Preparation method of aromatic ketone compound

Abstract

The invention belongs to the technical field of organic synthetic chemistry, and discloses a preparation method of an aromatic ketone compound, which comprises the following steps: by taking an unsaturated carbonyl compound obtained by condensing aryl acetaldehyde / acid and aldehyde / ketone molecules as a precursor, carrying out a reaction on the unsaturated carbonyl compound in the presence of a free radical precursor and molecular oxygen under the conditions of illumination and / or heating to obtain the aromatic ketone compound. And carrying out free radical mediated decarbonylation functionalization reaction in an organic solvent to obtain the aromatic ketone compound. The functional group contained in the free radical precursor is introduced to the alpha position of the ketone compound. By improving reaction participants and a reaction mechanism, the aromatic ketone compounds with various structures can be efficiently and highly selectively constructed in one step, the functionalization of the alpha position of the aromatic ketone compounds is synchronously realized, and the preparation method which is simple and convenient to operate, high in atom economy, green and environment-friendly is provided for the aromatic ketone compounds; the obtained compound is especially applicable to the fields of drug synthesis and synthesis of other materials.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis chemistry, and more specifically, relates to a method for preparing aromatic ketone compounds. Background Technology

[0002] Aromatic ketones are an extremely important class of organic molecular skeletons, widely found in natural products, drug molecules (such as anti-tuberculosis drugs, anti-inflammatory drugs, and antidepressants), pesticides, and various functional materials. The carbonyl group and aromatic ring in their structure make them key intermediates in many chemical transformations. Therefore, developing efficient, atom-economical, and simple methods to construct structurally diverse complex aromatic ketones has always been a research hotspot and challenge in the field of organic synthesis.

[0003] Traditional synthetic methods for aromatic ketones mainly include Friedel-Crafts acylation reactions, addition reactions of organometallic reagents with acyl chlorides / nitriles, and transition metal-catalyzed carbonylation coupling reactions. However, these methods also have some limitations: Friedel-Crafts reactions require the use of stoichiometric Lewis or Brønsted acids to activate the substrate, generating a large amount of waste, and regioselectivity is sometimes difficult to control; organometallic reagents (e.g., Grignard reagents or organolithium metal reagents) are sensitive to water and oxygen, and have poor functional group compatibility; catalytic coupling methods, although effective, often rely on noble metal catalysts (e.g., Pd, Rh, etc.), resulting in high costs. Furthermore, these methods typically have limited ability to achieve α-position functionalization of ketones, requiring additional synthetic steps. Therefore, developing a novel synthetic strategy for aromatic ketones that is mild, economical, requires no noble metal catalysts, and can directly introduce functional groups at the α-position has significant scientific importance and enormous application potential. Summary of the Invention

[0004] To address the aforementioned deficiencies or improvement needs of existing technologies, the present invention aims to provide a method for preparing aromatic ketone compounds. By improving the reaction participants and reaction mechanism, and using unsaturated carbonyl compounds obtained by the condensation of aryl acetaldehyde / acid with aldehyde / ketone molecules as precursors, a variety of aromatic ketone compounds can be constructed in one step with high efficiency and selectivity, while simultaneously achieving α-position functionalization. This provides a simple, atom-economical, and environmentally friendly preparation method for aromatic ketone compounds, and the resulting compounds are particularly applicable to drug synthesis and other material synthesis fields.

[0005] To achieve the above objectives, according to the present invention, a method for preparing aromatic ketone compounds is provided, characterized in that an unsaturated carbonyl compound is used as a precursor, and a radical-mediated decarbonylation functionalization reaction is carried out in an organic solvent under the conditions of light and / or heating in the presence of a free radical precursor and molecular oxygen to obtain an aromatic ketone compound; the functional group contained in the free radical precursor is introduced into the α-position of the ketone compound; The unsaturated carbonyl compound has the chemical structure of the condensation product obtained by condensing aryl acetaldehyde and aldehyde compounds. Alternatively, the unsaturated carbonyl compound has the chemical structure of the condensation product obtained by condensing aryl acetaldehyde with a ketone compound; Alternatively, the unsaturated carbonyl compound has the chemical structure of the condensation product obtained by condensing arylacetic acid with an aldehyde compound; Alternatively, the unsaturated carbonyl compound has the chemical structure of a condensation product obtained by condensing arylacetic acid with a ketone compound.

[0006] As a further preferred embodiment of the present invention, the synthetic route is as follows:

[0007] in, R1 is aryl; R2 is any one of a hydrogen atom, an aryl group, or a C1 to C10 alkyl group; R3 is any one of a hydrogen atom, an aryl group, or a C1 to C10 alkyl group; R4 is any one of an aryl group or a C1 to C10 alkyl group or a chlorine atom or a bromine atom, derived from the radical precursor.

[0008] As a further preferred embodiment of the present invention, the free radical precursor is one of the following: chlorosuccinimide (NCS), bromosuccinimide (NBS), N-hydroxyphthalimide ester (NHPI ester), arylhydrazine compound (Ar-NHNH2), arylboronic acid (Ar-B(OH)2), organobismuth reagent, copper salt, iron salt, and bismuth salt. Wherein, the organic bismuth reagent is triarylbismuth or dichlorotriarylbismuth; the copper salt is CuBr2 or CuCl2; the iron salt is FeBr3 or FeCl3; and the bismuth salt is BiBr3 or BiCl3.

[0009] As a further preferred embodiment of the present invention, the organic solvent is one of dichloromethane (DCM), acetonitrile (MeCN), or 1,2-dichloroethane (DCE).

[0010] As a further preferred embodiment of the present invention, the molar ratio of the unsaturated carbonyl compound to the free radical precursor is 1:1 to 1:2.5.

[0011] As a further preferred embodiment of the present invention, the molecular oxygen is derived from air; Preferably, it is introduced by reacting in an air atmosphere; More preferably, it is introduced by reacting in an open container under an air atmosphere.

[0012] As a further preferred embodiment of the present invention, the reaction temperature is 25–90°C.

[0013] Compared with the prior art, the present invention, through the above-described technical solution, uses unsaturated carbonyl compounds as raw materials and utilizes the synergistic effect of free radical precursors and molecular oxygen to achieve the breaking and formation of multiple bonds, thereby realizing the process from simple raw material substrates (such as, formula...). The unsaturated carbonyl compounds shown (radical precursors containing R4 groups) efficiently constructed complex aromatic ketone structures (e.g., As shown; R4 can be an aromatic group in particular. The core of this invention lies in using unsaturated carbonyl compounds as substrates and achieving in-situ decarbonylation functionalization in a system through the cooperative reaction of free radical species with molecular oxygen.

[0014] This invention utilizes a radical-mediated decarbonylation functionalization strategy to efficiently and selectively synthesize aromatic ketones (especially polysubstituted aromatic ketones) from readily available unsaturated carbonyl precursors. The core of the strategy lies in a tandem process of "radical addition-decarbonylation-ketogenesis," guided by the unsaturated aldehyde / acid structure in the precursor molecule. In the presence of a radical initiator and molecular oxygen (O2, from air or oxygen), a radical-mediated decarbonylation functionalization reaction occurs in an organic solvent. This allows for the breaking of the critical C-C bond and the construction of new C-C, C-Br, or C-Cl bonds under mild conditions (the C in the newly formed C-C, the Br in the C-Br, and the Cl in the C-Cl correspond to the functional groups contained in the radical precursor). In this invention, a catalyst is optional, and even if a catalyst is used, a noble metal catalyst is not required.

[0015] The reaction mechanism of the method of this invention is presumably as follows: A free radical initiator undergoes homolytic cleavage under light or heat to generate free radicals. These free radicals selectively add to the double bond of an unsaturated aldehyde / acid, generating an alkyl free radical intermediate. This highly reactive intermediate is rapidly captured by molecular oxygen (O2), generating a peroxide free radical. Following a series of rapid free radical processes (such as H atom extraction), it promotes the removal of a CO / CO2 molecule, ultimately converting to the target ketone molecule with high selectivity. Furthermore, it successfully introduces the initial free radical source moiety into the α-position of the ketone, achieving highly efficient tandem functionalization.

[0016] In addition, the molecular oxygen (O2) in this invention can come from air or oxygen, and the preparation method of this invention can be carried out in an open container or in an air balloon atmosphere, which is extremely simple to operate.

[0017] In summary, the method of this invention has the advantages of high atom economy, simple steps, wide substrate applicability, good functional group compatibility, mild reaction conditions, and no need for precious metal catalysts. It provides a green and economical synthetic route for aromatic ketones (especially polysubstituted aromatic ketones) that are difficult to synthesize by traditional methods. Detailed Implementation

[0018] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention. Furthermore, the technical features involved in the various embodiments of this invention described below can be combined with each other as long as they do not conflict with each other.

[0019] All raw materials used in the following examples, unless otherwise specified, were commercially purchased; all reactions were carried out in air.

[0020] In the examples described below, the target product was separated from the system after the reaction using a common post-processing method, as follows: After the reaction, the solvent was removed by direct concentration under reduced pressure. The crude product was then purified by silica gel column chromatography (using petroleum ether / ethyl acetate as eluent) to obtain the target ketone compound.

[0021] The following are specific examples: Example 1: Preparation of 2-phenylbutyroylbenzene (all raw materials are commercially available)

[0022] In a 20 mL reaction tube equipped with a magnetic stirrer, 160 mg of 2-phenyl-2-pentenal and 440 mg of triphenylbismuth were dissolved in 5 mL of dichloromethane (DCM). The reaction mixture was irradiated with light and stirred at room temperature for 12 hours. After the reaction was complete, it was post-processed according to standard methods. The product was purified by column chromatography (petroleum ether:ethyl acetate, volume ratio 50:1) to give 157 mg of the white solid target product, 2-phenylbutyrylbenzene (yield 70%). This product is a synthetic intermediate for the known important drug, the selective estrogen receptor modulator Tamoxifen.

[0023] Example 1 above demonstrates the successful and efficient synthesis of 2-phenylbutyrylbenzene without the use of a catalyst.

[0024] Comparative Example 1: Preparation of 2-Phenylacetoylbenzene The route reported in recent years (Branched-selective hydroacylation of alkenes via photoredox cobalt and N-heterocyclic carbene cooperative triple catalysis). ACS Catalysis 2022, 12 (24), 15241–15248.) Using β-methylstyrene and excess benzoyl fluoride as raw materials, 2-phenylbutyrylbenzene was obtained under the triple catalysis of cobalt catalyst, iridium catalyst, and nitrogen heterocyclic carbene reagent, with a yield of 33%. This route uses expensive metal iridium and a complex catalytic system to obtain the target molecule, while the route of this invention avoids the use of precious metal reagents, is simple to operate, and has obvious advantages.

[0025] Comparative Example 2: The experimental method of this comparative example is similar to that of Example 1, except that the comparative example 2 is carried out under a nitrogen atmosphere, and the yield of the target product 2-phenylbutyrylbenzene is 0%.

[0026] Examples 2–4 The steps in Examples 2–4 are largely the same as in Example 1, the only difference being the type of free radical precursor reagent added. The specific setups and yields of 2-phenylbutyrylbenzene obtained in each example are shown in the table below:

[0027] Taking Example 2 as an example, the organic bismuth reagent used in this invention is stable in air and is not sensitive to water and oxygen.

[0028] Example 5: Preparation of 2-(4-methoxyphenyl)-1-phenylethane-1-one

[0029] In a 20 mL reaction tube equipped with a magnetic stirrer, add 2-phenylacrylic acid (150 mg, 1.0 mmol) and tris(4-methoxyphenyl)bismuth (510 mg, 1.0 mmol) (refer to...). The Journal of Organic Chemistry 2016, 81(13), prepared according to the experimental procedures in document 5401-5416), dissolved in 5 mL acetonitrile (MeCN). The reaction mixture was irradiated with light and stirred at room temperature for 12 hours. After the reaction was completed, it was post-processed according to general methods. Purified by column chromatography (petroleum ether:ethyl acetate volume ratio 50:1) to give 147 mg of the white solid target product 2-(4-methoxyphenyl)-1-phenylethane-1-one (yield 65%). This product is a commercially available fine chemical with a price of thousands of yuan per gram, which has certain economic benefits.

[0030] Comparative Example 3: Preparation of 2-(4-methoxyphenyl)-1-phenylethane-1-one Recent reports have highlighted work on the topic of "Copper-catalyzed base-accelerated direct oxidation of C–H bond to synthesize benzils, isatins, and quinoxalines with molecular oxygen as terminal oxidant." Tetrahedron Letters 2015, 56 (12), 1575–1580.) Using p-methoxyphenylacetic acid and benzene as raw materials, 2-(4-methoxyphenyl)-1-phenylethane-1-one was obtained in the presence of excess aluminum trichloride catalyst and the toxic reagent thionyl chloride, with a yield of only 25%. This route uses the conventional Friedel-Crafts acylation reaction to prepare aromatic ketones, which requires the use of stoichiometric Lewis activated substrates. In contrast, the route of this invention avoids the use of excessive acidic auxiliaries that generate waste and achieves a much higher product selectivity, far exceeding 25%, demonstrating significant advantages.

[0031] Example 6: Preparation of (1-bromocyclopentyl)(2-chlorophenyl) methyl ketone

[0032] In a 20 mL reaction tube equipped with a magnetic stirrer, add 2-(2-chlorophenyl)-2-cyclopentylmethyleneacetic acid (236 mg, 1.0 mmol) (refer to...). Organic Letters 2013, 15Bismuth tribromide (446 mg, 1.0 mmol) was prepared by the method reported in (14), 3722–3725, dissolved in 5 mL acetonitrile (MeCN). The reaction mixture was irradiated with light and stirred at room temperature for 20 hours. After the reaction was completed, it was post-processed according to general methods. The product was purified by column chromatography (petroleum ether:ethyl acetate volume ratio of 40:1) to give 212 mg of the white solid target product (1-bromocyclopentyl)(2-chlorophenyl) ketone (yield 74%). This product is an intermediate of the known important drug ketamine. The known route requires the preparation of a cyclopentyl Grignard reagent using magnesium powder, followed by reaction with o-chlorobenzonitrile, and then refluxing the resulting product with 2.5 equivalents of copper bromide to obtain the target molecule (CN112521295 A). The method used in this invention is simpler to operate than the known synthetic route and avoids the generation of excessive copper salt waste, which has obvious advantages.

[0033] The above embodiments are merely examples. For instance, the unsaturated carbonyl compound precursor can also be an arylacetaldehyde or a condensation product of arylacetic acid and an aldehyde or ketone compound. Furthermore, the reaction time can be flexibly adjusted; for example, the completion of the reaction can be monitored using TLC. Additionally, in this invention, the aromatic group can also be an aromatic heterocycle such as furan or pyrrole (since the properties of aromatic substituents are similar, different aromatic groups will not affect the preparation method of this invention).

[0034] Those skilled in the art will readily understand that the above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for preparing aromatic ketone compounds, characterized in that, Using an unsaturated carbonyl compound as a precursor, an aromatic ketone compound is obtained by undergoing a radical-mediated decarbonylation functionalization reaction in an organic solvent under the presence of a free radical precursor and molecular oxygen, and under light and / or heating conditions; the functional group contained in the free radical precursor is introduced into the α-position of the ketone compound. The unsaturated carbonyl compound has the chemical structure of the condensation product obtained by condensing aryl acetaldehyde and aldehyde compounds. Alternatively, the unsaturated carbonyl compound has the chemical structure of the condensation product obtained by condensing aryl acetaldehyde with a ketone compound; Alternatively, the unsaturated carbonyl compound has the chemical structure of the condensation product obtained by condensing arylacetic acid with an aldehyde compound; Alternatively, the unsaturated carbonyl compound has the chemical structure of a condensation product obtained by condensing arylacetic acid with a ketone compound.

2. The preparation method according to claim 1, characterized in that, The synthesis route is as follows: in, R1 is aryl; R2 is any one of a hydrogen atom, an aryl group, or a C1 to C10 alkyl group; R3 is any one of a hydrogen atom, an aryl group, or a C1 to C10 alkyl group; R4 is any one of an aryl group or a C1 to C10 alkyl group or a chlorine atom or a bromine atom, derived from the radical precursor.

3. The preparation method according to claim 1, characterized in that, The free radical precursor is one of the following: chlorosuccinimide (NCS), bromosuccinimide (NBS), N-hydroxyphthalimide ester (NHPI ester), arylhydrazine compound (Ar-NHNH2), arylboronic acid (Ar-B(OH)2), organobismuth reagent, copper salt, iron salt, and bismuth salt. Wherein, the organic bismuth reagent is triarylbismuth or dichlorotriarylbismuth; the copper salt is CuBr2 or CuCl2; the iron salt is FeBr3 or FeCl3; and the bismuth salt is BiBr3 or BiCl3.

4. The preparation method according to claim 1, characterized in that, The organic solvent is one of dichloromethane (DCM), acetonitrile (MeCN), or 1,2-dichloroethane (DCE).

5. The preparation method according to claim 1, characterized in that, The molar ratio of the unsaturated carbonyl compound to the free radical precursor is 1:1 to 1:2.

5.

6. The preparation method according to claim 1, characterized in that, The molecular oxygen comes from the air; Preferably, it is introduced by reacting in an air atmosphere; More preferably, it is introduced by reacting in an open container under an air atmosphere.

7. The preparation method according to claim 1, characterized in that, The reaction temperature is 25–90°C.

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