Method for synthesizing organic gem-peroxy alcohol by catalyzing aldehyde ketone compound through stannous benzoate

Abstract

The invention discloses a method for synthesizing organic gem-peroxy alcohol by catalyzing an aldehyde ketone compound through stannous benzoate, and belongs to the technical field of organic synthesis. The method comprises the following steps: fully mixing an aldehyde ketone compound, a hydrogen peroxide aqueous solution and an organic solvent, and adding a catalyst stannous benzoate for reaction; and extracting, drying, filtering and purifying the obtained product to obtain the organic gem-peroxy alcohol. Compared with the prior art, the synthesis method disclosed by the invention is relatively mild in reaction condition, high in reaction rate, high in yield, wide in applicable substrate and relatively pure in product, and meanwhile, stannous benzoate is relatively easy to prepare, is non-corrosive and is suitable for reaction equipment made of various materials.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for synthesizing an organic geminal peroxy alcohol using stannous benzoate as a catalyst for aldehyde and ketone compounds. Background Art

[0002] Organic geminal peroxy alcohols (DHPs) are basic chemicals with very important applications in the fields of chemistry and biology. For example, the key intermediates of many antimalarial drugs are derived from organic geminal peroxy alcohols (Angew. Chem. Int. Ed. 2003, 42, 5274; Med. Res. Rev. 2004, 24, 425; Mini-Rev. Med. Chem. 2005, 5, 1035). Organic geminal peroxy alcohols are also precursors for the synthesis of various organic peroxides, such as the synthesis of trioxane compounds (Org. Lett. 2005, 7, 5673), the synthesis of tetraoxane compounds (J. Bioorg. Med. Chem. 2006, 14, 7790), the synthesis of intracyclic peroxy compounds (Tetrahedron 2003, 59, 525), and the synthesis of acyclic compounds with various functional groups (J. Med. Chem. 2002, 45, 1374). In addition, organic peroxy alcohols can be used as free radical initiators and oxidants in organic synthesis (Peroxide Chemistry: Mechanistic and Preparative Aspects of Oxygen Transfers; Adam, W., Ed.; Wiley-VCH: Weinheim, 2000), and can also be used for the epoxidation reaction of α, β-unsaturated ketones (Tetrahedron Lett. 2007, 48, 1395).

[0003] Direct oxidation of aldehydes or ketones to organic peroxy alcohols is currently the simplest and most effective method. In this process, many researchers have made many reports on direct oxidation of aldehydes and ketones. One of the more effective methods is to peroxidize aldehydes or ketones under the catalysis of Lewis acid or Bronsted acid, such as: Chinese Patent CN 101823991A reported a method of using acetal as raw material, aqueous hydrogen peroxide as oxidant, phosphomolybdic acid as catalyst, and ether as solvent to obtain geminal peroxy alcohol derivatives with high yield, but phosphomolybdic acid is corrosive and its use will increase the cost of industrial equipment; in 2009, the Bunge group used camphorsulfonic acid to catalyze the reaction of aldehydes and successfully synthesized the corresponding geminal peroxy alcohol products, but the acidity of camphorsulfonic acid is low, resulting in a reaction time of 20 to 40 hours, and 70% hydrogen peroxide is required, and the yield is only 50% (Tetrahedron Lett. 2009, 50, 524-526); the Azarifar group used stannous chloride as a catalyst to oxidize aldehydes or ketones in a mixed solution of 30% aqueous hydrogen peroxide and acetonitrile at room temperature. Alkyl or cycloalkyl aldehyde and ketone compounds need to react for more than 4 hours to achieve a yield of more than 90%, while aldehyde and ketone compounds with aromatic rings need to react for more than 9 hours to achieve a yield of more than 45% (Synthesis 2009, 2553-2556). The group also tried strontium chloride as a catalyst to catalyze the preparation of geminal peroxides from aldehydes or ketones under the same conditions as above. Although the reaction time and yield were improved, strontium chloride is expensive and not easy to use on a large scale (Molecules 2010, 15, 1433-1441). Summary of the invention

[0004] In view of the shortcomings of the prior art, the present invention provides a method for synthesizing organic geminal peroxy alcohols by catalyzing aldehyde and ketone compounds with stannous benzoate.

[0005] The purpose of the present invention can be achieved through the following technical solutions:

[0006] A method for synthesizing an organic geminal peroxy alcohol comprises the following steps:

[0007] After the aldehyde and ketone compounds, the hydrogen peroxide aqueous solution and the organic solvent are fully mixed, a catalyst stannous benzoate is added to react;

[0008] The obtained product is extracted, dried, filtered and purified to obtain the organic geminal peroxy alcohol.

[0009] Optionally, the reaction temperature is 10 to 50 degrees Celsius.

[0010] Optionally, the aldehyde ketone compound is cyclohexanone, methyl isobutyl ketone, 3-pentanone, 2-nonanone, cyclopentanone, cycloheptanone, acetophenone, 4-methoxyacetophenone, benzaldehyde, 4-methylbenzaldehyde, 4-chlorobenzaldehyde, 4-methoxybenzaldehyde, 4-cyanobenzaldehyde, n-octanal or phenylpropionaldehyde.

[0011] Optionally, the organic solvent is one or more of acetonitrile, dioxane, dichloromethane, chloroform, and tetrahydrofuran.

[0012] Optionally, the concentration of the aqueous hydrogen peroxide solution is 20% to 50%.

[0013] Optionally, the amount of stannous benzoate added is 1 mol% to 50 mol% of the total amount of the aldehyde and ketone compounds.

[0014] Optionally, the purification method is silica gel chromatography column purification.

[0015] Optionally, the extraction comprises the following steps: extracting the reaction product several times with ethyl acetate, combining the organic phases, and then washing with a saturated NaHCO3 solution.

[0016] Optionally, the eluent of the silica gel chromatography column is a mixed solution of petroleum ether and EtOAc.

[0017] Optionally, the reaction formula of the reaction is:

[0018]

[0019] or:

[0020]

[0021] In the formula, R is: a C1-C7 straight chain or substituted C1-C7 branched chain alkyl;

[0022] R1, R2 are:

[0023] The same or different C1-C7 straight chain, substituted C1-C7 branched or cyclic alkyl groups, H, phenyl or substituted phenyl;

[0024] Alternatively, a C5-C7 cycloalkyl group or cycloalkene group, or a substituted cycloalkyl group or cycloalkene group.

[0025] Beneficial effects of the present invention:

[0026] Compared with the prior art, the reaction conditions of the present invention are milder, the reaction rate is faster, the yield is higher, the applicable substrates are wider, and the product is purer. At the same time, stannous benzoate is easier to prepare and is non-corrosive, and is suitable for reaction equipment made of various materials. DETAILED DESCRIPTION

[0027] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0028] The raw materials used in this example are all commercially available raw materials or prepared by known conventional methods. The benzoic acid used is prepared by the method described in reference CN100526282C.

[0029] Example 1

[0030] This embodiment provides a method for synthesizing a peroxide compound, and the reaction formula is:

[0031]

[0032] Cyclohexanone (1.47 g, 15 mmol), 30% aqueous hydrogen peroxide solution (45 mL), stannous benzoate (0.54 g, 1.5 mmol) were dissolved in 60 mL of acetonitrile, stirred at room temperature for 4 h, and after the reaction, 75 mL of water was added, and then 75 mL of ethyl acetate was used for repeated extraction three times each time, and the organic phases were combined, washed with saturated NaHCO3 solution (45 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was fully concentrated by rotary evaporator to obtain a crude product. The crude product was further purified by silica gel chromatography (eluent: a mixed solution of petroleum ether and EtOAc) to obtain the target product 1 (yield: 2.15 g; yield: 97%).

[0033] Example 2

[0034] This embodiment provides a method for synthesizing a peroxide compound, and the reaction formula is:

[0035]

[0036] Methyl isobutyl ketone (1.50 g, 15 mmol), 30% aqueous hydrogen peroxide solution (45 mL), stannous benzoate (0.54 g, 1.5 mmol) were dissolved in 60 mL of acetonitrile, stirred at room temperature for 3.5 h, and after the reaction, 75 mL of water was added, and then 75 mL of ethyl acetate was used for repeated extraction three times each time, and the organic phases were combined, washed with saturated NaHCO3 solution (45 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was fully concentrated by rotary evaporator to obtain a crude product. The crude product was further purified by silica gel chromatography (eluent: a mixed solution of petroleum ether and EtOAc) to obtain the target product 2 (yield: 2.11 g; yield: 94%).

[0037] Example 3

[0038] This embodiment provides a method for synthesizing a peroxide compound, and the reaction formula is:

[0039]

[0040] 3-Pentanone (1.29 g, 15 mmol), 30% aqueous hydrogen peroxide solution (45 mL), stannous benzoate (0.54 g, 1.5 mmol) were dissolved in 60 mL of acetonitrile, stirred at room temperature for 3 h, and after the reaction, 75 mL of water was added, and then 75 mL of ethyl acetate was used for repeated extraction three times each time, and the organic phases were combined, washed with saturated NaHCO3 solution (45 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was fully concentrated by rotary evaporator to obtain a crude product. The crude product was further purified by silica gel chromatography (eluent: a mixed solution of petroleum ether and EtOAc) to obtain the target product 3 (yield: 1.92 g; yield: 94%).

[0041] Example 4

[0042] This embodiment provides a method for synthesizing a peroxide compound, and the reaction formula is:

[0043]

[0044] 2-nonanone (2.13 g, 15 mmol), 30% aqueous hydrogen peroxide solution (45 mL), stannous benzoate (0.54 g, 1.5 mmol) were dissolved in 60 mL of acetonitrile, stirred at room temperature for 4 h, and after the reaction, 75 mL of water was added, and then 75 mL of ethyl acetate was used for repeated extraction three times each time, and the organic phases were combined, washed with saturated NaHCO3 solution (45 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was fully concentrated by rotary evaporator to obtain a crude product. The crude product was further purified by silica gel chromatography (eluent: a mixed solution of petroleum ether and EtOAc) to obtain the target product 4 (yield: 2.76 g; yield: 96%).

[0045] Example 5

[0046] This embodiment provides a method for synthesizing a peroxide compound, and the reaction formula is:

[0047]

[0048] Cyclopentanone (1.26 g, 15 mmol), 30% aqueous hydrogen peroxide solution (45 mL), stannous benzoate (0.54 g, 1.5 mmol) were dissolved in 60 mL of acetonitrile, stirred at room temperature for 3.5 h, and after the reaction, 75 mL of water was added, and then 75 mL of ethyl acetate was used for repeated extraction three times each time, and the organic phases were combined, washed with saturated NaHCO3 solution (45 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was fully concentrated by rotary evaporator to obtain a crude product. The crude product was further purified by silica gel chromatography (eluent: a mixed solution of petroleum ether and EtOAc) to obtain the target product 5 (yield: 1.93 g; yield: 96%).

[0049] Example 6

[0050] This embodiment provides a method for synthesizing a peroxide compound, and the reaction formula is:

[0051]

[0052] Cycloheptanone (1.68 g, 15 mmol), 30% aqueous hydrogen peroxide solution (45 mL), and stannous benzoate (0.54 g, 1.5 mmol) were dissolved in 60 mL of acetonitrile and stirred at room temperature for 3 h. After the reaction, 75 mL of water was added, and then 75 mL of ethyl acetate was used for repeated extraction three times each time. The organic phases were combined, washed with saturated NaHCO3 solution (45 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was fully concentrated by rotary evaporator to obtain a crude product. The crude product was further purified by silica gel chromatography (eluent: a mixed solution of petroleum ether and EtOAc) to obtain the target product 6 (yield: 2.23 g; yield: 92%).

[0053] Example 7

[0054] This embodiment provides a method for synthesizing a peroxide compound, and the reaction formula is:

[0055]

[0056] Acetophenone (1.80 g, 15 mmol), 30% aqueous hydrogen peroxide solution (45 mL), and stannous benzoate (0.54 g, 1.5 mmol) were dissolved in 60 mL of acetonitrile and stirred at room temperature for 8 h. After the reaction, 75 mL of water was added, and then 75 mL of ethyl acetate was used for repeated extraction three times each time. The organic phases were combined, washed with saturated NaHCO3 solution (45 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was fully concentrated by rotary evaporator to obtain a crude product. The crude product was further purified by silica gel chromatography (eluent: a mixed solution of petroleum ether and EtOAc) to obtain the target product 7 (yield: 1.66 g; yield: 65%).

[0057] Example 8

[0058] This embodiment provides a method for synthesizing a peroxide compound, and the reaction formula is:

[0059]

[0060] 4-Methoxyacetophenone (2.25 g, 15 mmol), 30% aqueous hydrogen peroxide solution (45 mL), stannous benzoate (0.54 g, 1.5 mmol) were dissolved in 60 mL of acetonitrile, stirred at room temperature for 7 h, and after the reaction, 75 mL of water was added, and then 75 mL of ethyl acetate was used for repeated extraction three times each time, and the organic phases were combined, washed with saturated NaHCO3 solution (45 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was fully concentrated by rotary evaporator to obtain a crude product. The crude product was further purified by silica gel chromatography (eluent: a mixed solution of petroleum ether and EtOAc) to obtain the target product 8 (yield: 2.16 g; yield: 72%).

[0061] Example 9

[0062] This embodiment provides a method for synthesizing a peroxide compound, and the reaction formula is:

[0063]

[0064] Benzaldehyde (1.59 g, 15 mmol), 30% aqueous hydrogen peroxide solution (45 mL), stannous benzoate (0.54 g, 1.5 mmol) were dissolved in 60 mL of acetonitrile, stirred at room temperature for 8 h, and after the reaction was completed, 75 mL of water was added, and then 75 mL of ethyl acetate was used to extract three times, and the organic phases were combined, washed with saturated NaHCO3 solution (45 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was fully concentrated by rotary evaporator to obtain a crude product. The crude product was further purified by silica gel chromatography (eluent: a mixed solution of petroleum ether and EtOAc) to obtain the target product 9 (yield: 1.50 g; yield: 64%).

[0065] Example 10

[0066] This embodiment provides a method for synthesizing a peroxide compound, and the reaction formula is:

[0067]

[0068] 4-Methylbenzaldehyde (1.80 g, 15 mmol), 30% aqueous hydrogen peroxide solution (45 mL), stannous benzoate (0.54 g, 1.5 mmol) were dissolved in 60 mL of acetonitrile, stirred at room temperature for 10 h, and after the reaction, 75 mL of water was added, and then 75 mL of ethyl acetate was used for repeated extraction three times each time, and the organic phases were combined, washed with saturated NaHCO3 solution (45 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was fully concentrated by rotary evaporator to obtain a crude product. The crude product was further purified by silica gel chromatography (eluent: a mixed solution of petroleum ether and EtOAc) to obtain the target product 10 (yield: 1.84 g; yield: 72%).

[0069] Embodiment 11

[0070] This embodiment provides a method for synthesizing a peroxide compound, and the reaction formula is:

[0071]

[0072] 4-Chlorobenzaldehyde (2.10 g, 15 mmol), 30% aqueous hydrogen peroxide solution (45 mL), stannous benzoate (0.54 g, 1.5 mmol) were dissolved in 60 mL of acetonitrile, stirred at room temperature for 6 h, and after the reaction, 75 mL of water was added, and then 75 mL of ethyl acetate was used for repeated extraction three times each time, and the organic phases were combined, washed with saturated NaHCO3 solution (45 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was fully concentrated by rotary evaporator to obtain a crude product. The crude product was further purified by silica gel chromatography (eluent: a mixed solution of petroleum ether and EtOAc) to obtain the target product 11 (yield: 2.42 g; yield: 85%).

[0073] Example 12

[0074] This embodiment provides a method for synthesizing a peroxide compound, and the reaction formula is:

[0075]

[0076] 4-Methoxybenzaldehyde (2.04 g, 15 mmol), 30% aqueous hydrogen peroxide solution (45 mL), stannous benzoate (0.54 g, 1.5 mmol) were dissolved in 60 mL of acetonitrile, stirred at room temperature for 5 h, and after the reaction was completed, 75 mL of water was added, and then 75 mL of ethyl acetate was used to extract three times, and the organic phases were combined, washed with saturated NaHCO3 solution (45 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was fully concentrated on a rotary evaporator to obtain a crude product. The crude product was further purified by silica gel chromatography (eluent: a mixed solution of petroleum ether and EtOAc) to obtain the target product 12 (yield: 2.37 g; yield: 85%).

[0077] Embodiment 13

[0078] This embodiment provides a method for synthesizing a peroxide compound, and the reaction formula is:

[0079]

[0080] 4-Cyanobenzaldehyde (1.96 g, 15 mmol), 30% aqueous hydrogen peroxide solution (45 mL), and stannous benzoate (0.54 g, 1.5 mmol) were dissolved in 60 mL of acetonitrile and stirred at room temperature for 5 h. After the reaction was completed, 75 mL of water was added, and then 75 mL of ethyl acetate was used to extract three times each time. The organic phases were combined, washed with saturated NaHCO3 solution (45 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was fully concentrated on a rotary evaporator to obtain a crude product. The crude product was further purified by silica gel chromatography (eluent: a mixed solution of petroleum ether and EtOAc) to obtain the target product 13 (yield: 2.14 g; yield: 79%).

[0081] Embodiment 14

[0082] This embodiment provides a method for synthesizing a peroxide compound, and the reaction formula is:

[0083]

[0084] n-Octanal (1.92 g, 15 mmol), 30% aqueous hydrogen peroxide solution (45 mL), stannous benzoate (0.54 g, 1.5 mmol) were dissolved in 60 mL of acetonitrile and stirred at room temperature for 3 h. After the reaction, 75 mL of water was added, and then 75 mL of ethyl acetate was used for repeated extraction three times each time. The organic phases were combined, washed with saturated NaHCO3 solution (45 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was fully concentrated by rotary evaporator to obtain a crude product. The crude product was further purified by silica gel chromatography (eluent: a mixed solution of petroleum ether and EtOAc) to obtain the target product 14 (yield: 2.24 g; yield: 92%).

[0085] Embodiment 15

[0086] This embodiment provides a method for synthesizing a peroxide compound, and the reaction formula is:

[0087]

[0088] Phenylpropanaldehyde (2.01 g, 15 mmol), 30% aqueous hydrogen peroxide solution (45 mL), stannous benzoate (0.54 g, 1.5 mmol) were dissolved in 60 mL of acetonitrile, stirred at room temperature for 4 h, and after the reaction was completed, 75 mL of water was added, and then 75 mL of ethyl acetate was used to extract three times, and the organic phases were combined, washed with saturated NaHCO3 solution (45 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was fully concentrated on a rotary evaporator to obtain a crude product. The crude product was further purified by silica gel chromatography (eluent: a mixed solution of petroleum ether and EtOAc) to obtain the target product 15 (yield: 2.34 g; yield: 93%).

[0089] Comparative Examples 1-15

[0090] The stannous benzoate in Example 1-15 was replaced with stannous chloride dihydrate, and the other conditions remained unchanged. The reference is: Synthesis 2009, 2553-2556;

[0091] The table shows the time and yield of aldehyde and ketone hydroperoxidation reaction with different catalysts.

[0092] surface:

[0093]

[0094] It can be seen from the above experimental results that the preparation method of the present application can prepare a variety of different peroxide compounds. Compared with the comparative example, the preparation method of the present application has a higher yield and reaction rate, especially when preparing aldehyde compounds, the reaction time is shortened by half compared with the comparative example, and the yield is higher.

[0095] In the description of this specification, the description with reference to the terms "one embodiment", "example", "specific example", etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representation of the above terms does not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or examples in a suitable manner.

[0096] The above shows and describes the basic principles, main features and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments, and the above embodiments and descriptions are only for explaining the principles of the present invention. Without departing from the spirit and scope of the present invention, the present invention may have various changes and improvements, and these changes and improvements all fall within the scope of the present invention to be protected.

Claims

1. A method for synthesizing an organic geminal peroxy alcohol, characterized in that: The following steps are involved: After the aldehyde and ketone compounds, the hydrogen peroxide aqueous solution and the organic solvent are fully mixed, a catalyst stannous benzoate is added to react; The obtained product is extracted, dried, filtered and purified to obtain the organic geminal peroxy alcohol.

2. The method of claim 1, wherein: The reaction temperature is 10 to 50 degrees Celsius.

3. The method of claim 1, wherein: The aldehyde and ketone compound is cyclohexanone, methyl isobutyl ketone, 3-pentanone, 2-nonanone, cyclopentanone, cycloheptanone, acetophenone, 4-methoxyacetophenone, benzaldehyde, 4-methylbenzaldehyde, 4-chlorobenzaldehyde, 4-methoxybenzaldehyde, 4-cyanobenzaldehyde, n-octanal or phenylpropionaldehyde.

4. The method of claim 1, wherein: The organic solvent is one or more of acetonitrile, dioxane, dichloromethane, chloroform and tetrahydrofuran.

5. The method of claim 1, wherein: The concentration of the hydrogen peroxide aqueous solution is 20% to 50%.

6. The method of claim 1, wherein: The amount of stannous benzoate added is 1 mol% to 50 mol% of the total amount of the aldehyde and ketone compounds.

7. The method of claim 1, wherein: The purification method is silica gel chromatography column purification.

8. The method of claim 1, wherein: The extraction comprises the following steps: extracting the obtained product several times with ethyl acetate, combining the organic phases, and then washing with a saturated NaHCO3 solution.

9. The method of claim 7, wherein: The eluent of the silica gel chromatography column is a mixed solution of petroleum ether and EtOAc.

10. The method of claim 1, wherein: The reaction formula of the reaction is: or: In the formula, R is: a C1-C7 straight chain or substituted C1-C7 branched chain alkyl; R1, R2 are: The same or different C1-C7 straight chain, substituted C1-C7 branched or cyclic alkyl groups, H, phenyl or substituted phenyl; Alternatively, a C5-C7 cycloalkyl group or cycloalkene group, or a substituted cycloalkyl group or cycloalkene group.

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