Preparation method of benzopyran derivative containing amide structure

Abstract

The invention discloses a preparation method of a benzopyran derivative containing an amide structure, which comprises the following steps: reacting a propargyl ether compound, hexafluoroisopropanol and N-iodo-succinimide at 60 DEG C for 1 hour, then adding a nitro compound, palladium acetate, 2-diphenylphosphine-biphenyl, carbonyl molybdenum, potassium carbonate and water, reacting at 100 DEG C for 24 hours, and after the reaction is completed, filtering, washing and drying to obtain the benzopyran derivative containing the amide structure. And performing post-treatment to obtain the benzopyran derivative containing the amide structure. The preparation method takes a nitro compound as a reactant and a nitrogen source and carbonyl molybdenum as a carbonyl source, and has the advantages of mild reaction conditions, simple operation, wide tolerance range of substrate functional groups and high reaction efficiency. Various benzopyran derivatives containing amide structures can be synthesized according to actual needs, and the practicability of the method is widened while the operation is convenient.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and in particular relates to a method for preparing a benzopyran derivative containing an amide structure. Background Art

[0002] Amides are important backbone molecules that are widely present in many natural products, bioactive substances, polymers and drugs (Chem. Rev. 1997, 97, 2243–2266). As intermediates in organic synthesis, amides play a vital role in a variety of organic transformations, such as esterification and cross-coupling. In addition, amides are important components of drugs, appearing in approximately 25% of approved drugs. Given the key role of amides in organic and medicinal chemistry, the formation of amide bonds has attracted continuous attention, and many methods for synthesizing amides have been developed. Traditional methods for obtaining amides mainly rely on the acylation reaction of carboxylic acids and their derivatives with amines. However, such methods still have some disadvantages, including harsh reaction conditions, the need for stoichiometric activation reagents, and the generation of large amounts of waste. Therefore, the development of mild, sustainable and atom-economical methods is of great interest and highly desired.

[0003] In the past few decades, palladium-catalyzed carbonylation reactions have attracted increasing attention due to their directness, high efficiency and atom economy, and people have also explored a variety of aminocarbonylation reactions to synthesize amides (Chem. Rev. 2019, 119, 2090-2127). In addition, nitro compounds are regarded as a very attractive nitrogen source due to their stability, low cost and easy availability. A series of aminocarbonylation reactions using nitro compounds as nitrogen sources have been reported for the synthesis of amides. On the other hand, 2H-benzopyran, as one of the most important heterocycles found in nature, is a component of a large number of natural products, drugs and biological compounds and has a wide range of biological activities. Considering the superior biological activity and synthetic value of amides and 2H-benzopyrans, the construction of 2H-benzopyrans with amides as functional groups will have broad development prospects in biology, drug discovery and materials science.

[0004] Therefore, we used propargyl ether compounds as raw materials, nitro group as nitrogen source, carbonyl molybdenum as carbonyl source, and palladium-catalyzed amine carbonylation reaction to synthesize a variety of benzopyran derivatives containing amide structures. This reaction has opened up a new synthetic route for the preparation of benzopyran derivatives containing amide structures. Summary of the invention

[0005] The invention provides a method for preparing a benzopyran derivative containing an amide structure. The preparation method has simple steps, and the reaction raw materials are cheap and readily available, and the method is compatible with a variety of functional groups and has good reaction applicability. A nitro compound is used as a nitrogen source, and carbonyl molybdenum is used as a carbonyl source, thereby providing a new direction for the synthesis of benzopyran derivatives containing an amide structure.

[0006] A method for preparing a benzopyran derivative containing an amide structure comprises the following steps: reacting a propargyl ether compound, hexafluoroisopropanol and N-iodosuccinimide at 50-60° C. for 1-2 hours, then adding a nitro compound, a palladium catalyst, a ligand, carbonyl molybdenum, a base and water at 80-100° C. for 20-28 hours, and after the reaction is complete, post-treating to obtain the benzopyran derivative containing an amide structure;

[0007] The structure of the propargyl ether compound is shown in formula (II):

[0008]

[0009] The structure of the nitro compound is shown in formula (III):

[0010] R 3 -NO2 (III);

[0011] The structure of the benzopyran derivative containing an amide structure is shown in formula (I):

[0012]

[0013] In formulas (I) to (III), R 1 is H, C1-C4 alkyl, C1-C4 alkoxy or halogen, R 2 is a substituted or unsubstituted phenyl group, wherein the substituent on the phenyl group is a C1-C4 alkyl group, a C1-C4 alkoxy group, a phenyl group or a halogen group, and R 3 It is naphthyl, thienyl or substituted phenyl, and the substituent on the phenyl is C1~C4 alkyl, C1~C4 alkoxy, C1~C4 alkanoyl or halogen.

[0014] The molar ratio of the palladium catalyst, the ligand and the base is 0.05:0.1:1.3;

[0015] R 1 The substitution position is para or ortho; R 2 The substitution position on the aromatic group of is para; R 3 The substitution position on the aryl group is para or meta.

[0016] The following is an example of a reaction:

[0017]

[0018] In the present invention, the optional post-treatment process includes: filtration, silica gel mixing, and finally column chromatography purification to obtain the corresponding benzopyran derivative containing an amide structure. Column chromatography purification is a commonly used technical means in the art.

[0019] As a preference, R 1 is H, methyl, tert-butyl, methoxy or Cl. 2 is a substituted or unsubstituted phenyl group, and the substituent on the phenyl group is methyl, methoxy, phenyl, F or Br. In this case, the propargyl ether compound is easy to obtain, and the reaction yield is high.

[0020] As a preference, R 3 It is naphthalene, thiophene or substituted phenyl, and the substituent on the phenyl is methyl, acetyl, or F. In this case, the nitro compound is easy to obtain and the reaction yield is high.

[0021] The propargyl ether compound and nitro compound used to prepare the benzopyran derivative containing an amide structure are relatively cheap and widely exist in nature. Preferably, on a molar basis, the propargyl ether compound: nitro compound: palladium catalyst = 1-1.5:1:0.05-0.1; and further preferably, on a molar basis, the propargyl ether compound: nitro compound: palladium catalyst = 1.5:1:0.05.

[0022] In the present invention, the molar ratio of nitro compound to water is 1:1.0 to 1.5.

[0023] Preferably, the reaction is carried out in acetonitrile, and the amount of acetonitrile used is sufficient to dissolve the raw materials well, and the amount of acetonitrile used for 0.2 mmol of nitro compound is about 1-2 mL.

[0024] Preferably, the palladium catalyst is palladium acetate. Among many palladium catalysts, palladium acetate is relatively cheap, and the reaction efficiency is higher when palladium acetate is used as a catalyst.

[0025] Preferably, the ligand is 2-diphenylphosphine-biphenyl.

[0026] Preferably, the base is potassium carbonate.

[0027] Preferably, the reaction is as follows:

[0028] First, the propargyl ether compound, the nitro compound, N-iodosuccinimide and a small amount of solvent are mixed, reacted at 50-60° C. for 1-2 hours, and then other substances and the remaining solvent are added and reacted at 80-100° C. for 20-28 hours.

[0029] As a further preference, the benzopyran derivative containing an amide structure is one of the compounds represented by formula (I-1) to formula (I-5):

[0030]

[0031] In the above preparation method, the nitro compound, carbonyl molybdenum, palladium acetate, 2-diphenylphosphine-biphenyl, hexafluoroisopropanol, N-iodosuccinimide and potassium carbonate are generally commercially available products and can be easily obtained from the market.

[0032] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0033] Using nitro compounds as raw materials and nitrogen sources, the preparation method is simple, easy to operate, and the post-treatment is simple. The starting materials for the reaction are cheap and easy to obtain, the substrate functional group tolerance range is wide, and the reaction efficiency is high. A variety of benzopyran derivatives containing amide structures can be synthesized according to actual needs, and the practicability is strong. DETAILED DESCRIPTION

[0034] The present invention is further described below in conjunction with specific embodiments.

[0035] Examples 1 to 15

[0036] According to the raw material ratio in Table 1, propargyl ether compound (II), hexafluoroisopropanol, N-iodosuccinimide and acetonitrile (0.3 mL) were added to a 15 mL sealed tube and reacted at 60° C. for 1 h. Then, nitro compound (III), palladium acetate, 2-diphenylphosphine-biphenyl, carbonyl molybdenum, potassium carbonate, water and acetonitrile (1 mL) were added and reacted according to the reaction conditions in Table 2. After the reaction was completed, the mixture was filtered, mixed with silica gel, and purified by column chromatography to obtain the corresponding benzopyran derivative (I) containing an amide structure. The reaction process is shown in the following formula:

[0037]

[0038] Table 1 Amount of raw materials added in Examples 1 to 15

[0039]

[0040]

[0041] Table 2

[0042]

[0043] In Table 1 and Table 2, T is the reaction temperature, t is the reaction time, Ph is a phenyl group, Me is a methyl group, OMe is a methoxy group, and tBu is a tert-butyl group.

[0044] The structural confirmation data of the compounds prepared in Examples 1 to 5 are as follows:

[0045] The NMR ( 1 H NMR and 13 C NMR) detection data are:

[0046]

[0047] 1 H NMR (400MHz, CDCl3) δ7.57–7.55(m,3H),7.39–7.38(m,2H),7.24(dt,J=8.1,1.9Hz,1H),6.97(t,J= 7.9Hz,3H),6.87–6.84(m,3H),6.77(s,1H),6.74(dd,J=7.8,1.5Hz,1H),5.14(s,2H),2.25(s,3H).

[0048] 13 C NMR (101MHz, CDCl3) δ163.4,155.2,138.5,135.6,134.7,133.8,131.1,129.6, 129.4,129.3,129.2,127.9,124.04,123.99,121.5,119.4,116.3,65.9,20.8.

[0049] The NMR ( 1 H NMR and 13 C NMR) detection data are:

[0050]

[0051] 1 H NMR (400MHz, CDCl3) δ7.79(d,J=8.7Hz,2H),7.59–7.58(m,3H),7.39(dd,J=6.5,2.9Hz,2H),7.29–7.24(m,1H),7.03(d,J=8 .7Hz,2H),6.99(s,1H),6.97(d,J=8.1Hz,1H),6.87(t,J=7.5Hz,1H),6.73(dd,J=7.8,1.4Hz,1H),5.14(s,2H),2.52(s,3H).

[0052] 13C NMR (101MHz, CDCl3) δ196.7,163.6,155.3,141.5,139.9,135.4,132.8,131.6 ,129.8,129.6,129.4,128.1,123.8,123.3,121.7,118.4,116.4,65.7,26.3.

[0053] The NMR ( 1 H NMR and 13 C NMR) detection data are:

[0054]

[0055] 1 H NMR (400MHz, CDCl3) δ7.55–7.54(m,3H),7.39–7.37(m,2H),6.98(d,J=8.2Hz,2H),6.91(d,J=8.8Hz,1H),6.84(d,J= 8.4Hz,2H),6.81(dd,J=8.9,3.0Hz,1H),6.74(s,1H),6.28(d,J=2.9Hz,1H),5.08(s,2H),3.64(s,3H),2.24(s,3H).

[0056] 13 C NMR (101MHz, CDCl3) δ163.5,154.1,149.2,138.5,135.5,134.7,133.9,129. 6,129.4,129.3,125.0,124.8,119.4,116.8,116.1,113.4,66.1,55.7,20.8.

[0057] The NMR ( 1 H NMR and 13 C NMR) detection data are:

[0058]

[0059] 1H NMR (400MHz, CDCl3) δ7.36(d,J=7.8Hz,2H),7.26(d,J=7.5Hz,2H),7.23(dd,J=7.6,1.1Hz,1H),7.00(d,J=8.3Hz,2H) ,6.96(dd,J=8.0,0.5Hz,1H),6.88–6.83(m,4H),6.76(dd,J=7.8,1.5Hz,1H),5.13(s,2H),2.47(s,3H),2.26(s,3H).

[0060] 13 C NMR (101MHz, CDCl3) δ163.6,155.2,139.2,138.7,134.8,133.7,132.4,131.0,1 30.2,129.3,129.3,127.9,124.2,123.8,121.5,119.4,116.2,65.9,21.3,20.8.

[0061] The NMR ( 1 H NMR and 13 C NMR) detection data are:

[0062]

[0063] 1 H NMR (400MHz, CDCl3) δ7.67(d,J=8.1Hz,2H),7.29–7.24(m,3H),7.03(d,J=8.2Hz,2H),6.96(d,J=8.0Hz,1H),6. 92(d,J=8.2Hz,2H),6.87(t,J=7.6Hz,1H),6.73(dd,J=7.7,1.1Hz,1H),6.69(s,1H),5.09(s,2H),2.27(s,3H).

[0064] 13 C NMR (101MHz, CDCl3) δ163.5,155.2,137.0,134.43,134.35,134.2,132.7,131. 3,131.1,129.4,127.6,124.7,123.5,123.4,121.7,119.5,116.4,66.0,20.8.

Claims

1. A method for preparing a benzopyran derivative containing an amide structure, characterized in that: The method comprises the following steps: reacting a propargyl ether compound, hexafluoroisopropanol and N-iodosuccinimide at 50-60° C. for 1-2 hours, then adding a nitro compound, a palladium catalyst, a ligand, carbonyl molybdenum, a base and water at 80-100° C. for 20-28 hours, and after the reaction is complete, post-treating to obtain the benzopyran derivative containing an amide structure; The structure of the propargyl ether compound is shown in formula (II): The structure of the nitro compound is shown in formula (III): R 3 -NO2 (III); The structure of the benzopyran derivative containing an amide structure is shown in formula (I): In formulas (I) to (III), R 1 is H, C1-C4 alkyl, C1-C4 alkoxy or halogen, R 2 is a substituted or unsubstituted phenyl group, wherein the substituent on the phenyl group is a C1-C4 alkyl group, a C1-C4 alkoxy group, a phenyl group or a halogen group, and R 3 It is naphthyl, thienyl or substituted phenyl, and the substituent on the phenyl is C1~C4 alkyl, C1~C4 alkoxy, C1~C4 alkanoyl or halogen.

2. The method for preparing a benzopyran derivative containing an amide structure according to claim 1, characterized in that: R 1 is H, methyl, tert-butyl, methoxy or Cl.

3. The method for preparing a benzopyran derivative containing an amide structure according to claim 1, characterized in that: R 2 is a substituted or unsubstituted phenyl group, wherein the substituent on the phenyl group is methyl, methoxy, phenyl, F or Br.

4. The method for preparing a benzopyran derivative containing an amide structure according to claim 1, characterized in that: R 3 is naphthyl, thienyl or substituted phenyl, and the substituent on the phenyl is methyl, acetyl or F.

5. The method for preparing a benzopyran derivative containing an amide structure according to claim 1, characterized in that: In terms of molar amount, propargyl ether compound: nitro compound: carbonyl molybdenum: palladium catalyst: ligand: N-iodosuccinimide: base: water = 1.2-1.5: 1: 1-1.5: 0.01-0.05: 0.02-0.1: 1-2: 1-1.5: 1-1.

5.

6. The method for preparing a benzopyran derivative containing an amide structure according to claim 1, characterized in that: The reaction used acetonitrile as solvent.

7. The method for preparing a benzopyran derivative containing an amide structure according to claim 1, characterized in that: The palladium catalyst is palladium acetate.

8. The method for preparing a benzopyran derivative containing an amide structure according to claim 1, characterized in that: The ligand is 2-diphenylphosphine-biphenyl.

9. The method for preparing a benzopyran derivative containing an amide structure according to claim 1, characterized in that: The alkali is potassium carbonate.

10. The method for preparing a benzopyran derivative containing an amide structure according to claim 1, characterized in that: The benzopyran derivative containing an amide structure is one of the compounds represented by formula (I-1) to formula (I-5):

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