CN117164534A - Preparation method of benzofuran derivative containing acetamide structure - Google Patents

Abstract

The invention discloses a preparation method of benzofuran derivatives containing an acetamide structure, which includes the following steps: adding palladium acetate, tricyclohexylphosphine, molybdenum carbonyl, potassium phosphate, water, iodoaromatic hydrocarbon propargyl ether and nitrogen The aromatic hydrocarbons were reacted at 100° C. for 24 hours. After the reaction was completed, post-processing was performed to obtain the benzofuran derivative containing an acetamide structure. The preparation method uses nitroaromatic hydrocarbons as the nitrogen source and molybdenum carbonyl as both the carbonyl source and the reducing agent. The operation is simple, the reaction starting materials are cheap and easily available, the substrate functional group tolerance range is wide, and the reaction efficiency is high. A variety of benzofuran derivatives containing acetamide structures can be synthesized according to actual needs, which facilitates operation and broadens the practicability of this method.

Description

A kind of preparation method of benzofuran derivative containing acetamide structure

Technical field

The invention belongs to the field of organic synthesis, and in particular relates to a method for preparing benzofuran derivatives containing an acetamide structure.

Background technique

The construction of heterocyclic compounds with different functional groups through one-step reactions plays an important role in the fields of biology, medicine, and materials science (Angew. Chem., Int. Ed., 2022, 61, e202112288). Therefore, exploring simple and direct methods for the synthesis of heterocyclic products with diverse functional groups is of great significance in organic chemistry. Among them, benzofuran derivatives are a class of structurally special and valuable skeleton molecules that are widely present in many natural products and exhibit a variety of biological and pharmaceutical activities. In addition, amide compounds serve as useful building blocks in life sciences and often appear in various natural products, drugs, and bioactive molecules. Due to their special biological activities and synthetic advantages, linking benzofurans and amides in one molecule will have important applications in medicinal chemistry, and it is expected to obtain heterocyclic compounds with pharmaceutical and biological activities.

In recent years, significant progress has been made in the synthesis of carbocyclic and heterocyclic compounds through the cyclization of alkynes starting from simple and readily available substrates (Chem. Rev., 2014, 114, 1783-1826). In particular, palladium-catalyzed cyclization of aryl propargyl ethers has attracted widespread attention as a powerful and efficient synthetic method for the preparation of benzofuran derivatives. Mechanistically, the reaction first proceeds through the intramolecular carbon palladation of alkynes to obtain active alkenyl palladium intermediates, and then obtains a variety of heterocyclic compounds with different structures through various subsequent transformations. However, most of the above reactions mainly produce 2,3-dihydrobenzofuran products, and there are very limited examples of synthesizing benzofuran derivatives with defined structures. Palladium-catalyzed carbonylation reaction is one of the most powerful methods to construct carbonyl-containing compounds and has the advantages of high efficiency, directness, and atom economy. Therefore, we believe that palladium-catalyzed alkyne cyclization/carbonylation reaction will be an ideal strategy for the preparation of heterocyclic compounds containing carbonyl structures.

Based on this, we developed a palladium-catalyzed cyclization/carbonylation reaction to synthesize benzofuran derivatives containing acetamide structures. Starting from the simple and easily available iodoaromatic propargyl ether and nitroaromatic compounds, the reaction uses molybdenum carbonyl as both a carbonyl source and a reducing agent, and nitroaromatics as a nitrogen source to synthesize a variety of benzene containing acetamide structures. Furan derivatives provide a new synthetic route for the carbonylation reaction to synthesize benzofuran derivatives containing acetamide structures.

Contents of the invention

The invention provides a preparation method of benzofuran derivatives containing an acetamide structure. The preparation method has simple steps, the reaction raw materials are cheap and easy to obtain, can be compatible with a variety of functional groups, has good reaction applicability, and uses nitroaromatic hydrocarbons as nitrogen sources. At the same time, using molybdenum carbonyl as both a carbonyl source and a reducing agent provides a new direction for the synthesis of benzofuran derivatives containing acetamide structures.

A method for preparing benzofuran derivatives containing an acetamide structure, including the following steps: adding palladium catalyst, tricyclohexylphosphine, carbonyl molybdenum, potassium phosphate, water, iodoaromatic hydrocarbon propargyl ether and nitroaromatic hydrocarbon at 90 React at ~110°C for 20-28 hours. After the reaction is complete, post-process to obtain the benzofuran derivative containing an acetamide structure;

The structure of the iodoaromatic propargyl ether is shown in formula (II):

The structure of the nitroaromatic hydrocarbon is shown in formula (III):

Ar ² -NO ₂ (III);

The structure of the benzofuran derivative containing an acetamide structure is shown in formula (I):

In formulas (I) to (III), R is hydrogen or halogen, Ar ¹ and Ar ² are independently phenyl or substituted phenyl;

The substituents on the phenyl group are trifluoromethoxy, C ₁ to C ₄ alkyl, phenyl, C ₁ to C ₄ alkylthio, C ₁ to C ₄ alkoxy, dimethylamino, trifluoro Methyl, cyano, Cl, F or bromine.

The molar ratio of the palladium catalyst, tricyclohexylphosphine and potassium phosphate is 0.02:0.04:2;

The substitution position of R is meta position; the substitution position of the phenyl group of Ar ¹ is para position, and the substitution position of the phenyl group of Ar ² is para position or ortho position.

The reaction formula is as follows:

In the present invention, optional post-treatment processes include: filtration, silica gel sample mixing, and finally purification by column chromatography to obtain the corresponding benzofuran derivatives containing an acetamide structure. Purification by column chromatography is a commonly used technical means in this field. .

Preferably, R is hydrogen or Cl, Ar ¹ is phenyl or substituted phenyl, and the substituent on the phenyl is trifluoromethoxy, methyl, phenyl, Cl or bromine. At this time, the iodoaromatic hydrocarbon propargyl ether is easy to obtain, and the reaction yield is high.

Preferably, Ar ² is phenyl or substituted phenyl, and the substituents on the phenyl are methyl, thiomethyl, N,N-dimethyl, methoxy, trifluoromethyl, cyano, F or Br. At this time, the nitroaromatic hydrocarbon is easily obtained, and the reaction yield is high.

The iodoaromatic hydrocarbon propargyl ether and nitroaromatic hydrocarbons used to prepare benzofuran derivatives containing an acetamide structure are relatively cheap and widely present in nature. As a preferred option, on a molar basis, iodoaromatic hydrocarbon alkyne Propyl ether: nitroaromatic hydrocarbon: palladium catalyst = 2 to 2.5: 1: 0.05 to 0.1; as a further preference, in molar terms, iodoaromatic hydrocarbon propargyl ether: nitro aromatic hydrocarbon: palladium catalyst = 2:1: 0.1.

Preferably, the reaction time is 24 hours. If the reaction time is too long, the reaction cost will increase. On the contrary, it will be difficult to ensure the completeness of the reaction.

Preferably, the reaction is carried out in acetonitrile, and the amount of acetonitrile can dissolve the raw materials well. The amount of acetonitrile used for 0.4 mmol of iodinated aromatic hydrocarbon propargyl ether is about 1 to 2 mL.

Preferably, the palladium catalyst is palladium acetate. Among many palladium catalysts, palladium acetate is relatively cheap, and the reaction efficiency is higher when using palladium acetate as the catalyst.

As a further preference, the benzofuran derivative containing an acetamide structure is one of the compounds represented by formula (I-1) to formula (I-5):

In the above preparation method, the nitroaromatic hydrocarbon, molybdenum carbonyl, palladium acetate, tricyclohexylphosphine and potassium phosphate are generally commercially available products and can be easily obtained from the market.

Compared with the existing technology, the beneficial effects of the present invention are reflected in: using nitroaromatic hydrocarbons as nitrogen sources, the preparation method is simple, easy to operate, simple post-processing, the reaction starting materials are cheap and easy to obtain, the substrate functional group tolerance range is wide, and the reaction efficient. A variety of benzofuran derivatives containing acetamide structures can be synthesized according to actual needs, and are highly practical.

Detailed ways

The present invention will be further described below in conjunction with specific embodiments.

Examples 1 to 15

According to the raw material ratio in Table 1, add palladium acetate, tricyclohexylphosphine, molybdenum carbonyl, potassium phosphate, water, iodoaromatic hydrocarbon propargyl ether (II) and nitroaromatic hydrocarbon (III) into a 15mL sealed tube, and then add Acetonitrile (1 mL), mix and stir evenly, react according to the reaction conditions in Table 2. After the reaction is completed, filter, mix with silica gel, and purify through column chromatography to obtain the corresponding benzofuran derivative (Ⅰ) containing an acetamide structure. Reaction The process is as follows:

Table 1 Amount of raw materials added in Examples 1 to 15

Table 2

In Table 1 and Table 2, T is the reaction temperature, t is the reaction time, Ph is phenyl, OCF ₃ is trifluoromethoxy, Me is methyl, SMe is methylthio, and NMe ₂ is N,N-di Methyl, OMe is methoxy, CF ₃ is trifluoromethyl, and CN is cyano.

Structural confirmation data of the compounds prepared in Examples 1 to 5:

The nuclear magnetic resonance ( ¹ HNMR and ¹³ C NMR) detection data of the benzofuran derivative (I-1) containing an acetamide structure prepared in Example 1 is:

¹ H NMR (400MHz, CDCl ₃ ) δ7.59 (s, 1H), 7.51–7.49 (m, 2H), 7.43 (d, J = 7.5Hz, 2H), 7.39–7.33 (m, 5H), 7.31– 7.28(m,2H),7.17(t,J＝7.5Hz,1H),7.08(d,J＝8.0Hz,2H),5.11(s,1H),2.29(s,3H).

¹³ C NMR (101MHz, CDCl ₃ ) δ169.0,155.6,143.8,137.7,135.0,134.5,129.6,129.2,128.6,128.1,127.1,124.9,123.0,120.2,120.1,119.0,111.8,50 .9,21.0.

The nuclear magnetic resonance ( ¹ HNMR and ¹³ C NMR) detection data of the benzofuran derivative (I-2) containing an acetamide structure prepared in Example 2 is:

¹ H NMR (400MHz, CDCl ₃ ) δ7.58(s,1H),7.51–7.49(m,2H),7.43–7.41(m,2H),7.39–7.36(m,5H),7.33–7.28(m ,2H),7.19(d,J＝8.6Hz,3H),5.11(s,1H),2.44(s,3H).

¹³ C NMR (101MHz, CDCl ₃ ) δ169.1,155.7,143.9,137.6,135.2,134.4,129.3,128.6,128.2,128.0,127.0,124.9,123.1,120.8,120.0,118.9,111.9,50 .9,16.8.

The nuclear magnetic resonance ( ¹ HNMR and ¹³ C NMR) detection data of the benzofuran derivative (I-3) containing an acetamide structure prepared in Example 3 is:

¹ H NMR (400MHz, CDCl ₃ ) δ7.58(s,1H),7.51–7.47(m,2H),7.44–7.42(m,2H),7.41–7.36(m,5H),7.34–7.33(m ,1H),7.32–7.29(m,1H),7.18(t,J＝7.5Hz,1H),6.97(t,J＝8.6Hz,2H),5.12(s,1H).

¹³ C NMR (101MHz, CDCl ₃ ) δ 169.2, 159.8 (CF, d, ¹ J _CF = 244.3Hz), 155.7, 143.9, 137.5, 133.5 (CF, d, ⁴ J _CF = 2.4Hz), 129.3, 128.6, 128.2 ,127.0,125.0,123.1,122.1(CF,d, ³ J _CF =7.9Hz),120.0,118.8,115.8(CF,d, ² J _CF =22.5Hz),111.9,50.8.

The nuclear magnetic resonance ( ¹ HNMR and ¹³ C NMR) detection data of the benzofuran derivative (I-4) containing an acetamide structure prepared in Example 4 is:

¹ H NMR (400MHz, CDCl ₃ ) δ7.59(s,1H),7.54–7.42(m,4H),7.39–7.36(m,1H),7.35–7.29(m,3H),7.23–7.17(m ,3H),7.09(d,J=8.1Hz,2H),5.10(s,1H),2.30(s,3H).

¹³ C NMR (101MHz, CDCl ₃ ) δ 168.6, 155.7, 148.9, 143.8, 136.3, 134.8, 130.1, 129.7, 126.7, 125.1, 123.2, 121.5, 120.6 (CF, q, ¹ J _CF = 257.5Hz), 120.3, 1 19.9 ,118.6,112.0,50.0,21.0.

The nuclear magnetic resonance ( ¹ HNMR and ¹³ C NMR) detection data of the benzofuran derivative (I-5) containing an acetamide structure prepared in Example 5 is:

¹ H NMR (400MHz, CDCl ₃ ) δ7.62 (s, 1H), 7.54 (d, J = 8.3Hz, 1H), 7.42–7.37 (m, 5H), 7.37–7.33 (m, 4H), 7.22 ( t,J＝7.5Hz,1H),7.13(d,J＝8.1Hz,2H),5.10(s,1H),2.33(s,3H).

¹³ C NMR (101MHz, CDCl ₃ ) δ168.5,155.7,143.8,136.2,134.9,134.8,134.0,130.0,129.7,129.4,126.8,125.1,123.2,120.3,120.0,118.7,112.0,50 .2,21.0.

Claims (9)

1. a process for the preparation of benzofuran derivatives having an acetamide structure comprising the steps of: reacting palladium catalyst, ligand, molybdenum carbonyl, alkali, water, iodo arene propargyl ether and nitroarene at 90-110 ℃ for 20-28 hours, and after the reaction is completed, carrying out post-treatment to obtain the benzofuran derivative containing the acetamide structure;

the structure of the iodo arene propargyl ether is shown in a formula (II):

the structure of the nitroarene is shown in a formula (III):

Ar ² -NO ₂ (III)；

the structure of the benzofuran derivative containing the acetamide structure is shown as a formula (I):

in the formulae (I) to (III), R is hydrogen or halogen, ar ¹ ，Ar ² Independently phenyl or substituted phenyl;

the substituent on the phenyl is trifluoromethoxy and C ₁ ～C ₄ Alkyl, phenyl, C ₁ ～C ₄ Alkylthio, C ₁ ～C ₄ Alkoxy, dimethylamino, trifluoromethyl, cyano, cl, F or bromo.

2. The process for preparing benzofuran derivatives having an acetamide structure according to claim 1, wherein R is hydrogen or Cl, ar ¹ Is phenyl or substituted phenyl, and the substituent on the phenyl is trifluoromethoxy, methyl, phenyl, cl or bromine.

3. The process for producing benzofuran derivatives having an acetamide structure according to claim 1, wherein Ar is ² Is phenyl or substituted phenyl, and the substituent on the phenyl is methyl, methylthio, dimethylamino, methoxy, trifluoromethyl, cyano, F or Br.

4. The process for the preparation of benzofuran derivatives containing an acetamide structure according to claim 1, wherein the aromatic iodo propargyl ether is present in molar amounts: nitroaromatics: molybdenum carbonyl: palladium catalyst: ligand: alkali: water=2 to 2.5:1:1.5 to 2:0.1 to 0.2:0.2 to 0.4:1.5 to 2:1 to 1.5.

5. The process for producing a benzofuran derivative having an acetamide structure according to claim 1, wherein acetonitrile is used as a solvent.

6. The process for producing benzofuran derivatives having an acetamide structure according to claim 1, wherein the palladium catalyst is palladium acetate.

7. The process for the preparation of benzofuran derivatives having an acetamide structure according to claim 1 wherein the ligand is tricyclohexylphosphine.

8. The process for producing benzofuran derivatives having an acetamide structure according to claim 1, wherein the base is potassium phosphate.

9. The process for the preparation of benzofuran derivatives having an acetamide structure according to claim 1, wherein the benzofuran derivative having an acetamide structure is one of the compounds of formula (I-1) -formula (I-5):