Process for the preparation of benzopyran derivatives containing hexafluoroisopropyl

Abstract

The application discloses a preparation method of a benzopyran derivative containing hexafluoroisopropyl ester, which comprises the following steps: reacting propargyl ether compound, hexafluoroisopropanol and N-iodosuccinimide at room temperature for 15 min, then adding palladium acetate, tris(2-furyl)phosphine, formic acid, acetic anhydride and potassium phosphate to react at 60 DEG C for 24 hours, and after the reaction is completed, post-treatment is carried out to obtain the benzopyran derivative containing hexafluoroisopropyl ester. The preparation method uses hexafluoroisopropanol as a reactant and a promoter, uses formic acid 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, a plurality of benzopyran derivatives containing hexafluoroisopropyl ester 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 a benzopyran derivative containing hexafluoroisopropyl ester. Background Technology

[0002] Fluorine-containing compounds have wide applications in medicine, pesticides, and materials science. The presence of fluorine atoms often has a significant impact on the lipophilicity, bioavailability, and metabolic stability of organic molecules. Among these fluorine-containing compounds, hexafluoroisopropanol is frequently used as a versatile organic solvent, attracting widespread attention from chemists due to its unique physicochemical properties. Hexafluoroisopropanol contains two strongly electron-deficient CF3 groups, which are significant hydrogen bond donors, possessing strong ionization energy and low nucleophilicity. Therefore, introducing hexafluoroisopropanol into organic molecules has good practical value. In particular, hexafluoroisopropyl esters are frequently used in acylation reactions and are also well-suited for various asymmetric reactions. The synthesis of hexafluoroisopropyl esters mainly relies on the esterification of carboxylic acids and the oxidative esterification of aldehydes. In recent years, with increasing attention to atom-economical reactions, palladium-catalyzed carbonylation reactions have gradually become an important method for preparing hexafluoroisopropyl esters. However, in carbonylation reactions, CO is odorless, highly toxic, and difficult to handle; therefore, developing carbonylation reactions involving alternative carbonyl sources remains crucial.

[0003] In recent years, the construction of high-value-added skeletal structures by introducing different functional groups into heterocyclic compounds has attracted widespread attention and played an important role in the fields of biology, pharmaceuticals, and materials science. Benzopyrans, as a class of valuable heterocyclic compounds, are widely found in various natural products, drugs, and bioactive molecules, and possess a variety of pharmacological activities, such as anti-HIV, anti-diabetic, antiviral, antitumor, and antibacterial activity. Therefore, considering the physicochemical properties of hexafluoroisopropyl ester and the important biological activities of benzopyrans, developing simple and efficient carbonylation reactions to synthesize benzopyran derivatives containing hexafluoroisopropyl ester has a very broad prospect.

[0004] Based on this, we developed a palladium-catalyzed carbonylation-cyclization reaction to synthesize benzopyran derivatives containing hexafluoroisopropyl ester. Starting from readily available propargyl ether compounds and hexafluoroisopropanol compounds, and using formic acid as the carbonyl source, the reaction synthesized various benzopyran derivatives containing hexafluoroisopropyl ester. This reaction opens up a new synthetic route for the preparation of fluorinated heterocyclic molecules. Summary of the Invention

[0005] This invention provides a method for preparing benzopyran derivatives containing hexafluoroisopropyl ester. The method is simple, uses inexpensive and readily available raw materials, is compatible with a variety of functional groups, and has good applicability. Hexafluoroisopropanol is used as a raw material and promoter, and formic acid is used as a carbonyl source, providing a new direction for the synthesis of benzopyran derivatives containing hexafluoroisopropyl ester.

[0006] A method for preparing a benzopyran derivative containing hexafluoroisopropyl ester includes the following steps: reacting palladium catalyst, tris(2-furanyl)phosphine, N-iodosuccinimide, formic acid, acetic anhydride, potassium phosphate, propargyl ether compound, and hexafluoroisopropanol at 50-70°C for 20-28 hours; after the reaction is complete, post-treatment is performed to obtain the benzopyran derivative containing hexafluoroisopropyl ester.

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

[0008]

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

[0010]

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

[0012]

[0013] In equations (I) to (III), R 1 It is H, C1-C4 alkyl, nitro, cyano, or halogen, R 2 The phenyl group is naphthyl, substituted or unsubstituted, and the substituent on the phenyl group is C1-C4 alkyl, C1-C4 alkoxy, cyano, trifluoromethyl, trifluoromethoxy, C1-C4 alkoxycarbonyl, cyano or halogen.

[0014] The molar ratio of the palladium catalyst, tris(2-furanyl)phosphine, and potassium phosphate is 0.05:0.1:1.5.

[0015] R 1 The replacement position is the opposite position; R 2 The substitution position on the aryl group is para.

[0016] The 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 hexafluoroisopropyl ester. Column chromatography purification is a commonly used technique in this field.

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

[0020] The propargyl ether compound and hexafluoroisopropanol used to prepare benzopyran derivatives containing hexafluoroisopropyl ester are inexpensive and widely available in nature. Preferably, the molar ratio of propargyl ether compound: hexafluoroisopropanol: palladium catalyst is 1:20-25:0.05-0.1; more preferably, the molar ratio of propargyl ether compound: hexafluoroisopropanol: palladium catalyst is 1:24:0.05.

[0021] Preferably, the reaction time is 24 hours. A reaction time that is too long increases the reaction cost, while a reaction that is too long makes it difficult to guarantee the completeness of the reaction.

[0022] 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 propargyl ether compound is about 1 to 2 mL.

[0023] 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.

[0024] As a preferred option, the reaction method is as follows:

[0025] First, mix the propargyl ether compound, hexafluoroisopropanol and N-iodosuccinimide and react at 20-30°C for 10-20 min. Then add other substances and react at 50-70°C for 20-28 hours.

[0026] As a further preferred embodiment, the benzopyran derivative containing hexafluoroisopropyl ester is one of the compounds shown in formulas (I-1) to (I-5):

[0027]

[0028] The compounds shown in formulas (I-1)-(I-5) are all known compounds.

[0029] In the above preparation method, the hexafluoroisopropanol, formic acid, acetic anhydride, palladium acetate, tris(2-furanyl)phosphine, N-iodosuccinimide, and potassium phosphate are generally commercially available products that can be easily obtained from the market.

[0030] Compared with the prior art, the beneficial effects of the present invention are reflected in:

[0031] Using hexafluoroisopropanol as a raw material and promoter, the preparation method is simple, easy to operate, and the post-processing is convenient. The starting materials are inexpensive and readily available, the substrate has a wide range of functional group tolerances, and the reaction efficiency is high. Various benzopyran derivatives containing hexafluoroisopropane can be synthesized according to actual needs, making it highly practical. Detailed Implementation

[0032] The present invention will be further described below with reference to specific embodiments.

[0033] Examples 1-15

[0034] According to the raw material ratio in Table 1, propargyl ether compound (II), hexafluoroisopropanol (III), and N-iodosuccinimide were added to a 15 mL sealed tube and reacted at room temperature for 15 min. Then, palladium acetate, tris(2-furanyl)phosphine, formic acid, and the pre-reaction product of acetic anhydride, formic acid acetic anhydride, and potassium phosphate were added. Then, acetonitrile (1 mL) was added, and the mixture was stirred evenly. The reaction was carried out 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 hexafluoroisopropyl ester. The reaction process is shown in the following formula:

[0035]

[0036] Table 1. Raw material addition amounts for Examples 1-15

[0037]

[0038]

[0039] Table 2

[0040]

[0041] In Tables 1 and 2, T represents the reaction temperature, t represents the reaction time, Ph represents phenyl, nBu represents n-butyl, CN represents cyano, OMe represents methoxy, Me represents methyl, OCF3 represents trifluoromethoxy, CF3 represents trifluoromethyl, and NO2 represents nitro.

[0042] Structural confirmation data of the compounds prepared in Examples 1-5:

[0043] Nuclear magnetic resonance (NMR) of the benzopyran derivative (I-1) containing hexafluoroisopropyl ester prepared in Example 11 HNMR and 13 The C NMR detection data are as follows:

[0044]

[0045] 1 H NMR (400MHz, CDCl3) δ7.51–7.46(m,3H),7.33(t,J=7.1Hz,1H),7.26–7.21(m,2H),7.03(d,J= 8.2Hz, 1H), 6.90 (t, J = 7.5Hz, 1H), 6.83 (d, J = 7.8Hz, 1H), 5.82 (p, J = 6.1Hz, 1H), 5.16 (s, 2H).

[0046] 13 C NMR (101MHz, CDCl3) δ161.6,156.0,150.6,136.2,132.8,129.5,128.4,128.2 ,124.2,122.0,120.4(q,J=283.9Hz),116.5,115.1,66.4(p,J=34.8Hz),64.9.

[0047] Nuclear magnetic resonance (NMR) of the benzopyran derivative (I-2) containing hexafluoroisopropyl ester prepared in Example 2 1 HNMR and 13 The C NMR detection data are as follows:

[0048]

[0049] 1 H NMR (400MHz, CDCl3) δ7.31(t,J=7.7Hz,1H),7.14(d,J=6.9Hz,4H),6.97(d,J=8.1Hz, 1H), 6.88 (t, J = 7.6Hz, 1H), 6.72 (d, J = 7.8Hz, 1H), 5.71 (p, J = 6.1Hz, 1H), 5.08 (s, 2H).

[0050] 13 C NMR (101MHz, CDCl3) δ162.9 (d, J = 247.8Hz) 161.4, 155.9, 149.6, 133.0, 131.8 (d, J = 3.5Hz), 130.1 (d, J = 8.2H z),129.3,124.0,120.2(q,J=281.2Hz),121.6,118.8,116.6,115.5(d,J=21.8Hz),66.3(p,J=34.8Hz)64.8.

[0051] Nuclear magnetic resonance (NMR) of the benzopyran derivative (I-3) containing hexafluoroisopropyl ester prepared in Example 3 1 HNMR and 13 The C NMR detection data are as follows:

[0052]

[0053] 1 H NMR (400MHz, CDCl3) δ7.82–7.78(m,2H),7.50–7.46(m,1H),7.45–7.40(m,1H),7.39–7.35(m,1H),7.28(t,J=7.6Hz,1H),7.1 9–7.14(m,2H),6.91(d,J=8.0Hz,1H),6.62(t,J=7.5Hz,1H),6.49(d,J=7.8Hz,1H),5.44(p,J=6.1Hz,1H),5.18–5.08(m,2H).

[0054] 13 C NMR (101MHz, CDCl3) δ161.4,155.8,149.4,133.8,133.6,133.0,131.3,129.4,128.7,128.5,126.7,12 6.2,125.5,125.3,124.9,124.1,122.2,119.9(q,J=281.3Hz) 117.1,116.6,66.3(p,J=34.8Hz),65.0.

[0055] Nuclear magnetic resonance (NMR) of the benzopyran derivative (I-4) containing hexafluoroisopropyl ester prepared in Example 4 1 HNMR and 13 The C NMR detection data are as follows:

[0056]

[0057] 1H NMR (400MHz, CDCl3) δ7.45(dd,J=5.0,1.9Hz,3H),7.17(dd,J=6.4,3.1Hz,2H),7.13(d,J=6.2Hz,1H),6.90(d,J=8.3Hz,1H),6.53(d,J= 2.1Hz,1H),5.72(p,J=6.1Hz,1H),5.07(s,2H),2.41(t,J=7.7Hz,2H),1.42(q,J=7.8Hz,2H),1.26–1.23(m,2H),0.86(t,J=7.3Hz,3H).

[0058] 13 C NMR (101MHz, CDCl3) δ161.7,154.1,151.1,136.5,136.2,133.0,129.1,128.4,128.3,124.0, 121.8, 120.4 (q, J = 281.9Hz), 116.3, 114.8, 66.4 (p, J = 34.7Hz), 65.0, 34.9, 33.7, 22.2, 13.9.

[0059] Nuclear magnetic resonance (NMR) of the benzopyran derivative (I-5) containing hexafluoroisopropyl ester prepared in Example 5 1 HNMR and 13 The C NMR detection data are as follows:

[0060]

[0061] 1 H NMR (400MHz, CDCl3) δ7.54(d,J=10.4Hz,1H),7.49–7.45(m,3H),7.13(dd,J=6.7,2.9Hz,2H),7.04–7.00(m,2H),5.68(p,J=6.1Hz,1H),5.19(s,2H).

[0062] 13 C NMR (101MHz, CDCl3) δ161.1,158.9,148.1,136.1,134.4,133.5,129.1,129.0,128.9,12 7.9,124.6,120.1(d,J=282.9Hz),118.4,117.8,116.6,105.7,66.5(p,J=35.0Hz),65.3.

Claims

1. A method for preparing a benzopyran derivative containing hexafluoroisopropyl ester, characterized in that, The process includes the following steps: reacting palladium catalyst, ligand, N-iodosuccinimide, formic acid, acetic anhydride, base, propargyl ether compound, and hexafluoroisopropanol at 60-70 °C. o After reacting for 20-28 hours and the reaction is complete, the benzopyran derivative containing hexafluoroisopropyl ester is obtained through post-treatment. The structure of the propyl ether compound is shown in formula (II): ； The structure of the hexafluoroisopropanol is shown in formula (III): ； The structure of the benzopyran derivative containing hexafluoroisopropyl ester is shown in formula (I): ； In equations (I) to (III), R 1 It is H, C1~C4 alkyl, nitro, cyano or halogen, R 2 The phenyl group is naphthyl, substituted or unsubstituted, wherein the substituent on the phenyl group is C1-C4 alkyl, C1-C4 alkoxy, cyano, trifluoromethyl, trifluoromethoxy, C1-C4 alkoxycarbonyl, cyano or halogen; The ligand is tris(2-furanyl)phosphine; The alkali mentioned is potassium phosphate; The reaction uses acetonitrile as a solvent; The palladium catalyst is palladium acetate.

2. The method for preparing hexafluoroisopropyl-containing benzopyran derivative according to claim 1, characterized by, R 1 is H, methyl, n-butyl, t-butyl, nitro, cyano or Br.

3. The method for preparing the benzopyran derivative containing hexafluoroisopropyl ester according to claim 1, characterized in that, R 2 It is a naphthyl, substituted or unsubstituted phenyl group, wherein the substituent on the phenyl group is methyl, tert-butyl, methoxy, trifluoromethoxy, trifluoromethyl, methoxycarbonyl, cyano or F.

4. The method for preparing hexafluoroisopropyl-containing benzopyran derivative according to claim 1, characterized by, In molar amounts, the ratio of propargyl ether compound: hexafluoroisopropanol: formic acid: acetic anhydride: palladium catalyst: ligand: N-iodosuccinimide: base = 1:20~25: 5~10: 5~10: 0.05~0.1:0.1~0.2:0.5~1:1~1.

5.

5. The method for preparing the benzopyran derivative containing hexafluoroisopropyl ester according to claim 1, characterized in that, The benzopyran derivative containing hexafluoroisopropyl ester is one of the compounds shown in formulas (I-1) to (I-5): ； ； ； ； 。

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