ H ₂₇ NNaO ₂ , [M+Na] ⁺ : 384.1934, found 384.1939.

Inferred from the above data, the following structure is obtained:

Example 11

In the reaction tube, first add 0.03 mmol of palladium acetate, 0.5 mmol of copper chloride, 0.2 mmol of tetrabutylammonium bromide, 0.4 mmol of potassium carbonate, and finally add alkynone oxime ether (R ¹ =R ² = Ph) and 0.4 millimoles of 2-iodo-4-methyl 1-(vinyloxy)benzene were dissolved in 2.5 ml of tetrahydrofuran solvent, and the reaction was stirred at 60 degrees Celsius at 700 rpm for 12 hours, and the stirring was stopped. Add 5 mL of water, extract 3 times with ethyl acetate, combine the organic phases and dry with 0.5 g of anhydrous sodium sulfate, filter, concentrate under reduced pressure, and then separate and purify by thin layer chromatography to obtain the target product. The thin layer chromatography used The developing agent is a petroleum ether:ethyl acetate mixed solvent with a volume ratio of 150:1, and the yield is 47%.

The hydrogen spectrum and carbon spectrum of the product obtained in this example are shown in Figure 21 and Figure 22, respectively; the structural characterization data are shown below:

¹ H NMR (400MHz, CDCl ₃ ) δ 7.74 (d, J = 7.2 Hz, 2H), 7.66 (d, J = 7.4 Hz, 2H), 7.46 (d, J = 6.6 Hz, 3H), 7.36 (m ,3H),6.97(d,J=8.0Hz,1H),6.81-6.68(m,2H),5.81(t,J=10.0Hz,1H),3.09(q,J=15.6Hz,2H),2.26 (s,3H);

¹³ C NMR (100MHz, CDCl ₃ ) δ 169.6, 156.6, 130.4, 130.1, 129.6, 129.0, 128.9, 128.8, 128.6, 128.5, 128.4, 127.5, 126.8, 125.1, 112.7, 109.0, 99.9, 75.6, 34.8, 20.7;

IR(KBr)ν _max 3504,3232,3163,3062,2927,2848,2762,2678,2421,2256,2081, 1964,1876,1622,1477,1215,1117,1016,910,807,714,616,525,438cm ^-1 ;

HRMS (ESI) Calcd for Chemical Formula: C ₂₄ H ₂₀ NO ₂ , [M+H] ⁺ : 354.1489, found 354.1490.

Inferred from the above data, the following structure is obtained:

The above examples are only preferred embodiments of the present invention, and are only used to explain the present invention, but not to limit the present invention. Changes, substitutions, modifications, etc. made by those skilled in the art without departing from the spirit of the present invention shall belong to the present invention. The scope of protection of the invention.

Claims

A multi-substituted benzodihydrofuro heterocyclic compound, which is characterized in that the structural formula is as follows:

Wherein, R 1 is selected from at least one of phenyl, 4-methylphenyl, 4-chlorophenyl, naphthalene ring, and 3-methoxyphenyl;

R 2 is selected from at least one of 4-methoxyphenyl, 3-methylphenyl, 4-propyl-1,1'-biphenyl, thiophene, and n-heptyl;

R 3 is selected from 4-methylphenyl.
A preparation method of polysubstituted benzodihydrofuro heterocyclic compounds, characterized in that the reaction formula is as follows:

Wherein, R 1 is selected from at least one of phenyl, 4-methylphenyl, 4-chlorophenyl, naphthalene ring, and 3-methoxyphenyl;

R 2 is selected from at least one of 4-methoxyphenyl, 3-methylphenyl, 4-propyl-1,1'-biphenyl, thiophene, and n-heptyl;

R 3 is selected from 4-methylphenyl.
The method for preparing polysubstituted benzodihydrofuro heterocyclic compounds according to claim 2, characterized in that it comprises the following steps:

Add palladium salt catalyst, oxidant, additives and alkali into the reactor, and then add

Dissolved in an organic solvent, stirred and reacted to obtain a reaction liquid, and after separation and purification of the reaction liquid, the polysubstituted chromatic dihydrofuro heterocyclic compound was obtained.
The method for preparing multi-substituted chromatic dihydrofuro heterocyclic compounds according to claim 3, wherein the palladium salt catalyst is palladium acetate; the added amount of the palladium salt catalyst and the mole of the reaction substrate The ratio is (0.10～0.20):1; the reaction substrate includes
and
The method for preparing a polysubstituted chromatic dihydrofuro heterocyclic compound according to claim 3, wherein the oxidizing agent is copper chloride; the molar ratio of the added amount of the oxidizing agent to the reaction substrate is ( 2.0～3.0):1; The reaction substrate includes
and
The method for preparing polysubstituted benzodihydrofuroheterocyclic compounds according to claim 3, wherein the additive is tetrabutylammonium bromide; The ratio is (0.5～1.0):1; the reaction substrate includes
and
The method for preparing multi-substituted chromatic dihydrofuro heterocyclic compounds according to claim 3, wherein the base is potassium carbonate; the molar ratio of the added amount of the base to the reaction substrate is (1.5～2.0 ):1; The reaction substrate includes
and
The method for preparing multi-substituted chromatic dihydrofuro heterocyclic compounds according to claim 3, wherein the organic solvent is tetrahydrofuran; and the stirring reaction time is 10-16 hours.
The method for preparing polysubstituted chromatic dihydrofuro heterocyclic compounds according to claim 3, wherein the separation and purification comprises: cooling the reaction solution to room temperature, extracting with ethyl acetate, and combining the organic phases, It is dried with anhydrous sodium sulfate, filtered, and distilled under reduced pressure to remove the solvent to obtain a crude product, which is purified by thin-layer chromatography to obtain the polysubstituted chromatic dihydrofuro heterocyclic compound.
The method for preparing a polysubstituted chromatic dihydrofuro heterocyclic compound according to claim 9, wherein the thin layer chromatography is purified by using a mixed solvent of petroleum ether and ethyl acetate as a developing agent. In layer chromatography, the volume ratio of petroleum ether to ethyl acetate is (50-200):1.