A method for preparing a benzopyran derivative containing an amide structure

Abstract

The application discloses a preparation method of a benzopyran derivative containing an amide structure, which comprises the following steps: reacting propargyl ether compound, hexafluoroisopropanol and N-iodosuccinimide at 60 DEG C for 1 h, then adding a nitro compound, palladium acetate, 2-diphenylphosphine-biphenyl, carbonyl molybdenum, potassium carbonate and water to react at 100 DEG C for 24 h, and after the reaction is completed, post-treatment is carried out to obtain the benzopyran derivative containing the amide structure. The preparation method uses the nitro compound as a reactant and a nitrogen source, and uses the carbonyl molybdenum as a carbonyl source, has mild reaction conditions, simple operation, a wide functional group tolerance range of a substrate and high reaction efficiency. According to actual needs, various benzopyran derivatives containing the amide structure can be synthesized, and the method is convenient to operate and wide in practicability.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, and particularly relates to a method for preparing benzopyran derivatives containing an amide structure. Background Technology

[0002] Amides are important skeletal molecules widely found in many natural products, bioactive substances, polymers, and pharmaceuticals (Chem. Rev. 1997, 97, 2243–2266). As intermediates in organic synthesis, amides play a crucial role in various organic transformations, such as esterification and cross-coupling. Furthermore, amides are essential components of pharmaceuticals, appearing in approximately 25% of approved drugs. Given the critical role of amides in organic and medicinal chemistry, the formation of amide bonds has attracted continuous attention, and numerous 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 drawbacks, including harsh reaction conditions, the need for stoichiometric activating 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 anticipated.

[0003] Over the past few decades, palladium-catalyzed carbonylation reactions have attracted increasing attention due to their directness, efficiency, and atom economy. Various amino carbonylation reactions have been explored for the synthesis of amides (Chem. Rev. 2019, 119, 2090-2127). Furthermore, nitro compounds are considered a highly attractive nitrogen source due to their stability, low cost, and ease of acquisition; a series of amino carbonylation reactions using nitro compounds as nitrogen sources have been reported for the synthesis of amides. On the other hand, 2H-benzopyrans, as one of the most important heterocycles discovered in nature, are components of a large number of natural products, drugs, and biocompounds, exhibiting broad biological activities. Considering the superior biological activity and synthetic value of amides and 2H-benzopyrans, the construction of 2H-benzopyrans using amides as functional groups holds great promise in biology, drug discovery, and materials science.

[0004] Therefore, using propargyl ether compounds as raw materials, nitro groups as nitrogen sources, and molybdenum carbonyl as carbonyl group source, we synthesized various benzopyran derivatives containing amide structures via palladium-catalyzed amine carbonylation reactions. This reaction opens up a new synthetic route for the preparation of benzopyran derivatives containing amide structures. Summary of the Invention

[0005] This invention provides a method for preparing benzopyran derivatives containing an amide structure. The method is simple, uses inexpensive and readily available raw materials, is compatible with a variety of functional groups, and has good applicability. It uses a nitro compound as a nitrogen source and molybdenum carbonyl as a carbonyl source, 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 includes the following steps: reacting propargyl ether compound, hexafluoroisopropanol and N-iodosuccinimide at 50-60°C for 1-2 h, then adding nitro compound, palladium catalyst, ligand, carbonyl molybdenum, base and water and reacting at 80-100°C for 20-28 h, and after the reaction is complete, post-treatment to obtain the benzopyran derivative containing an amide structure;

[0007] The structure of the propyl 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 the amide structure is shown in formula (I):

[0012]

[0013] In equations (I) to (III), R 1 H, C1-C4 alkyl, C1-C4 alkoxy, or halogen, R 2 The phenyl group is substituted or unsubstituted, wherein the substituent on the phenyl group is a C1-C4 alkyl, C1-C4 alkoxy, phenyl, or halogen, R 3 It is a naphthyl, thiophene, or substituted phenyl group, wherein the substituent on the phenyl group is a C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylacyl, or halogen.

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

[0015] R 1 The substitution position is either opposite or adjacent; R 2 The substitution position on the aryl group is para; R 3 The substitution position on the aryl group is para or meta.

[0016] An example of a reaction formula is as follows:

[0017]

[0018] In this invention, the optional post-processing steps include: filtration, silica gel mixing, and finally purification by column chromatography to obtain the corresponding benzopyran derivative containing an amide structure. Column chromatography purification is a commonly used technique in this field.

[0019] As a preferred option, R 1 It can be H, methyl, tert-butyl, methoxy, or Cl. R 2 The phenyl group may be substituted or unsubstituted, and the substituent on the phenyl group is methyl, methoxy, phenyl, F, or Br. In this case, the propargyl ether compound is readily available, and the reaction yield is high.

[0020] As a preferred option, R 3 The phenyl group is naphthalene, thiophene, or a substituted phenyl group, wherein the substituent on the phenyl group is methyl, acetyl, or F. In this case, the nitro compound is readily available, and the reaction yield is high.

[0021] The propargyl ether compound and nitro compound used to prepare benzopyran derivatives containing amide structures are inexpensive and widely available in nature. Preferably, the molar ratio of propargyl ether compound: nitro compound: palladium catalyst is 1-1.5:1:0.05-0.1; more preferably, the molar ratio of propargyl ether compound: nitro compound: palladium catalyst is 1.5:1:0.05.

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

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

[0024] Preferably, the palladium catalyst is palladium acetate, which is relatively inexpensive among many palladium catalysts and has high reaction efficiency when used as a catalyst.

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

[0026] Preferably, the alkali is potassium carbonate.

[0027] As a preferred option, the reaction method is as follows:

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

[0029] As a further preferred embodiment, the benzopyran derivative containing an amide structure is one of the compounds shown in formulas (I-1) to (I-5):

[0030]

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

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

[0033] Using nitro compounds as raw materials and nitrogen sources, the preparation method is simple, easy to operate, and the post-processing is convenient. The starting materials are inexpensive and readily available, the substrate functional group tolerance is wide, and the reaction efficiency is high. Various benzopyran derivatives containing amide structures can be synthesized according to actual needs, making it highly practical. Detailed Implementation

[0034] The present invention will be further described below with reference to specific embodiments.

[0035] Examples 1-15

[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. Subsequently, nitro compound (III), palladium acetate, 2-diphenylphosphine-biphenyl, molybdenum carbonyl, potassium carbonate, water, and acetonitrile (1 mL) were added, and the reaction was carried out under 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. Raw material addition amounts for Examples 1-15

[0039]

[0040]

[0041] Table 2

[0042]

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

[0044] Structural confirmation data of the compounds prepared in Examples 1-5:

[0045] Nuclear magnetic resonance (NMR) of the benzopyran derivative (I-1) containing an amide structure prepared in Example 1 1 H NMR and 13 The C NMR detection data are as follows:

[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] Nuclear magnetic resonance (NMR) of the benzopyran derivative (I-2) containing an amide structure prepared in Example 2 1 H NMR and 13 The C NMR detection data are as follows:

[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] Nuclear magnetic resonance (NMR) of the benzopyran derivative (I-3) containing an amide structure prepared in Example 3 1 H NMR and 13 The C NMR detection data are as follows:

[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] Nuclear magnetic resonance (NMR) of the benzopyran derivative (I-4) containing an amide structure prepared in Example 4 1 H NMR and 13 The C NMR detection data are as follows:

[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] Nuclear magnetic resonance (NMR) of the benzopyran derivative (I-5) containing an amide structure prepared in Example 5 1 H NMR and 13 The C NMR detection data are as follows:

[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 process includes the following steps: reacting the propargyl ether compound, hexafluoroisopropanol, and N-iodosuccinimide at 50-60 °C. o React at C for 1-2 hours, then add nitro compound, palladium catalyst, ligand, carbonyl molybdenum, base and water at 80-100°C. o C is reacted for 20-28 hours. After the reaction is complete, post-treatment is performed to obtain the benzopyran derivative containing the amide structure. The structure of the propyl ether compound is shown in formula (II): ； The structure of the nitro compound is shown in formula (III): ； The structure of the benzopyran derivative containing the amide structure is shown in formula (I): ； In equations (I) to (III), R 1 R is H, C1-C4 alkyl, C1-C4 alkoxy, or halogen. 2 The phenyl group is substituted or unsubstituted, wherein the substituent on the phenyl group is a C1-C4 alkyl, C1-C4 alkoxy, phenyl, or halogen, R 3 It is a naphthyl, thiophene, or a substituted phenyl group, wherein the substituent on the phenyl group is a C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylacyl, or halogen; The reaction uses acetonitrile as a solvent; The palladium catalyst is palladium acetate; The ligand is 2-diphenylphosphine-biphenyl; The alkali mentioned is potassium carbonate.

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

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

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

5. The method for preparing the benzopyran derivative containing an amide structure according to claim 1, characterized in that, In molar amounts, the ratio of 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 the 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 shown in formulas (I-1) to (I-5): ； ； ； ； 。

Images