A method for preparing 2-hydrocarbyl-3-iodo-chromone compounds

Abstract

The application discloses a preparation method of 2-hydrocarbon-3-iodine chromone compounds and belongs to the field of organic synthesis. The preparation method comprises the following steps: taking o-hydroxyphenyl propargyl ketone compounds and iodine reagent as starting materials, and performing a tandem cyclization reaction in the presence of halosilane and a solvent to obtain the 2-hydrocarbon-3-iodine chromone compounds. The substrate of the preparation method has a wide application range and can be used for synthesizing compounds with different molecular structures. The reaction of the preparation method is mild, the atomic economy is good, the product post-treatment is simple, and the yield is high, so that the industrialized production and application of the compounds are facilitated.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to a method for preparing 2-alkyl-3-iodochrome ketone compounds. Background Technology

[0002] Chromones are an important class of oxygen-containing heterocyclic structural units, widely found in many natural products and drug molecules with significant biological activities. In recent years, an increasing number of studies have discovered that chromone derivatives possess immunosuppressive activity. For molecules containing the chromone skeleton, a close correlation has been shown between different substituents and biological activity, with the 2,3-position showing the most prominent effect among the various substitution positions in chromones.

[0003] Among various chromone compounds, 2-substituted 3-iodochromones are an important class. Besides possessing inherent biological activity and significant application value, these compounds can also undergo 3-position functionalization via carbon-iodine bond coupling reactions to yield structurally richer chromone compounds, thus expanding their application scope. Therefore, 2-alkyl 3-iodochromones are also an important intermediate in organic synthesis.

[0004] Currently, the preparation of 2-alkyl-3-iodochrome ketones mainly relies on the iodination reaction of 2-alkylchrome ketones. In 1993, Li Yulin et al. achieved the iodination reaction of flavonoids at 55-60 °C through the action of I2 / cerium ammonium nitrate. Synthesis 1993, 565). This method is limited to the iodination of flavonoid derivatives, and the overall product yield is low (mostly between 20-30%), with some even failing to react. Furthermore, the reaction requires the addition of large amounts of the oxidant cerium ammonium nitrate, and post-treatment requires the addition of a reducing agent, resulting in significant exothermic reactions, which is unfavorable for industrial production applications. In 2020, Wang Lin's research team also reported the iodination reaction of flavonoids (…). TetrahedronLett 2020, 61 (151511), this reaction requires the combined action of the oxidant Oxone and KI. In 2007, Wang Shaomeng's research group reported the iodination of 8-isobutyl-5,6,7-trimethoxy-2-methylchromone at 0 °C via the action of I2 / silver trifluoroacetate. J. Med. Chem. 2007, 50, 3163). This method was only reported for the synthesis of 3-iodo-8-isobutyl-5,6,7-trimethoxy-2-methylchromone; other compounds were not reported. The reagent used was the relatively expensive silver trifluoroacetate. In 2020, Kenneth K. Laali et al. used the NIS / BMIM-ILs reaction system to iodinate 2-methyl-7-iodochromone at 100℃. TetrahedronLett2020, 61 (152179). This method involves a high reaction temperature and requires an ionic liquid, and only 2-methyl-3,7-diiodocrone was synthesized.

[0005] Therefore, in order to improve the synthesis efficiency of 2-alkyl-3-iodochrome ketones and reduce costs, it is urgent to develop a new green, economical and efficient preparation method that is suitable for industrial production and promotes their practical application. Summary of the Invention

[0006] This invention provides a method for preparing 2-alkyl-3-iodochrome ketone compounds, developing a novel, green, economical, and efficient preparation method. This method has a wide range of applicable substrates and can be used to synthesize compounds with different molecular structures. Furthermore, the reaction conditions are mild, the reagents are inexpensive and readily available, the atom economy is good, the product post-processing is simple, and the yield is high. It is suitable for industrial production and promotes its practical application.

[0007] To solve the above-mentioned technical problems, the present invention provides the following technical solution: The present invention provides a method for preparing 2-alkyl-3-iodochrome ketone compounds, characterized in that the preparation method is as follows:

[0008] Using the compound shown in formula (I) and the iodinated reagent as starting materials, and with halosilane as a catalyst, a tandem cyclization reaction was carried out in the presence of anhydrous organic solvent to obtain the 2-alkyl-3-iodochrome ketone compound shown in formula (II).

[0009] The structures of equations (I) and (II) above are shown below:

[0010]

[0011] In the formula, R 1 Selected from one of the hydrocarbon groups;

[0012] R 2 It is selected from one of the following groups: hydrogen, halogen, acyl, cyano, nitro, amino, hydroxyl, sulfonyl, sulfonic acid, ester, alkoxy, haloalkyl, and hydrocarbon.

[0013] Furthermore, the iodination reagent is N-iodosuccinimide.

[0014] Furthermore, the catalyst is trimethylchlorosilane.

[0015] Furthermore, the catalyst is diluted with an anhydrous organic solvent; the organic solvent is tetrahydrofuran or an alcohol solvent.

[0016] Furthermore, according to the molar ratio, the compound represented by Formula I: iodinated reagent = 1:1~2.5.

[0017] Furthermore, according to the molar ratio, the compound represented by Formula I: trimethylchlorosilane = 1:1~2.5.

[0018] Furthermore, the reaction temperature is 0℃~80℃.

[0019] Furthermore, the reaction time is 1 hour to 6 hours.

[0020] Further, the post-processing steps specifically involve: quenching the reaction product with water, extracting with ethyl acetate at least twice, combining the organic phases, washing with water and saturated NaHCO3 solution respectively, drying with anhydrous Na2SO4, rotary evaporating under reduced pressure, and purifying the residue by column chromatography to obtain 2-alkyl-3-iodochrome ketone compounds.

[0021] Compared with the prior art, the present invention provides a new process for synthesizing 2-alkyl-3-iodochrome ketones from o-hydroxyphenylpropynones as raw materials.

[0022] The synthesis process of this invention features mild reaction conditions, good atom economy, inexpensive and readily available reagents, and a wide range of applications. It can be used to synthesize compounds with different molecular structures, and the product post-processing is simple and yields high, which is conducive to large-scale industrial applications. Detailed Implementation

[0023] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used herein in the specification of this invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. The term "and / or" as used herein includes any and all combinations of one or more of the associated listed items. "Comprising" or "containing" as used herein means that it may include or contain other components in addition to the stated components. "Comprising" or "containing" as used herein may also be replaced with the closed form "is" or "consisting of".

[0024] The present invention will be further described below with reference to specific embodiments, so that those skilled in the art can better understand and implement the present invention, but the embodiments are not intended to limit the present invention.

[0025]

[0026] In the formula, R 1 Selected from one of the hydrocarbon groups; R 2 It is selected from one of the following groups: hydrogen, halogen, acyl, cyano, nitro, amino, hydroxyl, sulfonyl, sulfonic acid, ester, alkoxy, haloalkyl, and hydrocarbon.

[0027] The preparation method comprises the following steps: using the o-hydroxyphenylpropynone compound shown in formula (I) and the iodinated reagent (N-iodosuccinimide NIS) as starting materials, and using a halosilane (trimethylchlorosilane TMSCl) as a catalyst, stirring the reaction at 0℃~80℃ for 1h~6h, quenching with water, extracting with ethyl acetate at least twice, combining the organic phases, washing with water and saturated NaHCO3 solution respectively, drying with anhydrous Na2SO4, rotary evaporating under reduced pressure, and separating and purifying the residue by column chromatography to obtain the compound shown in formula II, which is a 2-alkyl-3-iodochromene compound. The molar ratio of the compound shown in formula (I) to the iodinated reagent is 1:1~2.5 (preferably 1:2.0); the molar ratio of the compound shown in formula (I) to trimethylchlorosilane is 1:1~2.5 (preferably 1:2.0).

[0028] Table 1. Compound structures and yields in the examples

[0029]

[0030] Example 1

[0031] In a reaction tube, 0.2 mmol of the compound shown in formula Ia of Table 1 and 2.0 equiv of NIS were weighed. In a vial, 2.0 equiv of TMSCl was weighed and diluted with anhydrous methanol (3 mL), then added to the reaction tube. The mixture was stirred at room temperature for 6 hours. After the reaction was confirmed to be complete by thin-layer chromatography, water was added to quench the reaction. The mixture was extracted three times with 40 mL of ethyl acetate. The combined organic phases were washed once with 20 mL of water and once with 20 mL of saturated NaHCO3 solution. The mixture was dried over anhydrous Na2SO4 for 2 h. The solvent was removed by rotary evaporation under reduced pressure. The residue was purified by column chromatography with an eluent of V (petroleum ether): V (ethyl acetate) = 15:1. The product was the compound shown in formula IIa of Table 1, 3-iodo-2-phenylchromone (3-iodoflavonoid): white solid, mp 124℃-126℃.

[0032] The products were analyzed using 1H NMR spectroscopy, 1C NMR spectroscopy, infrared spectroscopy, and high-resolution mass spectrometry.

[0033] 1 H NMR (400 MHz, CDCl3) δ: 8.30-8.27 (m, 1H), 7.79-7.77 (m, 2H), 7.71(ddd, J = 8.8, 7.2, 1.6 Hz, 1H), 7.56-7.52 (m, 3H), 7.50-7.44 (m, 2H);

[0034] 13 C-NMR (100 MHz, CDCl3) δ: 174.6, 164.7, 156.0, 135.2, 134.3, 131.1,129.6, 128.4, 126.9, 126.0, 120.1, 117.7, 88.5;

[0035] IR (cm -1 ): 2227, 1643, 1459, 1326, 1057, 911, 750, 686;

[0036] HR ESI-MS: [C 15 H 10 IO2] + = [M + H] + requires 348.9725; found 348.9713.

[0037] Example 2

[0038] The difference between this embodiment and Example 1 is that the raw material is replaced with the compound shown in Formula Ib in Table 1, while the rest is the same as in Example 1. The product is the compound shown in Formula IIb in Table 1, 2-(4-chlorophenyl)-3-iodochrome: a white solid, mp 158℃-159℃.

[0039] The products were analyzed using 1H NMR spectroscopy, 1C NMR spectroscopy, infrared spectroscopy, and high-resolution mass spectrometry.

[0040] 1 H NMR (400 MHz, CDCl3) δ: 8.26 (dd, J = 8.0, 1.4 Hz, 1H), 7.76-7.70 (m, 3H), 7.52-7.44 (m, 4H);

[0041] 13 C-NMR (100 MHz, CDCl3) δ: 174.5, 163.5, 155.9, 137.4, 134.4, 133.5,131.0, 128.8, 128.5, 128.2, 126.9, 126.1, 120.0, 117.7, 88.5;

[0042] IR (cm -1 ): 2229, 1646, 1464, 1327, 1059, 916, 754, 690;

[0043] HR ESI-MS: [C 15 H9ClIO2] + = [M + H] + requires 382.9336; found 382.9306.

[0044] Example 3

[0045] The difference between this embodiment and Example 1 is that the raw materials are replaced with the compounds shown in Formula Ic in Table 1, while the rest is the same as in Example 1. The product is the compound shown in Formula IIc in Table 1, 3-iodo-2-p-tolyl chromone: a white solid, mp 163℃-164℃.

[0046] The products were analyzed using 1H NMR spectroscopy, 1C NMR spectroscopy, infrared spectroscopy, and high-resolution mass spectrometry.

[0047] 1 H NMR (400 MHz, CDCl3) δ: 8.27 (ddd, J = 8.0, 1.8, 0.4 Hz, 1H), 7.72-7.68 (m, 3H), 7.49-7.44 (m, 2H), 7.35-7.32 (m, 2H), 2.46 (s, 3H);

[0048] 13 C-NMR (100 MHz, CDCl3) δ: 174.7, 164.8, 156.0, 141.7, 134.2, 132.3,129.5, 129.1, 126.8, 125.9, 120.1, 117.7, 88.1, 21.7;

[0049] IR (cm -1 ): 2215, 1635, 1459, 1327, 1054, 916, 816, 692;

[0050] HR ESI-MS: [C 16 H 12 IO2] + = [M + H] + requires 362.9882; found 362.9877.

[0051] Example 4

[0052] The difference between this embodiment and Example 1 is that the raw material is replaced with the compound shown in Formula Id in Table 1, while the rest is the same as in Example 1. The product is the compound shown in Formula IId in Table 1, 3-iodo-2-(4-methoxyphenyl)chromone: a white solid, mp 155 ℃-157 ℃.

[0053] The products were analyzed using 1H NMR spectroscopy, 1C NMR spectroscopy, infrared spectroscopy, and high-resolution mass spectrometry.

[0054] 1 H NMR (400 MHz, CDCl3) δ: 8.29-8.26 (m, 1H), 7.82-7.79 (m, 2H), 7.70(ddd, J = 8.8, 7.2, 1.8 Hz, 1H), 7.50-7.44 (m, 2H), 7.05-7.01 (m, 2H), 3.90 (s,3H);

[0055] 13 C-NMR (100 MHz, CDCl3) δ: 174.8, 164.5, 161.8, 156.0, 134.2, 131.5,127.3, 126.9, 125.8, 120.1, 117.7, 113.7, 87.8, 55.6;

[0056] IR (cm -1 ): 1650, 1608, 1504, 1256, 1020, 824, 753, 692;

[0057] HR ESI-MS: [C 16 H 12 IO3] + = [M + H] + requires 378.9831; found 378.9812.

[0058] Example 5

[0059] The difference between this embodiment and Example 1 is that the raw material is replaced with the compound shown in Formula Ie in Table 1, while the rest is the same as in Example 1. The product is the compound shown in Formula IIe in Table 1, 3-iodo-2-(3-methoxyphenyl)chromone: a white solid, mp 151 ℃-152 ℃.

[0060] The products were analyzed using 1H NMR spectroscopy, 1C NMR spectroscopy, infrared spectroscopy, and high-resolution mass spectrometry.

[0061] 1H NMR (400 MHz, CDCl3) δ: 8.30-8.27 (m, 1H), 7.72 (ddd, J = 8.6, 7.2,1.8 Hz, 1H), 7.50-7.43 (m, 3H), 7.35 (ddd, J = 7.6, 1.6, 1.0 Hz, 1H), 7.29 (dd, J = 2.4, 1.7 Hz, 1H), 7.09 (ddd, J = 8.3, 2.6, 1.0 Hz, 1H), 3.89 (s, 3H);

[0062] 13 C-NMR (100 MHz, CDCl3) δ: 174.6, 164.5, 159.4, 156.0, 136.4, 134.3,129.6, 126.0, 121.9, 120.2, 117.8, 117.0, 115.0, 88.5, 55.7;

[0063] IR (cm -1 ): 1630, 1609, 1464, 1248, 1223, 1027, 752, 692;

[0064] HR ESI-MS: [C 16 H 12 IO3] + = [M + H] + requires 378.9831; found 378.9815.

[0065] Example 6

[0066] The difference between this embodiment and Example 1 is that the raw material is replaced with the compound shown in Formula If in Table 1, while the rest is the same as in Example 1. The product is the compound 2-(2-chlorophenyl)-3-iodochromene shown in Formula IIf in Table 1: a yellow liquid.

[0067] The products were analyzed using 1H NMR spectroscopy, 1C NMR spectroscopy, infrared spectroscopy, and high-resolution mass spectrometry.

[0068] 1 H NMR (400 MHz, CDCl3) δ: 8.30 (dd, J= 8.4, 1.8 Hz, 1H), 7.75-7.70 (m,1H), 7.57-7.54 (m, 1H), 7.51-7.44 (m, 5H);

[0069] 13 C-NMR (100 MHz, CDCl3) δ: 174.2, 163.5, 156.2, 135.0, 134.4, 133.0,132.0, 130.8, 130.1, 127.1, 126.8, 126.1, 120.4, 117.9, 91.0;

[0070] IR (cm -1 ): 2215, 1642, 1611, 1461, 1328, 1071, 920, 751;

[0071] HR ESI-MS: [C 15 H9ClIO2] + = [M + H] + requires 382.9336; found 382.9308.

[0072] Example 7

[0073] The difference between this embodiment and Example 1 is that the raw material is replaced with the compound shown in Formula Ig in Table 1, while the rest is the same as in Example 1. The product is the compound shown in Formula IIg in Table 1, 3-iodo-2-(naphth-2-yl)chromone: white solid, mp 157℃-158℃.

[0074] The products were analyzed using 1H NMR spectroscopy, 1C NMR spectroscopy, infrared spectroscopy, and high-resolution mass spectrometry.

[0075] 1 H NMR (400 MHz, CDCl3) δ: 8.33-8.30 (m, 2H), 7.99-7.92 (m, 3H), 7.84(dd, J = 8.6, 1.8 Hz, 1H), 7.73 (ddd, J = 8.6, 7.2, 1.8 Hz, 1H), 7.64-7.57 (m,2H), 7.53-7.45 (m, 2H);

[0076] 13C-NMR (100 MHz, CDCl3) δ: 174.6, 164.7, 156.1, 134.3, 132.5, 132.4,130.3, 128.9, 128.2, 128.1, 128.0, 127.1, 126.9, 126.0, 125.9, 120.2, 117.8,88.7;

[0077] IR (cm -1 ): 1609, 1505, 1460, 1323, 1256, 1056, 825, 752, 691;

[0078] HR ESI-MS: [C 19 H 12 IO2] + = [M + H] + requires 398.9882; found 398.9870.

[0079] Example 8

[0080] The difference between this embodiment and Example 1 is that the raw material is replaced with the compound shown in Formula Ih in Table 1, while the rest is the same as in Example 1. The product is the compound shown in Formula IIh in Table 1, 3-iodo-phenylethyl chromone: white solid, mp 91 ℃-92 ℃.

[0081] The products were analyzed using 1H NMR spectroscopy, 1C NMR spectroscopy, infrared spectroscopy, and high-resolution mass spectrometry.

[0082] 1 H NMR (400 MHz, CDCl3) δ: 8.22 (dd, J = 8.2, 1.8 Hz, 1H), 7.68 (ddd, J =8.8, 7.2, 1.8 Hz, 1H), 7.44-7.39 (m, 2H), 7.33-7.21 (m, 5H), 3.35 (t, J = 8 Hz, 2H), 3.10 (t, J = 8 Hz, 2H);

[0083] 13C-NMR (100 MHz, CDCl3) δ: 174.0, 167.9, 155.7, 139.7, 134.0, 128.8,128.5, 126.8, 126.7, 125.8, 120.2, 117.5, 88.9, 40.8, 33.0;

[0084] IR (cm -1 ): 2214, 1644, 1600, 1460, 1357, 981, 751, 683;

[0085] HR ESI-MS: [C 17 H 14 IO2] + = [M + H] + requires 377.0038; found 377.0031.

[0086] Example 9

[0087] The difference between this embodiment and Example 1 is that the raw materials are replaced with compounds shown in Formula Ii in Table 1, while the rest is the same as in Example 1. The product is compound 2-(furan-2-yl)-3-iodochromene shown in Formula IIi in Table 1: a yellow solid, mp 128 ℃-129 ℃.

[0088] The products were analyzed using 1H NMR spectroscopy, 1C NMR spectroscopy, infrared spectroscopy, and high-resolution mass spectrometry.

[0089] 1 H NMR (400 MHz, acetone) δ: 8.13 (ddd, J = 8.0, 2.0, 0.4 Hz, 1H), 8.01(dd, J = 1.6, 0.4 Hz, 1H), 7.86-7.82 (m, 2H), 7.67-7.64 (m, 1H), 7.52 (ddd, J =8.0, 6.8, 0.8 Hz, 1H), 6.83 (dd, J = 3.6, 1.8 Hz, 1H);

[0090] 13C-NMR (100 MHz, acetone) δ: 174.2, 156.2, 154.8, 147.3, 147.2,135.4, 126.9, 126.7, 120.6, 119.2, 118.6, 113.3, 84.2;

[0091] IR (cm -1 ): 1609, 1592, 1517, 1458, 1324, 945, 753, 694;

[0092] HR ESI-MS: [C 13 H8IO3] + = [M + H] + requires 338.9518; found 338.9503.

[0093] Example 10

[0094] The difference between this embodiment and Example 1 is that the raw material is replaced with the compound shown in Formula Ij in Table 1, while the rest is the same as in Example 1. The product is the compound shown in Formula IIj in Table 1: 6-rh-3-iodo-2-phenylchromone: white solid, mp 175℃-176℃.

[0095] The products were analyzed using 1H NMR spectroscopy, 1C NMR spectroscopy, infrared spectroscopy, and high-resolution mass spectrometry.

[0096] 1 H NMR (400 MHz, acetone) δ: 8.09 (d, J = 2.8 Hz, 1H), 7.87-8.83 (m,3H), 7.70 (d, J = 8.8 Hz, 1H), 7.63-7.59 (m, 3H);

[0097] 13 C-NMR (100 MHz, acetone) δ: 173.7, 165.9, 155.4, 136.2, 135.3,131.9, 131.8, 130.4, 129.2, 125.9, 121.7, 121.3, 88.4;

[0098] IR (cm -1 ): 1645, 1603, 1548, 1427, 1309, 1059, 765, 685;

[0099] HR ESI-MS: [C 15 H9ClIO2] + = [M + H] + requires 382.9336; found 382.9329.

[0100] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these modifications and improvements all fall within the scope of protection of the present invention. Therefore, the scope of protection of this patent should be determined by the appended claims.

Claims

1. A method for preparing a 2-alkyl-3-iodochrome ketone compound, characterized in that, The preparation method is as follows: Using the compound shown in formula (I) and the iodinated reagent as starting materials, and a halosilane as a catalyst, a tandem cyclization reaction was carried out in the presence of a solvent, and the post-treatment yielded the 2-alkyl-3-iodochrome ketone compound shown in formula (II). The structure of the above formula (I) is as follows: , , , , , , , , or ; The structure of equation (II) is as follows: , , , , , , , , or ; The iodination reagent is N-iodosuccinimide; the solvent is anhydrous methanol. The post-processing steps are as follows: water is added to the reaction product for quenching, ethyl acetate is extracted at least twice, the organic phases are combined, washed with water and saturated NaHCO3 solution respectively, dried with anhydrous Na2SO4, rotary evaporated under reduced pressure, and the residue is separated and purified by column chromatography to obtain 2-alkyl-3-iodochrome ketone compounds.

2. The method for preparing a 2-alkyl-3-iodochrome ketone compound according to claim 1, characterized in that, The catalyst used is trimethylchlorosilane.

3. The method for preparing a 2-alkyl-3-iodochrome ketone compound according to claim 1, characterized in that, According to the molar ratio, the compound represented by formula (Ⅰ) : iodide reagent = 1:1~2.

5.

4. The method for preparing a 2-alkyl-3-iodochrome ketone compound according to claim 2, characterized in that, According to the molar ratio, the compound represented by formula (Ⅰ) : catalyst = 1:1~2.

5.

5. The method for preparing a 2-alkyl-3-iodochrome ketone compound according to claim 1, characterized in that, The reaction temperature is 0℃~80℃.

6. The method for preparing a 2-alkyl-3-iodochrome ketone compound according to claim 5, characterized in that, The reaction time is 1 hour to 6 hours.

Images