A method for synthesizing 6H-benzo[c]chromen-6-one

Abstract

The present invention proposes a method for synthesizing 6H-benzo[c]chromen-6-one, which belongs to the field of organic synthesis technology. Benzoic acid and iodobenzene are reacted to prepare 6H-benzo[c]chromen-6-one. The present invention starts from benzoic acid, first undergoes an arylation reaction with iodobenzene, and after obtaining the important reaction intermediate 2-arylbenzoic acid, continues to undergo an intramolecular cyclization reaction. A catalyst, an oxidant, an additive, and a solvent are added to a reactor, and the reaction is started. After the reaction is completed, the target product is purified by column chromatography or recrystallization to obtain the target product. Compared with the prior art, the present invention has the advantages of simple reaction operation, short steps, and low cost.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to a method for synthesizing 6H-benzo[c]chromen-6-one. Background Art

[0002] 6H-benzo[c]chromen-6-one compounds are widely found in natural products and pharmaceutical molecules. Among oxygen-containing fused heterocyclic compounds, 6H-benzo[c]chromen-6-one compounds have attracted increasing attention in organic synthesis and medicinal chemistry due to their excellent antibacterial and antitumor effects. Numerous methods for synthesizing 6H-benzo[c]chromen-6-one compounds have been reported. However, existing synthetic methods are often limited by difficult substrate preparation, harsh reaction conditions, and lengthy reaction steps.

[0003] Shi Zhangjie's research group (Org. Lett. 2017, 19, 1326-1329) successfully synthesized 6H-benzo[c]chromen-6-one using benzoic acid and phenol as reactants. However, the high reaction temperature and long reaction time seriously hampered the application prospects of this reaction.

[0004] Mahiuddin Baidya's group (ACS Catal. 2018, 8, 10173-10179) successfully achieved a self-coupling reaction of benzoic acid using [Ru(p-cymene)Cl₂]₂ as a catalyst, copper oxide as an oxidant, DBU as an additive, and 1,4-dioxane as a solvent. This synthetic route, with its lengthy reaction steps, limited the scale-up of 6H-benzo[c]chromen-6-one.

[0005] Therefore, it is very necessary and of great significance to develop a greener, more environmentally friendly and efficient synthesis method of 6H-benzo[c]chromen-6-one compounds. Summary of the Invention

[0006] The purpose of the present invention is to provide a method for synthesizing 6H-benzo[c]chromen-6-one, which has the advantages of simple reaction operation, short steps and low cost compared with the prior art.

[0007] The technical solution of the present invention is achieved as follows:

[0008] The invention provides a method for synthesizing 6H-benzo[c]chromen-6-one. Benzoic acid and iodobenzene are reacted to prepare 6H-benzo[c]chromen-6-one.

[0009] As a further improvement of the present invention, a catalyst, an oxidant, an additive, an acid, and a solvent are further added.

[0010] As a further improvement of the present invention, the catalyst is palladium acetate.

[0011] As a further improvement of the present invention, the oxidant is silver oxide.

[0012] As a further improvement of the present invention, the additive is N-acetyl-L-isoleucine.

[0013] As a further improvement of the present invention, the acid is trifluoromethanesulfonic acid.

[0014] As a further improvement of the present invention, the solvent is hexafluoroisopropanol.

[0015] As a further improvement of the present invention, the reaction temperature is 75-85° C. and the reaction time is 6-24 h.

[0016] As a further improvement of the present invention, the molar ratio of benzoic acid to iodobenzene is 1:1-1:3.

[0017] As a further improvement of the present invention, the molar ratio of benzoic acid to iodobenzene is 1:1.5.

[0018] The present invention has the following beneficial effects:

[0019] The present invention starts with benzoic acid, first undergoes an arylization reaction with iodobenzene, and after obtaining an important reaction intermediate 2-arylbenzoic acid, continues to undergo an intramolecular cyclization reaction. A catalyst, an oxidant, an additive, and a solvent are added to a reactor to start the reaction. After the reaction is completed, the target product is purified by column chromatography or recrystallization to obtain the target product. Compared with the existing technology, the present invention has the advantages of simple reaction operation, short steps, and low cost. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the embodiments or the description of the prior art. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0021] Figure 1 This is the hydrogen spectrum of 6H-benzo[c]chromen-6-one prepared in Example 1 of the present invention;

[0022] Figure 2 This is the carbon spectrum of 6H-benzo[c]chromen-6-one prepared in Example 1 of the present invention;

[0023] Figure 3 This is the infrared spectrum of 6H-benzo[c]chromen-6-one prepared in Example 1 of the present invention. DETAILED DESCRIPTION

[0024] The following is a clear and complete description of the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making any creative efforts are within the scope of protection of the present invention.

[0025] Drug sources: Hexafluoroisopropanol was purchased from Bidex Pharmaceuticals, silver oxide was purchased from Roan Reagents, iodobenzene and trifluoromethanesulfonic acid were purchased from Anage Chemical Reagents.

[0026] Example 1

[0027] This embodiment provides a method for synthesizing 6H-benzo[c]chromen-6-one, comprising the following steps:

[0028] Synthesis route:

[0029]

[0030] Preparation method:

[0031] Benzoic acid (0.2 mol, 24.0 g) and iodobenzene (0.2 mol, 40.8 g) were charged into a reactor in a molar ratio of 1:1. Palladium acetate (0.02 mol, 4.49 g), silver oxide (0.4 mol, 92.7 g), N-acetyl-L-isoleucine (0.02 mol, 3.46 g), trifluoromethanesulfonic acid (0.4 mol, 60 g), and 100 mL of hexafluoroisopropanol were added. The temperature was raised to 80°C under a nitrogen atmosphere and the reaction was carried out for 6 hours. The reaction was quenched by water, and the organic phase was separated, concentrated under reduced pressure, and separated by column chromatography to obtain 23.5 g of the product 6H-benzo[c]chromen-6-one in a yield of 60% with a melting point of 88-89°C.

[0032] like Figure 1 , 1 H NMR (400 MHz, Chloroform- d ) δ 8.38 (d, J = 8.0 Hz, 1H), 8.09(d, J = 8.0 Hz, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.80 (t, J = 8.0 Hz, 1H), 7.56(t, J = 8.0 Hz, 1H), 7.46 (t,J = 8.0 Hz, 1H), 7.35-7.30 (m, 2H) ppm.

[0033] like Figure 2 , 13 C NMR (101 MHz, Chloroform- d ) δ 161.29, 151.38, 134.93,134.85, 130.65, 130.53, 128.97, 124.66, 122.86, 121.78, 121.34, 118.13,117.86 ppm.

[0034] like Figure 3 , IR (ν max / cm -1 ): 3459, 2906, 2856, 2767, 1660, 1396, 792.

[0035] Example 2

[0036] This embodiment provides a method for synthesizing 6H-benzo[c]chromen-6-one, comprising the following steps:

[0037] Benzoic acid (0.2 mol, 24 g) and iodobenzene (0.6 mol, 122.4 g) were charged into a reactor at a molar ratio of 1:3. Palladium acetate (0.02 mol, 4.49 g), silver oxide (0.4 mol, 92.7 g), N-acetyl-L-isoleucine (0.02 mol, 3.46 g), trifluoromethanesulfonic acid (0.4 mol, 60 g), and 100 mL of hexafluoroisopropanol were added. The temperature was raised to 80°C under a nitrogen atmosphere and the reaction was carried out for 24 hours. The reaction was quenched by water, and the organic phase was separated, concentrated under reduced pressure, and separated by column chromatography to obtain 21.5 g of the product, 6H-benzo[c]chromen-6-one, in a yield of 55%.

[0038] Example 3

[0039] This embodiment provides a method for synthesizing 6H-benzo[c]chromen-6-one, comprising the following steps:

[0040] Benzoic acid (0.2 mol, 24.0 g) and iodobenzene (0.4 mol, 81.6 g) were charged into a reactor at a molar ratio of 1:2. Palladium acetate (0.02 mol, 4.6 g), silver oxide (0.4 mol, 92.7 g), N-acetyl-L-isoleucine (0.02 mol, 3.46 g), trifluoromethanesulfonic acid (0.4 mol, 60 g), and 100 mL of hexafluoroisopropanol were added. The temperature was raised to 80°C under a nitrogen atmosphere and the reaction was carried out for 12 hours. The reaction was quenched by water, and the organic phase was separated, concentrated under reduced pressure, and separated by column chromatography to obtain 20.8 g of the product, 6H-benzo[c]chromen-6-one, in a yield of 53%.

[0041] Comparative Example 1

[0042] Reference: Org. Lett. 2017, 19, 1326-1329.

[0043]

[0044] Shi Zhangjie's research group successfully synthesized 6H-benzo[c]chromen-6-one using benzoic acid and phenol as reactants. The reaction used palladium acetate as a catalyst, copper acetate as an oxidant, lithium phosphate as an additive, and a mixed solvent of tert-butylbenzene and 1,4-dioxane. The reaction was carried out at 140°C for 24 hours, successfully completing the synthesis of 6H-benzo[c]chromen-6-one. However, the high reaction temperature and long reaction time severely limited the potential for future applications.

[0045] Comparative Example 2

[0046] Reference: ACS Catal. 2018, 8, 10173-10179.

[0047]

[0048] Starting with benzoic acid, Mahiuddin Baidya's research group successfully achieved a self-coupling reaction using [Ru(p-cymene)Cl2]2 as a catalyst, copper oxide as an oxidant, DBU as an additive, and 1,4-dioxane as a reaction solvent. Esterification of this reaction yielded dimethyl [1,1'-biphenyl]-2,2'-dicarboxylate in a 58% yield. After hydrolysis and subsequent reaction under a silver nitrate catalyst for 36 hours, 6H-benzo[c]chromen-6-one was obtained in a 90% yield. This synthetic route, however, suffers from lengthy reaction steps, which limits its scalable production.

[0049] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A method for synthesizing 6H-benzo[c]chromen-6-one, characterized in that: Benzoic acid and iodobenzene are reacted to prepare 6H-benzo[c]chromen-6-one; the molar ratio of benzoic acid to iodobenzene is 1:1-1:3; the reaction temperature is 75-85°C and the reaction time is 6-24 hours; a catalyst, an oxidant, an additive, an acid, and a solvent are also added, wherein the catalyst is palladium acetate, the oxidant is silver oxide, the additive is N-acetyl-L-isoleucine, the acid is trifluoromethanesulfonic acid, and the solvent is hexafluoroisopropanol.

2. The synthesis method according to claim 1, characterized in that The molar ratio of the benzoic acid to iodobenzene is 1:1.5.

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