Preparation method of thiochromene derivative containing hexafluoroisopropyl ester

Abstract

The preparation method comprises the following steps: reacting a propargyl ether compound, N-iodo-succinimide and dichloromethane at room temperature for 24 hours, then adding palladium acetate and bis (2-diphenylphosphinophenyl) ether, and reacting at room temperature for 24 hours, so as to obtain the thiochromene derivative containing hexafluoroisopropyl ester. The preparation method comprises the following steps: carrying out reaction on hexafluoroisopropanol, formic acid, acetic anhydride, potassium carbonate and dimethyl sulfoxide at 120 DEG C for 24 hours, and after the reaction is completed, carrying out post-treatment to obtain the thiochromene 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 thiochromene derivatives containing hexafluoroisopropyl ester 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 present invention belongs to the field of organic synthesis, and particularly relates to a method for preparing a thiochromene derivative containing hexafluoroisopropyl ester. Background Art

[0002] Fluorine-containing compounds usually have a significant impact on their lipophilicity, metabolic stability and bioavailability due to the presence of fluorine atoms, and have various uses in the fields of materials, drugs, chemical engineering, etc. Among them, hexafluoroisopropyl ester, as a valuable synthetic compound, the two strongly electron-deficient CF 3 groups in the molecule endow it with special physical and chemical properties and have very wide applications in organic synthesis. Hexafluoroisopropyl ester can be converted into other types of esters or amides under mild conditions, and can also be used as the starting material for organic catalytic asymmetric reactions. In addition, they are more lipophilic than their non-fluorinated analogues and have other unique properties. Therefore, the synthesis of hexafluoroisopropyl ester has attracted extensive attention, and a variety of synthesis methods, including organocatalytic cross-coupling of aldehydes with hexafluoroisopropanol, palladium-catalyzed alkoxycarbonylation, etc., have been developed for the preparation of such compounds.

[0003] On the other hand, sulfur-containing compounds have very wide applications in biology, materials science and food chemistry. For example, thiochromene and its derivatives have a variety of pharmaceutical activities, such as anti-cancer, antibacterial, anti-inflammatory and antipsychotic. The synthesis of such compounds has always been one of the important tasks in organic synthesis. Usually, the synthesis of thiochromene and its derivatives requires multiple steps, with a limited substrate scope and low yields. Therefore, the development of efficient methods for the synthesis of thiochromene and its derivatives has always been one of the focuses of attention.

[0004] Considering the special physical and chemical properties of hexafluoroisopropyl ester and the important physiological and pharmacological activities of thiochromene, the development of simple and efficient reactions for the synthesis of thiochromene derivatives containing hexafluoroisopropyl ester has broad prospects. Based on this, we have developed a palladium-catalyzed carbonylation cyclization reaction for the synthesis of thiochromene derivatives containing hexafluoroisopropyl ester. The reaction starts from easily available propargyl ether compounds and hexafluoroisopropanol compounds, and uses formic acid as the carbonyl source to synthesize a variety of thiochromene derivatives containing hexafluoroisopropyl ester. This reaction opens up a new synthetic route for the preparation of heterocyclic molecules containing hexafluoroisopropyl ester. Summary of the Invention

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

[0006] A preparation method of a thiochromene derivative containing hexafluoroisopropyl ester, comprising the following steps: reacting a propargyl ether compound, N-iodosuccinimide and dichloromethane at 20-30 °C for 20-24 hours, then adding a palladium catalyst, a ligand, hexafluoroisopropanol, formic acid, acetic anhydride, potassium carbonate and an organic solvent and reacting at 100-120 °C for 20-28 hours. After the reaction is complete, post-treatment is carried out to obtain the thiochromene 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 thiochromene derivative containing hexafluoroisopropyl ester is shown in formula (I):

[0012]

[0013] In formulas (I)-(III), R 1 is C 1 -C 4 alkyl, C 1 -C 4 alkoxy, trifluoromethyl or one or more of halogens, and R 2 is H, C 1 -C 4 alkyl, trifluoromethoxy, phenyl or one or more of halogens.

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

[0015] R 1 is substituted at the ortho, para or meta position; the substitution position on the aryl group of R 2 is at the ortho, para or meta position.

[0016] The reaction formula is as follows:

[0017]

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

[0019] Preferably, R1 is one or more of methyl, tert-butyl, methoxy, trifluoromethyl, F or Cl. R 2 is one or more of H, methyl, tert-butyl, phenyl, trifluoromethoxy, F or Br. At this time, the propargyl ether compound is easily obtained and the reaction yield is high.

[0020] The propargyl ether compound and hexafluoroisopropanol used for preparing the thiochromene derivative containing hexafluoroisopropyl ester are relatively cheap and widely exist 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, and conversely, it is difficult to ensure the completion of the reaction.

[0022] Preferably, the reaction is carried out in dimethyl sulfoxide. The amount of dimethyl sulfoxide used only needs to dissolve the raw materials well. The amount of dichloromethane and 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 cheap, and the reaction efficiency is high when palladium acetate is used as the catalyst.

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

[0025]

[0026]

[0027] In the above preparation method, the hexafluoroisopropanol, formic acid, acetic anhydride, palladium acetate, bis(2-diphenylphosphinophenyl) ether, N-iodosuccinimide and potassium carbonate generally use commercially available products and can be easily obtained from the market.

[0028] 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 thiochromene derivatives containing hexafluoroisopropyl ester can be synthesized according to actual needs, and the practicability is strong. Specific Embodiments

[0029] The following further describes the present invention in conjunction with specific embodiments.

[0030] Examples 1 to 15

[0031] Add the propargyl ether compound (II), N-iodosuccinimide and dichloromethane 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-reaction product of palladium acetate, bis(2-diphenylphosphinophenyl) ether, formic acid and acetic anhydride, potassium carbonate, then add hexafluoroisopropanol and 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 thiochromene derivative (I) containing hexafluoroisopropyl ester. The reaction process is shown in the following formula:

[0032]

[0033] Table 1 Raw material addition amounts of Examples 1 to 15

[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, Ph is phenyl, OMe is methoxy, CF 3 is trifluoromethyl, OCF 3 is trifluoromethoxy.

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

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

[0040]

[0041] 1 H NMR (40000 MHz, CDCl 3 ) δ 7.69 (d, J = 7.6 Hz, 1H), 7.40 (d, J = 8.0 Hz, 2H), 7.27 (d, J = 4.7 Hz, 3H), 7.13 (d, J = 7.9 Hz, 2H), 5.95 (hept, J = 6.1 Hz, 1H), 2.35 (s, 3H), 1.30 (s, 6H).

[0042] 13 C NMR (101 MHz, CDCl3 ) δ 160.1, 152.3, 138.8, 136.9, 133.1, 129.8, 127.8, 127.4, 126.1, 125.4, 121.5, 121.2, 120.57 (q, J = 282.4 Hz), 66.18 (p, J = 34.9 Hz), 55.2, 25.5, 21.2.

[0043] The nuclear magnetic resonance ( 1 HNMR and 13 C NMR) test data of the thiochromene derivative (I-2) containing hexafluoroisopropyl ester prepared in Example 2 are as follows:

[0044]

[0045] 1 H NMR (400 MHz, CDCl 3 ) δ 7.69 (d, J = 7.5 Hz, 1H), 7.41 (d, J = 8.5 Hz, 2H), 7.33 (d, J = 8.4 Hz, 3H), 7.29 (dd, J = 6.2, 2.7 Hz, 2H), 5.89 (hept, J = 6.2 Hz, 1H), 1.33 (s, 6H), 1.31 (s, 9H).

[0046] 13 C NMR (101 MHz, CDCl 3 ) δ 159.9, 152.2, 151.9, 137.0, 132.5, 129.9, 128.2, 127.4, 126.1, 126.1, 125.4, 121.5, 121.3, 120.54 (q, J = 282.6 Hz), 66.13 (p, J = 34.8 Hz), 55.0, 34.7, 31.1, 25.4.

[0047] The nuclear magnetic resonance ( 1 HNMR and 13 C NMR) test data of the thiochromene derivative (I-3) containing hexafluoroisopropyl ester prepared in Example 3 are as follows:

[0048]

[0049] 1 H NMR (400 MHz, CDCl 3)δ7.69(d, J = 7.6Hz, 1H), 7.39(d, J = 7.9Hz, 1H), 7.33–7.29(m, 1H), 7.25(d, J = 7.2Hz, 2H), 7.06(s, 1H), 6.96(d, J = 7.9Hz, 1H), 5.95(hept, J = 6.2Hz, 1H), 2.42(s, 3H), 2.32(s, 3H), 1.27(s, 6H).

[0050] 13 C NMR(101MHz, CDCl 3 )δ160.1, 152.3, 141.5, 140.3, 139.4, 137.0, 134.2, 131.4, 127.4, 126.8, 125.9, 125.0, 121.4, 121.1, 120.60(q, J = 282.8Hz), 66.32(p, J = 34.6Hz), 55.4, 25.3, 21.1, 20.9.

[0051] 1H NMR and 1 1H NMR and 13 13C NMR) detection data of the thiochromene derivative (I-4) containing hexafluoroisopropyl ester prepared in Example 4 are as follows:

[0052]

[0053] 1 1H NMR(400MHz, CDCl 3 )δ7.68(d, J = 8.5Hz, 1H), 7.41(d, J = 8.0Hz, 2H), 7.16(t, J = 9.5Hz, 3H), 7.10(s, 1H), 5.94(hept, J = 6.1Hz, 1H), 2.36(s, 3H), 1.29(s, 6H).

[0054] 13 13C NMR(101MHz, CDCl 3 )δ159.7, 154.0, 147.8, 139.3, 135.5, 133.6, 129.9, 127.1, 122.4, 122.51(d, J = 270.9Hz), 120.58(d, J = 277.5Hz), 120.2, 114.5, 66.07(p, J = 35.0Hz), 55.4, 25.5, 21.2.

[0055] 1H NMR and 1 1H NMR and 13The detection data by \(^{13}\)C NMR are as follows:

[0056]

[0057] 1 \(^{1}\)H NMR (400 MHz, CDCl 3 ) δ 7.75 (d, J = 8.1 Hz, 1H), 7.61 (d, J = 7.3 Hz, 2H), 7.56 (dd, J = 8.1, 1.6 Hz, 1H), 7.48–7.41 (m, 5H), 7.35 (t, J = 7.3 Hz, 1H), 7.15 (d, J = 8.0 Hz, 2H), 5.97 (hept, J = 6.1 Hz, 1H), 2.36 (s, 3H), 1.35 (s, 6H).

[0058] 13 \(^{13}\)C NMR (101 MHz, CDCl 3 ) δ 160.0, 152.9, 141.1, 139.3, 138.9, 136.1, 133.2, 129.8, 128.8, 127.8, 127.3, 127.2, 126.5, 125.1, 121.8, 120.56 (d, J = 278.8 Hz), 120.0, 66.04 (p, J = 34.9 Hz), 55.3, 25.6, 21.2。

Claims

1. A method for preparing a thiochromene derivative containing hexafluoroisopropyl ester, characterized in that: The method comprises the following steps: reacting a propargyl ether compound, N-iodosuccinimide and dichloromethane at 20-30° C. for 20-24 hours, then adding a palladium catalyst, a ligand, hexafluoroisopropanol, formic acid, acetic anhydride, potassium carbonate and an organic solvent at 100-120° C. for 20-28 hours, and after the reaction is complete, post-treating to obtain the thiochromene 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 thiochromene 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, trifluoromethyl or halogen, R 2 It is one or more of H, C1-C4 alkyl, trifluoromethoxy, phenyl or halogen.

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

3. The method for preparing a thiochromene derivative containing hexafluoroisopropyl ester according to claim 1, characterized in that: R 2 It is one or more of H, methyl, tert-butyl, phenyl, trifluoromethoxy, F or Br.

4. The method for preparing a thiochromene 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: potassium 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 a thiochromene derivative containing hexafluoroisopropyl ester according to claim 1, characterized in that: The organic solvent is dimethyl sulfoxide.

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

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

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