A method for synthesizing a five-membered aromatic heterocycle-indane derivative

Abstract

The application discloses a kind of synthesis methods for rapidly synthesizing five-membered aromatic heterocycle-indane derivative, belong to the field of organic synthesis. With five-membered aromatic heterocyclic compound, chloroalkyl-1,3-dithiane substituent as raw material, under the action of Lewis acid, five-membered aromatic heterocycle-indane derivative is efficiently constructed through one-step experimental operation. The method has the advantages of good selectivity, mild reaction conditions, high yield, simple and safe operation, etc. The five-membered aromatic heterocycle-indane derivative synthesized by the application has a thioxane molecular structure, which can realize further chemical conversion. At the same time, it overcomes the deficiency of requiring expensive noble metal catalyst and multiple steps in most indene ring synthesis reactions, and has certain application prospect in the field of organic synthesis and medicinal chemistry.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of organic synthesis, and particularly relates to a synthetic method of a five-membered aromatic heterocycle-indane derivative. BACKGROUND

[0002] Indene compounds are an important part of organic chemistry and organometallic chemistry, and exist in many natural or synthetic bioactive drugs, including anti-tumor, anti-allergy, antibacterial, anti-inflammatory, anti-Alzheimer's disease, and bactericidal active drugs, such as indriline (1) having an antidepressant effect; (2) being a muscarinic receptor antagonist; Fenistil (3) being an antihistamine.

[0003]

[0004] Due to the fact that natural or synthetic products containing an indene ring are continuously found to have attractive pharmacological activities, the efficient synthesis of indene compounds has attracted extensive attention from synthetic chemists. So far, many methods for synthesizing indene ring systems have been developed. For example, the reductive dehydration of indenone, the intramolecular cyclization of aryl-substituted allyl alcohol, the ring expansion of cyclopropene, the Lewis acid-mediated cyclization between aryl and 1,3-butadiene groups, and various transition metal complexes such as Pd, Ni, Pt, Co, Au, and Fe have been used for the synthesis of indene. However, most of these reactions require expensive noble metal catalysts such as rhodium, gold, and palladium, and the multiple steps and removal of the auxiliary reduce the overall reaction efficiency. Therefore, it is of great value to develop a method for rapidly synthesizing five-membered aromatic heterocycle-indane derivatives. SUMMARY

[0005] Due to the importance of substituted indene and its related indenone derivative structure in medicinal chemistry, and in order to overcome the defects pointed out above, we further seek a simple method for synthesizing five-membered aromatic heterocycle-indane derivatives. The present application provides a method for synthesizing five-membered aromatic heterocycle-indane derivatives using aryl-β-chloro-alkenyl-1,3-dithiane, which overcomes the shortcomings of existing methods, and the method is simple and easy to operate, the raw materials are cheap and easy to obtain, and different series of five-membered aromatic heterocycle-indane skeleton derivatives are synthesized.

[0006] A synthetic method of a five-membered aromatic heterocycle-indane derivative is characterized in that, under the action of a Lewis acid, a five-membered aromatic heterocycle and chloroalkenyl-1,3-dithiane react in a suitable reaction solvent and at a suitable temperature to generate a five-membered aromatic heterocycle-indane derivative, and the chemical reaction is as follows:

[0007]

[0008] R in the chloroalkenyl-1,3-dithiane 1Cl; X in the five-membered aromatic heterocycle structure is S, O, N; the structure of the five-membered aromatic heterocycle-indan derivative is:

[0009]

[0010] The synthesis method of the five-membered aromatic heterocycle-indan derivative is characterized in that the Lewis acid used is one of indium trichloride, indium tribromide, indium triiodide, boron trifluoride diethyl ether, and tris(pentafluorophenyl)boron.

[0011] The synthesis method of the five-membered aromatic heterocycle-indan derivative is characterized in that the solvent used is one of dichloromethane, 1,2-dichloroethane, and chloroform.

[0012] The synthesis method of the five-membered aromatic heterocycle-indan derivative according to claim 1 is characterized in that the molar ratio of the reactants used in the operation steps is chloroalkenyl-1,3-dithiane: five-membered aromatic heterocycle = 1: (0.5-3.0).

[0013] The synthesis method of the five-membered aromatic heterocycle-indan derivative according to claim 1 is characterized in that the reaction temperature ranges from 0 to 100°C. DETAILED DESCRIPTION

[0014] The application will be further described in conjunction with specific examples, which are used to explain the application but not to limit the scope of the application. In the following examples, the test methods are conventional methods unless otherwise specified, and the materials and reagents used are commercially available unless otherwise specified.

[0015] The product structure of the specific example is as follows:

[0016]

[0017]

[0018] The specific steps are as follows: in a 10-milliliter round-bottom flask, five-membered aromatic heterocycle compounds (0.25 mmol) and aryl-β-chloro-alkenyl-1,3-dithiane (69 mg, 0.2 mmol) are added, dissolved with 6 milliliters of solvent, and then a catalyst (0.03 mmol) is added. The reaction is stirred at room temperature for 24-48 h, and TLC detection is performed until the raw material disappears. The reaction is poured into 10 ml of ice water, and extracted with 15 ml of ethyl acetate three times. The organic phase is combined and washed with 15 ml of saturated sodium bicarbonate and brine. The organic phase is dried over anhydrous sodium sulfate, filtered, and the obtained filtrate is rotary evaporated under reduced pressure. The remaining oily substance is separated by flash column chromatography to obtain the corresponding five-membered aromatic heterocycle-indan derivative.

[0019] The five-membered aromatic heterocyclic-indane derivatives

[0020]

[0021] When the heterocycle is thiophene, the aryl-β-chloro-alkenyl-1,3-dithiane substituent is 3-methoxyphenyl, the catalyst used is InBr3, the solvent used is dichloromethane, and the resulting compound is M1;

[0022] When the heterocycle is thiophene, the aryl-β-chloro-alkenyl-1,3-dithiane substituent is 3,4,5-trimethoxyphenyl, the catalyst used is InBr3, the solvent used is dichloromethane, and the resulting compound is M2;

[0023] When the heterocycle is 3-methylthiophene, the aryl-β-chloro-alkenyl-1,3-dithiane substituent is 3-methoxyphenyl, the catalyst used is boron trifluoride etherate, the solvent used is dichloromethane, and the resulting compound is M3;

[0024] When the heterocycle is 3-chlorothiophene, the aryl-β-chloro-alkenyl-1,3-dithiane substituent is 3-methoxyphenyl, the catalyst used is tris(pentafluorophenyl)boron, the solvent used is dichloromethane, and the resulting compound is M4;

[0025] When the heterocycle is 2-chlorothiophene, the aryl-β-chloro-alkenyl-1,3-dithiane substituent is 3,4,5-trimethoxyphenyl, the catalyst used is tris(pentafluorophenyl)boron, the solvent used is dichloromethane, and the resulting compound is M5;

[0026] When the heterocycle is 5-chlorobenzothiophene, the aryl-β-chloro-alkenyl-1,3-dithiane substituent is 3,4,5-trimethoxyphenyl, the catalyst used is InI3, the solvent used is dichloromethane, and the resulting compound is M6;

[0027] When the heterocycle is 3-methylthiophene, the aryl-β-chloro-alkenyl-1,3-dithiane substituent is 3,4,5-trimethoxyphenyl, the catalyst used is InCl3, the solvent used is dichloromethane, and the resulting compound is M7;

[0028] When the heterocycle is pyrrole, the aryl-β-chloro-alkenyl-1,3-dithiane substituent is 3,4,5-trimethoxyphenyl, the catalyst used is InBr3, the solvent used is chloroform, and the resulting compound is M8;

[0029] When the heterocycle is 2-acetylpyrrole, the aryl-β-chloro-alkenyl-1,3-dithiane substituent is 3,4,5-trimethoxyphenyl, the catalyst used is InBr3, the solvent used is 1,2-dichloroethane, and the resulting compound is M9;

[0030] When the heterocycle is 2,3-benzofuran, the aryl- -chloro-alkenyl-1,3-dithiane substituent is 3,4,5-trimethoxyphenyl, the catalyst used is InCl3, the solvent used is dichloromethane, and the resulting compound is M11.

[0031] When the heterocycle is 2,3-benzofuran, the aryl- -chloro-alkenyl-1,3-dithiane substituent is 3,4,5-trimethoxyphenyl, the catalyst used is InCl3, the solvent used is dichloromethane, and the resulting compound is M11.

[0032] The nuclear magnetic data of compounds M1-M11 are as follows:

[0033] 1, compound M1

[0034]

[0035] 1 H NMR (600 MHz, CDC13) δ 7.21 (dd, J = 4.6, 1.8 Hz, 1H), 7.08 (d, J = 2.5 Hz, 1H), 7.02 - 6.97 (m, 3H), 6.83 (dd, J = 8.4, 2.5 Hz, 1H), 4.78 (dd, J = 9.5, 7.3 Hz, 1H), 3.83 (s, 3H), 3.59 (dd, J = 12.8, 7.0 Hz, 1H), 3.27 - 3.14 (m, 2H), 2.95 - 2.84 (m, 2H), 2.74 (dd, J = 12.7, 9.8 Hz, 1H), 2.26 - 2.15 (m, 1H), 2.09 - 1.97 (m, 1H). 13 C NMR (151 MHz, CDC13) δ 159.9, 146.9, 145.6, 137.1, 126.9, 125.8, 125.2, 124.2, 116.4, 108.7, 57.5, 55.7, 54.5, 43.5, 30.2, 28.4, 25.1.

[0036] 2, compound M2

[0037]

[0038] 1H NMR (600 MHz, CDC13) δ 7.13 (dd, J = 5.0, 1.3 Hz, 1H), 6.95 - 6.91 (m, 2H), 6.88 (s, 1H), 4.89 - 4.82 (m, 1H), 3.91 (s, 3H), 3.82 (s, 3H), 3.53 (dd, J = 13.3, 8.2 Hz, 1H), 3.47 (s, 3H), 3.23 - 3.09 (m, 2H), 2.92 (dd, J = 13.4, 7.0 Hz, 1H), 2.89 - 2.82 (m, 2H), 2.22 - 2.17 (m, 1H), 2.05 - 1.93 (m, 1H). 13 C NMR (151 MHz, CDC13) δ 154.6, 150.3, 148.5, 143.1, 139.7, 129.6, 126.6, 124.6, 123.3, 103.0, 60.8, 60.2, 58.3, 56.3, 54.4, 42.5, 29.9, 29.0, 25.0.

[0039] 3, Compound M3

[0040]

[0041] 1 H NMR (600 MHz, CDC13) δ 7.11 - 7.07 (m, 2H), 6.93 (dd, J = 8.4, 1.1 Hz, 1H), 6.84 (d, J = 5.1 Hz, 1H), 6.82 (dd, J = 8.4, 2.5 Hz, 1H), 4.79 (dd, J = 10.0, 7.0 Hz, 1H), 3.83 (s, 3H), 3.56 (dd, J = 12.7, 7.0 Hz, 1H), 3.23 - 3.11 (m, 2H), 2.92 - 2.85 (m, 2H), 2.69 (dd, J = 12.7, 10.0 Hz, 1H), 2.24 (s, 3H), 2.23 - 2.18 (m, 1H), 2.08 - 1.98 (m, 1H). 13 C NMR (151 MHz, CDC13) δ 159.9, 145.5, 139.9, 137.1, 134.2, 130.2, 125.7, 122.5, 116.3, 108.8, 57.5, 55.7, 53.5, 41.5, 30.3, 28.3, 25.1, 14.2.

[0042] 4, Compound M4

[0043]

[0044] 1H NMR (400 MHz, Chloroform-d) δ 7.17 (dd, J = 5.3, 0.6 Hz, 1H), 7.09 (d, J = 2.4 Hz, 1H), 7.01 (dd, J = 8.4, 1.1 Hz, 1H), 6.93 (d, J = 5.4 Hz, 1H), 6.84 (dd, J = 8.4, 2.5 Hz, 1H), 4.95 (dd, J = 9.5, 7.1 Hz, 1H), 3.84 (s, 3H), 3.61 (dd, J = 12.8, 7.1 Hz, 1H), 3.35 - 3.08 (m, 2H), 2.94 - 2.83 (m, 2H), 2.69 (dd, J = 12.8, 9.5 Hz, 1H), 2.27 - 2.20 (m, 1H), 2.07 - 1.97 (m, 1H). 13 C NMR (151 MHz, CDCl3) δ 160.1, 145.8, 139.8, 136.0, 127.7, 125.8, 123.4, 123.3, 116.4, 109.0, 57.5, 55.7, 52.9, 41.4, 30.2, 28.4, 25.1.

[0045] 5, Compound M5

[0046]

[0047] 1 H NMR (400 MHz, Chloroform-d) δ 6.87 (s, 1H), 6.71 (d, J = 3.8 Hz, 1H), 6.69 (d, J = 0.7 Hz, 1H), 4.72 (dd, J = 8.4, 6.3 Hz, 1H), 3.91 (s, 3H), 3.82 (s, 3H), 3.59 (s, 3H), 3.52 - 3.42 (m, 1H), 3.16 (tdd, J = 12.5, 9.5, 2.6 Hz, 2H), 2.97 - 2.85 (m, 3H), 2.32 - 2.15 (m, 1H), 2.09 - 1.94 (m, 1H).

[0048] 6, Compound M6

[0049]

[0050] 1H NMR (600 MHz, CDC13) δ 7.79 (d, J = 8.6 Hz, 1H), 7.67 (d, J = 2.0 Hz, 1H), 7.32 (dd, J = 8.6, 2.0 Hz, 1H), 7.23 (s, 1H), 7.16 (d, J = 2.5 Hz, 1H), 6.97 (dd, J = 8.3, 1.0 Hz, 1H), 6.84 (dd, J = 8.4, 2.5 Hz, 1H), 4.86 (t, J = 8.3 Hz, 1H), 3.86 (s, 3H), 3.59 (dd, J = 13.0, 7.5 Hz, 1H), 3.28 - 3.19 (m, 1H), 3.17 - 3.08 (m, 1H), 2.96 - 2.85 (m, 2H), 2.81 (dd, J = 13.0, 9.2 Hz, 1H), 2.27 - 2.17 (m, 1H), 2.11 - 1.99 (m, 1H). 13 C NMR (151 MHz, CDC13) δ 160.1, 146.2, 139.9, 139.2, 137.7, 135.6, 130.5, 125.9, 125.0, 124.8, 124.1, 121.9, 116.6, 109.2, 57.9, 55.7, 51.8, 42.1, 30.1, 28.5, 25.1.

[0051] 7, Compound M7

[0052]

[0053] 1 H NMR (600 MHz, CDC13) δ 7.03 (d, J = 5.1 Hz, 1H), 6.88 (s, 1H), 6.79 (d, J = 5.0 Hz, 1H), 4.86 (t, J = 7.9 Hz, 1H), 3.91 (s, 3H), 3.81 (s, 3H), 3.56 (dd, J = 13.3, 8.0 Hz, 1H), 3.38 (s, 3H), 3.25 - 3.12 (m, 2H), 2.91 - 2.83 (m, 3H), 2.25 (s, 3H), 2.23 - 2.17 (m, 1H), 2.06 - 1.95 (m, 1H). 13 C NMR (151 MHz, CDC13) δ 154.5, 150.3, 143.3, 141.4, 139.6, 133.4, 130.0, 129.9, 121.7, 103.1, 60.9, 60.1, 58.3, 56.3, 53.7, 40.5, 30.2, 28.9.

[0054] 8, Compound M8

[0055]

[0056] 1 H NMR (600 MHz, CDCl3) δ 8.82 (s, 1H), 6.87 (s, 1H), 6.66–6.59 (m, 1H), 6.14–6.06 (m, 2H), 4.69 (dd, J = 9.3, 3.9 Hz, 1H), 3.88 (s, 3H), 3.82 (s, 3H), 3.47 (s, 3H), 3.31 (dd, J = 13.8, 9.3 Hz, 1H), 3.24–3.12 (m, 3H), 2.93–2.86 (m, 2H), 2.28–2.19 (m, 1H), 2.06–1.96 (m, 1H). 13 C NMR (151 MHz, CDCl3) δ 154.6, 150.1, 143.4, 139.3, 133.8, 129.6, 117.0, 107.8, 105.8, 103.6, 60.9, 60.7, 58.8, 56.4, 50.7, 40.4, 29.8, 29.4, 25.0.

[0057] 9. Compound M9

[0058]

[0059] 1 H NMR (400 MHz, Chloroform-d) δ 9.72 (s, 1H), 6.88 (s, 1H), 6.80–6.68 (m, 1H), 6.16 (dd, J = 3.8, 2.6 Hz, 1H), 4.65 (dd, J = 9.0, 4.3 Hz, 1H), 3.90 (d, J = 0.8 Hz, 3H), 3.82 (d, J = 0.9 Hz, 3H), 3.56 (d, J = 1.0 Hz, 3H), 3.41–3.30 (m, 1H), 3.24–3.06 (m, 2H), 2.98–2.82 (m, 1H), 2.35 (s, 3H), 2.28–2.14 (m, 1H), 2.11–1.93 (m, 1H). 13 C NMR (101 MHz, CHLOROFORM-D) δ 187.2, 155.0, 149.9, 143.3, 141.8, 139.6, 131.8, 127.9, 117.0, 109.0, 103.6, 60.9, 60.6, 58.6, 56.5, 50.6, 40.4, 29.6, 29.4, 25.2, 24.9.

[0060] 10. Compound M10

[0061]

[0062] 1 H NMR (400 MHz, CDC13) δ 7.53 - 7.45 (m, 1H), 7.43 - 7.37 (m, 1H), 7.24 - 7.05 (m, 2H), 6.92 (s, 1H), 6.50 (s, 1H), 4.75 (t, J = 7.6 Hz, 1H), 3.92 (s, 3H), 3.83 (s, 3H), 3.50 (s, 3H), 3.41 (dd, J = 13.1, 7.9 Hz, 1H), 3.23 - 3.03 (m, 3H), 2.93 - 2.79 (m, 2H), 2.24 - 2.13 (m, 1H), 2.05 - 1.92 (m, 1H). 13 C NMR (101 MHz, CDC13) δ 159.5, 154.8, 154.8, 150.3, 143.0, 140.3, 129.0, 126.7, 123.4, 122.6, 120.6, 111.0, 103.4, 102.8, 60.9, 60.5, 58.3, 56.4, 50.1, 41.0, 29.9, 29.0, 25.0.

[0063] 11. Compound M11

[0064]

[0065] 1 H NMR (400 MHz, CDC13) δ 7.53 - 7.45 (m, 1H), 7.43 - 7.37 (m, 1H), 7.24 - 7.05 (m, 2H), 6.92 (s, 1H), 6.50 (s, 1H), 4.75 (t, J = 7.6 Hz, 1H), 3.92 (s, 3H), 3.83 (s, 3H), 3.50 (s, 3H), 3.41 (dd, J = 13.1, 7.9 Hz, 1H), 3.23 - 3.03 (m, 3H), 2.93 - 2.79 (m, 2H), 2.24 - 2.13 (m, 1H), 2.05 - 1.92 (m, 1H). 13 C NMR (101 MHz, CDC13) δ 159.5, 154.8, 154.8, 150.3, 143.0, 140.3, 129.0, 126.7, 123.4, 122.6, 120.6, 111.0, 103.4, 102.8, 60.9, 60.5, 58.3, 56.4, 50.1, 41.0, 29.9, 29.0, 25.0.

Claims

1. A method for the synthesis of a five-membered aromatic heterocycle-indane derivative, characterized by: In the presence of a Lewis acid, a five-membered aromatic heterocycle and a chloroalkenyl-1,3-dithiane react in a suitable reaction solvent and at a suitable temperature to form a five-membered aromatic heterocycle-indane derivative, said chemical reaction being represented by the following formula: R in the chloroalkenyl-1,3-dithiane 1 is Cl; X in the five-membered aromatic heterocycle structure is S, O, N; the structure of the five-membered aromatic heterocycle-indane derivative is: The Lewis acid is one of indium trichloride, indium tribromide, indium triiodide, boron trifluoride etherate, and tris(pentafluorophenyl)boron; the solvent is one of dichloromethane, 1,2-dichloroethane, and chloroform.

2. The process for the synthesis of a five-membered aromatic heterocycle-indane derivative according to claim 1, characterized by the fact that: The molar ratio of the reactants used in the operation steps is chloroalkenyl-1,3-dithiane: five-membered aromatic heterocycle = 1: (0.5-3.0).

3. The method according to claim 1, characterized in that: The reaction temperature is in the range of 0-100℃.

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