Carbonyl compound and preparation method thereof

Abstract

The invention discloses a carbonyl compound and a preparation method thereof. According to the method, a malonic acid derivative is used as a substrate, and ferric nitrate nonahydrate is used as a catalyst to carry out photocatalytic decarboxylation oxidation reaction in an air atmosphere and under visible light irradiation. And after the reaction is finished, separating and purifying to obtain the target carbonyl compound. The method has the advantages of green and mild reaction conditions, simple operation, easily available reagents, low cost, and good functional group compatibility and substrate applicability. The method has potential application value in the fields of organic synthesis, pharmaceutical chemistry, bioactive molecule modification and the like.

Description

Technical Field

[0001] This invention belongs to the field of organic chemical synthesis technology, specifically relating to a method for preparing carbonyl compounds. The method uses inexpensive ferric nitrate as a catalyst and air as a green oxidant, and efficiently constructs carbonyl compounds through a free radical decarboxylation oxidation reaction of malonic acid derivatives under visible light. Background Technology

[0002] Carbonyl compounds are core functional groups that are widely used and crucial in organic synthesis. Their importance is reflected in three aspects: structurally, they are widely found in natural products, synthetic intermediates, and fine chemicals; reactively, they often serve as core substrates in various important transformations, efficiently derivatizing into alcohols, amines, alkenes, esters, amides, and other functional groups, providing a universal and crucial pathway for synthetic route design and functional molecule construction. The preparation methods for carbonyl compounds are relatively mature, mainly including the following classic pathways: oxidation of alcohols or alkenes, hydration of alkynes, Friedel-Crafts acylation of aromatic compounds, hydrolysis following reaction of nitriles with Grignard reagents, reaction of Weinreb amides with nucleophiles, and the transformation of carboxylic esters under the catalysis of organolithium reagents or transition metals such as palladium / nickel.

[0003] Carboxylic acids are a class of widely available, structurally diverse, stable, and relatively inexpensive compounds. Their carboxyl functional groups are commonly found in natural products and various drug molecules, making them important raw materials in organic synthesis. Although their derivatives (such as esters and amides) are frequently used to prepare carbonyl compounds, methods for directly converting carboxylic acids into carbonyl compounds have only recently made progress. Currently, there are four main pathways for this conversion: 1) using stoichiometric strong oxidants; 2) oxygen-involved metal-catalyzed oxidation; 3) oxygen-involved photo-redox catalysis; and 4) electrochemical decarboxylation oxidation.

[0004] Compared to monocarboxylic acids, malonic acid derivatives are also a class of classic organic synthesis raw materials with high stability and easy availability. Although the decarboxylation oxidation of monocarboxylic acids has become a research hotspot, there are still relatively few studies on the decarboxylation oxidation of malonic acid to the corresponding ketones. Using malonic acid derivatives as starting materials, free radical decarboxylation oxidation can occur in the presence of stoichiometric lead acetate to yield the corresponding carbonyl compounds (Tetrahedron Lett. 1966, 7, 6145); malonic acid derivatives can also be electrolyzed in ammonia-methanol solution and then hydrolyzed to obtain the corresponding carbonyl compounds (Org. Lett. 2015, 17, 4690).

[0005] Reports on the decarboxylation oxidation of malonic acid are relatively few, and most of them have some drawbacks, such as requiring the use of stoichiometric amounts of highly toxic lead acetate, or the use of electrochemical methods. Compared with the former, the electrochemical strategy is a greener method for converting malonic acid derivatives into carbonyl compounds, but its substrate is limited, only applicable to disubstituted malonic acid derivatives. In general, the reaction for preparing carbonyl compounds through the decarboxylation oxidation of malonic acid is still imperfect and requires further exploration and development. Considering the wide range of applications of carbonyl compounds in organic synthesis, medicinal chemistry, and industry, this invention proposes a method for synthesizing carbonyl compounds through the decarboxylation oxidation reaction of malonic acid radicals, using air as an oxidant and readily available inexpensive ferric iron as a catalyst, providing a greener and more efficient new route for the preparation of such compounds. Summary of the Invention

[0006] One object of this invention is to provide a method for preparing carbonyl compounds. This method aims to overcome the shortcomings of existing technologies by utilizing an iron-mediated ligand-to-metal charge transfer strategy under photocatalytic conditions to achieve radical decarboxylation oxidation of malonic acid derivatives, thereby efficiently and greenly synthesizing the target carbonyl compounds.

[0007] Another object of the present invention is to provide the application of the above method in the preparation of carbonyl compounds containing complex drug molecule fragments, to demonstrate its potential in late-stage functionalization and drug derivatization synthesis.

[0008] This invention is achieved by providing a carbonyl compound, the chemical structural formula of which is shown in the following structural formula (I):

[0009]

[0010] In equation (I), R 1 and R 2 Each is independently selected from hydrogen, C1-C6 alkyl, substituted or unsubstituted benzyl, substituted or unsubstituted phenethyl, C2-C10 hydrocarbon containing ester, ether, carbonyl, carbon-carbon double or triple bonds, or molecular fragments derived from estrone or dehydrocholic acid; or, R 1 and R 2 Together with the carbon atoms they are attached to, they form cyclobutane rings, pyran rings, benzo[a] five-membered heterocycles, or N-benzoylpiperidine rings.

[0011] The present invention further discloses a method for preparing the above-mentioned carbonyl compounds, the method comprising the following steps: (1) in an atmosphere containing oxygen, dissolving the malonic acid derivative of formula (II) and an iron catalyst in an organic solvent to form a reaction mixture; wherein the molar ratio of the iron catalyst to the malonic acid derivative of formula (II) is 0.02-0.2:1;

[0012] (2) Place the reaction mixture obtained in step (1) under blue light irradiation with a wavelength of 395-480nm and a power of 5-30W, and stir the reaction at a temperature of 30-60℃ for 6-24 hours to carry out photocatalytic decarboxylation oxidation;

[0013] (3) After the reaction is completed, the reaction system is quenched, extracted, dried and concentrated to obtain the carbonyl compound shown in formula (I).

[0014] Equation (II) is: Among them, R 1 and R 2 The definition is the same as in equation (I).

[0015] In step (1), the iron catalyst is selected from at least one of ferric nitrate nonahydrate, anhydrous ferric sulfate, ferric acetylacetone, ferric trifluoromethanesulfonate, and ferrous sulfate heptahydrate, preferably ferric nitrate nonahydrate;

[0016] In step (1), the organic solvent is selected from at least one of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, and acetonitrile, preferably N,N-dimethylformamide;

[0017] In step (1), the oxygen-containing atmosphere includes oxygen and air, preferably air at 1 atm;

[0018] In step (2), the light source is 5-30W, 395-480nm, preferably 5W, 460nm;

[0019] In step (2), the reaction temperature is 30-60℃, preferably 30℃;

[0020] In step (2), the reaction time is 6-24 hours, preferably 12 hours.

[0021] In this invention, starting from the need for simple and structurally diverse preparation of malonic acid derivatives, using ferric iron as a catalyst and air as an oxidant, and employing an iron-mediated ligand-to-metal charge transfer strategy, the oxidative decarboxylation reaction of malonic acid radicals was achieved, enabling the convenient and rapid preparation of important carbonyl compounds. The reaction equation is shown below:

[0022]

[0023] Compared with the shortcomings and deficiencies of existing technologies, the present invention has the following advantages:

[0024] (1) The present invention uses inexpensive and readily available ferric nitrate nonahydrate as a catalyst and air as a green oxidant. It can react efficiently under mild visible light driving conditions, avoiding the use of stoichiometric toxic metal reagents or harsh conditions. It is easy to operate and has good potential for process scale-up.

[0025] (2) The substrates of the present invention have a wide range of applications and good functional group compatibility. They can be applied to mono- and di-substituted malonic acid derivatives and can be successfully applied to the late decarboxylation and oxidation modification of malonic acid derived from drug molecules or natural products, providing a practical tool for the structural derivatization of active molecules. Attached Figure Description

[0026] Figure 1 This is the proton spectrum of compound 1 in Example 1 of this invention;

[0027] Figure 2 This is the carbon spectrum of compound 1 in Example 1 of the present invention;

[0028] Figure 3 This is the proton spectrum of the compound in Example 12 of this invention;

[0029] Figure 4 This is the carbon spectrum of the compound in Example 12 of this invention;

[0030] Figure 5 This is the proton spectrum of the compound in Example 13 of this invention;

[0031] Figure 6 This is the carbon spectrum of the compound in Example 13 of this invention. Detailed Implementation

[0032] 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 and accompanying drawings. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0033] Example 1

[0034] (1) Under an air atmosphere, 2-(4-chlorophenylethyl)-2-ethylmalonic acid and ferric nitrate nonahydrate were weighed in a molar ratio of 1:0.05, and then the reaction solvent N,N-dimethylformamide was added to obtain a mixture.

[0035] (2) The mixture obtained in step (1) was irradiated with 5W, 460nm blue light and stirred at 30℃ for 12h under an air atmosphere of 1 atm. The reaction system was cooled, the reaction was quenched with water, and the crude product was obtained by extraction with ethyl acetate, drying and rotary evaporation under reduced pressure to remove the low-boiling solvent. The crude product can be purified by silica gel column chromatography or preparative plate chromatography to obtain the expected carbonyl compound with a yield of 90%. Its structural formula is shown in the figure below:

[0036]

[0037] Example 2-10

[0038] Examples 2-10 are basically the same as Example 1, except for the substituent R of malonic acid. 1 and R 2 The structures of the various malonic acid derivatives and their corresponding synthetic compounds are detailed in the table below:

[0039] Table 1 Examples 2-10

[0040]

[0041]

[0042] Examples 11-13

[0043] Examples 11-13 are basically the same as Example 1, except for the substituent R of malonic acid. 1 As a drug molecule derivative, the structure of malonic acid and the structures of its corresponding synthetic compounds are detailed in the table below:

[0044] Table 2 Examples 11-13

[0045]

[0046] Example 14

[0047] This embodiment is essentially the same as Example 1, except that the reaction scale was increased from 0.1 mmol to 3.7 mmol, and the ketone was directly isolated. The yield of the scaled-up reaction was essentially the same as that of the 0.1 mmol small-scale reaction. This further demonstrates the excellent practicality of the preparation method of the present invention.

[0048] The reaction equations involved in the embodiments of the present invention are as follows:

[0049]

[0050] 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 or improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for preparing a carbonyl compound, characterized in that, The carbonyl compounds have the structure shown in formula (I): In equation (I), R 1 and R 2 Each is independently selected from hydrogen, C1-C6 alkyl, substituted or unsubstituted benzyl, substituted or unsubstituted phenethyl, C2-C10 hydrocarbon containing ester, ether, carbonyl, carbon-carbon double or triple bonds, or molecular fragments derived from estrone or dehydrocholic acid; or, R 1 and R 2 Together with the carbon atoms they are attached to, they form cyclobutane rings, pyran rings, benzo[5]-membered heterocycles, or N-benzoylpiperidine rings; The preparation method includes the following steps: (1) In an atmosphere containing oxygen, the malonic acid derivative of formula (II) and the iron catalyst are dissolved in an organic solvent to form a reaction mixture; wherein the molar ratio of the iron catalyst to the malonic acid derivative of formula (II) is 0.02-0.2:1; (2) Place the reaction mixture obtained in step (1) under blue light irradiation with a wavelength of 395-480nm and a power of 5-30W, and stir the reaction at a temperature of 30-60℃ for 6-24 hours to carry out photocatalytic decarboxylation oxidation; (3) After the reaction is completed, the reaction system is quenched, extracted, dried and concentrated to obtain the carbonyl compound shown in formula (I). Equation (II) is: Among them, R 1 and R 2 The definition is the same as in equation (I).

2. The preparation method according to claim 1, characterized in that, The iron catalyst is selected from at least one of ferric nitrate nonahydrate, anhydrous ferric sulfate, ferric acetylacetone, ferric trifluoromethanesulfonate, and ferrous sulfate heptahydrate.

3. The preparation method according to claim 1, characterized in that, The organic solvent is selected from at least one of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, and acetonitrile.

4. The preparation method according to claim 1, characterized in that, The oxygen-containing atmosphere is an oxygen atmosphere or an air atmosphere.

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