Preparation method of indene derivative containing hexafluoroisopropyl ester

Abstract

The invention discloses a preparation method of an indene derivative containing hexafluoroisopropyl ester, which comprises the following steps: reacting a propargyl ether compound, hexafluoroisopropanol and N-iodosuccinimide at room temperature for 0.5 hour, then adding palladium acetate, bis (2-diphenylphosphinophenyl) ether, formic acid, acetic anhydride, sodium carbonate and dimethyl sulfoxide, reacting at 120 DEG C for 24 hours, filtering, washing and drying to obtain the hexafluoroisopropyl ester-containing indene derivative. And after the reaction is completed, carrying out post-treatment to obtain the indene derivative containing hexafluoroisopropyl ester. According to the preparation method, hexafluoroisopropanol is taken as a reactant, formic acid is taken as a carbonyl source, the reaction condition is mild, the operation is simple, the tolerance range of substrate functional groups is wide, and the reaction efficiency is high. Various indene derivatives containing hexafluoroisopropyl ester can be synthesized according to actual needs, so that the method is convenient to operate, and the practicability of the method is widened.

Description

Technical Field

[0001] The present invention belongs to the field of organic synthesis, and particularly relates to a preparation method of indene derivatives containing hexafluoroisopropyl esters. Background Art

[0002] As a class of versatile organic solvents, hexafluoroisopropanol has special physical and chemical properties and is widely used in chemical synthesis (Chem. Rev. 2022, 122, 12544 - 12747). Affected by two strong electron-withdrawing groups CF3, hexafluoroisopropanol has a strong ionization energy and low nucleophilicity, and is a significant hydrogen bond donor. Utilizing these properties, various hexafluoroisopropanol-promoted reactions have been developed. Generally, hexafluoroisopropanol can be used in acylation reactions and various asymmetric reactions, and is also used to prepare corresponding hexafluoroisopropyl ethers in nucleophilic substitution and addition reactions. However, the synthesis of hexafluoroisopropyl esters is relatively less, mainly relying on the esterification of carboxylic acids and the oxidative esterification of aldehydes. In recent years, palladium-catalyzed carbonylation reactions, as an important means for synthesizing carbonyl-containing compounds (Chem. Soc. Rev. 2020, 49, 3187 - 3210), have also made certain progress in the preparation of hexafluoroisopropyl esters. In addition, as an important C1 source, CO gas plays a very important role in carbonylation reactions. However, CO gas is colorless, odorless, and highly toxic, which limits the application of carbonylation reactions in fine chemicals. Therefore, the development of carbonylation reactions involving alternative carbonyl sources has also become one of the focuses of attention of chemists.

[0003] Indene compounds are important building blocks in organic and organometallic chemistry and have various physiological and pharmacological activities, including anti-tumor, anti-hypercholesterolemia, anti-convulsant, anti-allergic, and antibacterial activities, etc. (J. Am. Chem. Soc. 2016, 138, 1065 - 1077). Therefore, the synthesis of compounds containing indene structures has potential pharmaceutical activities, and the synthesis of indene compounds has also attracted a great deal of attention. Considering the physical and chemical properties of hexafluoroisopropyl esters and the special biological activities of indene compounds, it is of great application value to develop simple and efficient carbonylation reactions to synthesize indene derivatives containing hexafluoroisopropyl esters.

[0004] Based on this, we have developed a palladium-catalyzed carbonylation cyclization reaction to synthesize indene derivatives containing hexafluoroisopropyl esters. The reaction uses formic acid as a carbonyl source and starts from easily available propargyl ether compounds and hexafluoroisopropanol compounds to synthesize various indene derivatives containing hexafluoroisopropyl esters. This reaction opens up a new synthetic route for the preparation of fluorine-containing heterocyclic molecules. Summary of the Invention

[0005] The present invention provides a preparation method of an indene derivative containing hexafluoroisopropyl ester. The preparation method has simple steps, inexpensive and easily available reaction raw materials, can be compatible with various functional groups, has good reaction applicability, uses hexafluoroisopropanol as a raw material and formic acid as a carbonyl source, providing a new direction for the synthesis of indene derivatives containing hexafluoroisopropyl ester.

[0006] A preparation method of an indene derivative containing hexafluoroisopropyl ester includes the following steps: reacting a propargyl ether compound, hexafluoroisopropanol and N-iodosuccinimide at 20-30 °C for 0.5-1 hour, then adding a palladium catalyst, a ligand, formic acid, acetic anhydride and sodium carbonate and reacting at 100-120 °C for 20-28 hours. After the reaction is complete, post-treatment is carried out to obtain the indene derivative containing hexafluoroisopropyl ester;

[0007] The structure of the propargyl 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 indene derivative containing hexafluoroisopropyl ester is shown in formula (I):

[0012]

[0013] In formulas (I)-(III), R 1 is one or more of C1-C4 alkyl, C1-C4 alkoxy or halogen, and R 2 is one or more of H, C1-C4 alkyl or C1-C4 alkoxy.

[0014] The molar ratio of the palladium catalyst, bis(2-diphenylphosphinophenyl) ether and sodium carbonate is 0.05:0.05:1.5;

[0015] R 1 is in the ortho, para or meta position; R 2 is in the ortho, para or meta position.

[0016] The reaction formula is as follows:

[0017]

[0018] In the present invention, the post-treatment process that can be selected includes: filtration, mixing with silica gel, and finally purification by column chromatography to obtain the corresponding indene derivative containing hexafluoroisopropyl ester. Purification by column chromatography is a commonly used technical means in the art.

[0019] Preferably, R 1 is one or more of methyl, tert-butyl, methoxy, F, Cl or Br. R 2 is one or more of H, methyl, tert-butyl or methoxy. At this time, the propargyl ether compound is easily obtained and the reaction yield is relatively high.

[0020] The propargyl ether compound and hexafluoroisopropanol used to prepare the indene derivatives containing hexafluoroisopropyl ester are relatively inexpensive and widely present in nature. Preferably, in terms of molar amount, propargyl ether compound: hexafluoroisopropanol: palladium catalyst = 1:40 - 50:0.05 - 0.1; As a further preference, in terms of molar amount, propargyl ether compound: hexafluoroisopropanol: palladium catalyst == 1:47.5:0.05.

[0021] Preferably, the reaction time is 24 hours. Too long reaction time increases the reaction cost, while too short reaction time makes it difficult to ensure the completion of the reaction.

[0022] Preferably, the reaction is carried out in dimethyl sulfoxide. The amount of dimethyl sulfoxide used can dissolve the raw materials well. The amount of dimethyl sulfoxide used for 0.2 mmol of propargyl ether compound is about 1 - 2 mL.

[0023] Preferably, the palladium catalyst is palladium acetate. Among many palladium catalysts, palladium acetate is relatively inexpensive, and the reaction efficiency is relatively high when palladium acetate is used as the catalyst.

[0024] As a further preference, the indene derivatives containing hexafluoroisopropyl ester are one of the compounds shown in formula (I-1) - formula (I-5):

[0025]

[0026] In the above preparation method, the hexafluoroisopropanol, formic acid, acetic anhydride, palladium acetate, bis(2-diphenylphosphinophenyl) ether, N-iodosuccinimide and sodium carbonate generally adopt commercially available products and can be conveniently obtained from the market.

[0027] Compared with the prior art, the beneficial effects of the present invention are as follows: Using hexafluoroisopropanol as the raw material, the preparation method is simple, easy to operate, the post-treatment is simple, the starting materials of the reaction are cheap and easy to obtain, the tolerance range of substrate functional groups is wide, and the reaction efficiency is high. A variety of indene derivatives containing hexafluoroisopropyl ester can be synthesized according to actual needs, and the practicability is relatively strong. Detailed Embodiments

[0028] The following further describes the present invention with specific embodiments.

[0029] Examples 1 - 15

[0030] Add the propargyl ether compound (II), hexafluoroisopropanol (III, 9.5 mmol), and N-iodosuccinimide into a 15 mL sealed tube according to the raw material ratio in Table 1, react at room temperature for 0.5 h, then add the pre-reacted product of palladium acetate, bis(2-diphenylphosphinophenyl) ether, formic acid, and acetic anhydride, sodium carbonate, and then add dimethyl sulfoxide (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 by column chromatography to obtain the corresponding indene derivative (I) containing hexafluoroisopropyl ester. The reaction process is shown in the following formula:

[0031]

[0032] Table 1 Raw material addition amounts of Examples 1 to 15

[0033]

[0034]

[0035] Table 2

[0036]

[0037] In Table 1 and Table 2, T is the reaction temperature, t is the reaction time, Me is methyl, tBu is tert-butyl, and OMe is methoxy.

[0038] Structure confirmation data of the compounds prepared in Examples 1 to 5:

[0039] The nuclear magnetic resonance ( 1 1H NMR and 13 13C NMR) detection data of the indene derivative (I-1) containing hexafluoroisopropyl ester prepared in Example 1 are as follows:

[0040]

[0041] 1 1H NMR (400 MHz, CDCl3) δ 7.42 (d, J = 8.1 Hz, 2H), 7.39–7.31 (m, 2H), 7.15 (d, J = 8.0 Hz, 2H), 7.01–6.97 (m, 1H), 6.62 (d, J = 8.0 Hz, 1H), 6.05 (hept, J = 6.1 Hz, 1H), 2.38 (s, 3H), 1.51 (s, 6H).

[0042] 1313C NMR (101 MHz, CDCl3) δ 160.7, 155.8, 154.4, 138.8, 138.5, 135.5, 132.8, 130.1, 129.4, 128.4, 126.7, 124.7, 121.8, 120.76 (d, J = 284.7 Hz), 65.96 (p, J = 34.6 Hz), 49.8, 24.4, 21.2.

[0043] 1H NMR and 1 1H NMR and 13 13C NMR) detection data of the indene derivative (I-2) containing hexafluoroisopropyl ester prepared in Example 2 are as follows:

[0044]

[0045] 1 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 8.4 Hz, 2H), 7.39–7.34 (m, 3H), 7.31 (d, J = 7.5 Hz, 1H), 6.96 (t, J = 7.6 Hz, 1H), 6.54 (d, J = 8.0 Hz, 1H), 6.03 (hept, J = 6.1 Hz, 1H), 1.51 (s, 6H), 1.33 (s, 9H).

[0046] 13 13C NMR (101 MHz, CDCl3) δ 160.7, 155.7, 152.2, 138.6, 134.6, 132.6, 129.4, 128.4, 126.7, 126.4, 124.7, 121.8, 121.22 (d, J = 282.3 Hz), 66.09 (p, J = 34.7 Hz), 49.8, 34.7, 31.2, 29.7, 24.4.

[0047] 1H NMR and 1 1H NMR and 13 13C NMR) detection data of the indene derivative (I-3) containing hexafluoroisopropyl ester prepared in Example 3 are as follows:

[0048]

[0049] 11H NMR (400 MHz, CDCl3) δ 7.38 (dd, J = 45.8, 7.9 Hz, 2H), 7.24 (s, 1H), 7.17 (d, J = 8.4 Hz, 1H), 7.11 (dd, J = 16.6, 8.2 Hz, 1H), 6.31 (s, 1H), 6.05 (hept, J = 6.2 Hz, 1H), 2.46 (d, J = 53.0 Hz, 3H), 2.21 (d, J = 111.4 Hz, 3H), 1.56 (d, J = 56.2 Hz, 6H).

[0050] 13 13C NMR (101 MHz, CDCl3) δ 160.2, 149.6, 148.9, 138.7, 137.7, 137.05 (d, J = 5.6 Hz), 132.9, 130.9, 129.8, 129.8, 129.2, 127.4, 126.9, 121.60 (d, J = 130.5 Hz), 120.45 (d, J = 285.1 Hz), 119.2, 66.18 (p, J = 34.4 Hz), 55.20 (d, J = 68.9 Hz), 25.6, 21.84 (d, J = 46.6 Hz), 21.10 (d, J = 11.0 Hz), 18.96.

[0051] The nuclear magnetic resonance ( 1 1H NMR 13 and

[0052]

[0053] 1 13C NMR) test data of the indene derivative (I-4) containing hexafluoroisopropyl ester prepared in Example 4 are as follows:

[0054] 13 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 7.9 Hz, 1H), 7.35 (s, 2H), 7.17 (d, J = 7.9 Hz, 2H), 7.00 (dd, J = 8.3, 1.4 Hz, 1H), 6.41 (d, J = 8.4 Hz, 1H), 6.05 (hept, J = 6.2 Hz, 1H), 2.41 (s, 3H), 1.49 (s, 6H), 1.29 (s, 9H).

[0054] 1313C NMR (101 MHz, CDCl3) δ 160.8, 155.9, 153.3, 139.1, 135.9, 133.7, 133.4, 130.1, 128.0, 124.2, 124.1, 120.77 (q, J = 284.8 Hz), 118.4, 65.83 (p, J = 34.5 Hz), 49.5, 35.1, 31.3, 24.6, 21.3.

[0055] 1H NMR and 13C NMR detection data of the indene derivative (I-5) containing hexafluoroisopropyl ester prepared in Example 5 are as follows: 1 1H NMR and 13 13C NMR) detection data are as follows:

[0056]

[0057] 1 1H NMR (400 MHz, CDCl3) δ 7.44 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 7.9 Hz, 2H), 6.86 (d, J = 2.0 Hz, 1H), 6.56–6.34 (m, 2H), 6.05 (hept, J = 6.0 Hz, 1H), 3.80 (s, 3H), 2.39 (s, 3H), 1.49 (s, 6H).

[0058] 13 13C NMR (101 MHz, CDCl3) δ 161.2, 160.6, 158.6, 155.3, 139.0, 133.2,

[0059] 132.6, 131.3, 130.1, 128.3, 126.0, 125.0, 120.81 (d, J = 281.8 Hz), 112.7,

[0060] 107.2, 65.79 (p, J = 34.3 Hz), 55.5, 49.4, 24.7, 21.3.

Claims

1. A method for preparing an indene derivative containing hexafluoroisopropyl ester, characterized in that: The method comprises the following steps: reacting a propargyl ether compound, hexafluoroisopropanol and N-iodosuccinimide at 20-30° C. for 0.5-1 hour, then adding a palladium catalyst, a ligand, formic acid, acetic anhydride, sodium carbonate and an organic solvent at 100-120° C. for 20-28 hours, and after the reaction is complete, post-treating to obtain the indene derivative containing hexafluoroisopropyl ester; The structure of the propargyl ether compound is shown in formula (III): The structure of the hexafluoroisopropanol is shown in formula (IV): The structure of the indene derivative containing hexafluoroisopropyl ester is shown in formula (I): In formulas (I) to (III), R 1 is one or more of C1-C4 alkyl, C1-C4 alkoxy or halogen, R 2 It is one or more of H, C1-C4 alkyl or C1-C4 alkoxy.

2. The method for preparing an indene derivative containing hexafluoroisopropyl ester according to claim 1, characterized in that: R 1 It is one or more of methyl, tert-butyl, methoxy, F, Cl or Br.

3. The method for preparing an indene derivative containing hexafluoroisopropyl ester according to claim 1, characterized in that: R 2 It is one or more of H, methyl, tert-butyl or methoxy.

4. The method for preparing an indene derivative containing hexafluoroisopropyl ester according to claim 1, characterized in that: In terms of molar amount, propargyl ether compound: hexafluoroisopropanol: formic acid: acetic anhydride: palladium catalyst: ligand: N-iodosuccinimide: sodium carbonate = 1:40-50:5-10:5-10:0.05-0.1:0.05-0.1:1-1.5:1-1.

5.

5. The method for preparing an indene derivative containing hexafluoroisopropyl ester according to claim 1, characterized in that: The organic solvent is dimethyl sulfoxide.

6. The method for preparing an indene derivative containing hexafluoroisopropyl ester according to claim 1, characterized in that: The palladium catalyst is palladium acetate.

7. The method for preparing an indene derivative containing hexafluoroisopropyl ester according to claim 1, characterized in that: The ligand is bis(2-diphenylphosphinophenyl) ether.

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