A method for synthesizing α-bromosulfone compounds

Abstract

The present invention discloses a method for synthesizing α-bromosulfone compounds. Using a mixed solvent and N-bromosuccinimide as the bromination reagent, the alkynyl sulfone compounds are converted into the corresponding α-bromosulfone compounds under alkaline conditions. The reaction is controlled by the equivalent ratio of N-bromosuccinimide and the base as well as the reaction time, realizing the selective synthesis of α-bromosulfone compounds. The method of the present invention has mild reaction conditions, simple operation, excellent yield and good functional group tolerance.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic compound synthesis, and particularly relates to a method for synthesizing α-bromosulfone compounds. Background Art

[0002] The application of α-halomethylsulfone compounds in agrochemistry and organic synthesis has received extensive attention. Due to the biological properties of halomethylsulfone compounds, they have been used in the synthesis of various drugs, such as herbicides, antibacterial agents, algicides, insecticides, etc. In addition, halomethylsulfone compounds also play a certain role in the fields of medicine and industry. For example, p-tolyldiiodomethylsulfone has a certain effect on treating skin diseases caused by bacteria and fungi and is an effective ingredient as a preservative in industrial products such as textiles, plastics, and coatings. Therefore, it is of great significance to explore simple and efficient methods for constructing α-halosulfone compounds. Summary of the Invention

[0003] The present invention aims to provide a simple, efficient, and selective method for synthesizing α-bromosulfone compounds. The method of the present invention has mild reaction conditions, simple operation, excellent yield, and good functional group tolerance.

[0004] The method for synthesizing α-bromosulfone compounds of the present invention uses a mixed solvent, with N-bromosuccinimide (NBS) as the brominating reagent, and converts alkynyl sulfone compounds into corresponding α-bromosulfone compounds under alkaline conditions. The reaction is controlled by the equivalent ratio of N-bromosuccinimide and base and the reaction time to achieve the selective synthesis of α-bromosulfone compounds.

[0005] Specifically, it includes:

[0006] Route 1: The alkynyl sulfone compound reacts with an equivalent amount of N-bromosuccinimide in a mixed solvent under alkaline conditions to obtain α-bromo-β-carbonyl sulfone;

[0007] The structure of the alkynyl sulfone compound is shown in the following formula IV, and the structure of the α-bromo-β-carbonyl sulfone is shown in the following formula I:

[0008]

[0009] Further, the alkynyl sulfone compound and N-bromosuccinimide (NBS) are dissolved in a mixed solvent, then a base is added, and the reaction is carried out at 25 °C for 1.5 hours to obtain the target product α-bromo-β-carbonyl sulfone.

[0010] The base is selected from one of potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, sodium ethoxide, sodium acetate, and potassium acetate. The yields obtained with the above different bases are 85%, 81%, 35%, 22%, 23%, 15%, 27%, and 12% respectively. Therefore, potassium hydroxide is preferred.

[0011] The amounts of potassium hydroxide selected are 1.0, 1.2, 1.3, 1.5, and 1.6 equivalents respectively, and the obtained yields are 65%, 70%, 78%, 85%, and 83% respectively. Therefore, 1.5 equivalents is preferred.

[0012] The amounts of NBS selected are 1.0, 1.1, 1.2, and 1.3 equivalents respectively, and the obtained yields are 85%, 82%, 78%, and 75% respectively. Therefore, 1.0 equivalent is preferred.

[0013] Furthermore, the molar ratio of the alkynyl sulfone compound, NBS, and the base is 1:1:1.5.

[0014] The mixed solvent is composed of one of dimethyl sulfoxide, N,N-dimethylformamide, toluene, acetonitrile, tetrahydrofuran, N-methylpyrrolidone, 1,4-dioxane and water mixed in a volume ratio of 1:0.3. The yields obtained with each mixed solvent are 85%, 45%, 15%, 10%, 5%, 21%, and 6% respectively. Therefore, water and dimethyl sulfoxide are preferred. The volume ratio of water and dimethyl sulfoxide can be 1:0.1, 1:0.2, 1:0.3, 1:0.4, 1:0.5, and the obtained yields are 76%, 80%, 85%, 83%, and 79% respectively. Therefore, 1:0.3 is preferred.

[0015] Furthermore, the molar ratio of the alkynyl sulfone compound, NBS, and the base is 1:1:1.5, and the reaction solvent is a mixed solvent of dimethyl sulfoxide and water with a volume ratio of 1:0.3.

[0016] Route 2: The alkynyl sulfone compound reacts with an excess of N-bromosuccinimide in a mixed solvent under basic conditions for 1 hour to obtain α,α,α-tribromosulfone, and its structure is shown in Formula III:

[0017]

[0018] Furthermore, the alkynyl sulfone compound and N-bromosuccinimide (NBS) are dissolved in a mixed solvent, and then a base is added, and the reaction is carried out at 25°C for 1 hour to obtain the target product α,α,α-tribromosulfone.

[0019] The base is selected from one of potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, sodium ethoxide, sodium acetate, and potassium acetate. The yields obtained with the above different bases are 90%, 85%, 15%, 10%, 11%, 7%, 15%, and 5% respectively. Therefore, potassium hydroxide is preferably used.

[0020] The amounts of potassium hydroxide selected are 1.5, 2.0, 3.0, and 3.2 equivalents respectively, and the obtained yields are 47%, 79%, 90%, and 77% respectively. Therefore, 3.0 equivalents is preferably used.

[0021] The amounts of NBS selected are 3.0, 3.1, and 3.2 equivalents respectively, and the obtained yields are 90%, 88%, and 85% respectively. Therefore, 3.0 equivalents is preferably used.

[0022] Furthermore, the molar ratio of the alkynyl sulfone compound, NBS, and the base is 1:3:3.

[0023] The mixed solvent is composed of one of dimethyl sulfoxide, N,N-dimethylformamide, toluene, and acetonitrile mixed with water in a volume ratio of 1:0.3. The yields obtained with each mixed solvent are 90%, 30%, 12%, and 6% respectively. Water and dimethyl sulfoxide are preferably used. The volume ratio of water to dimethyl sulfoxide can be 1:0.1, 1:0.2, 1:0.3, 1:0.4, 1:0.5, and the obtained yields are 70%, 75%, 90%, 85%, and 74% respectively. Therefore, 1:0.3 is preferably used.

[0024] Furthermore, the molar ratio of the alkynyl sulfone compound, NBS, and the base is 1:3:3, and the reaction solvent is a mixed solvent of dimethyl sulfoxide and water with a volume ratio of 1:0.3.

[0025] Route 3: The alkynyl sulfone compound reacts with an excess of N-bromosuccinimide in a mixed solvent under basic conditions for 12 hours to obtain α,α-dibromo sulfone, and its structure is shown in Formula II:

[0026]

[0027] Furthermore, the alkynyl sulfone compound and N-bromosuccinimide (NBS) are dissolved in a mixed solvent, and then a base is added, and the reaction is carried out at 25 °C for 12 hours to obtain the target product α,α-dibromo sulfone.

[0028] For the α,α-dibromo sulfone product, based on Route 2, the reaction time is extended. The extended times are 2, 3, 5, 7, 10, 12, and 13 hours respectively, and the obtained yields are 0%, 0%, 20%, 35%, 62%, 78%, and 75% respectively. Therefore, 12 hours is preferably used.

[0029] Furthermore, the molar ratio of the alkynyl sulfone compound, NBS, and the base is 1:3:3. The reaction solvent is a mixed solvent of dimethyl sulfoxide and water with a volume ratio of 1:0.3, and the reaction time is 12 hours.

[0030] Among them, R 1 and R 2 are each independently selected from any one of C1-C4 alkyl, aryl, and heteroaryl.

[0031] The C1-C4 alkyl is selected from methyl, ethyl, n-propyl, tert-butyl, and cyclopropyl.

[0032] The aryl is selected from phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-biphenyl, 3-methylphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 2-methylphenyl, 2-chlorophenyl, and 2-bromophenyl.

[0033] The heteroaryl is selected from 2-thienyl, 3-furyl, 3-pyridyl, and 2-naphthyl.

[0034] Preferably, R 1 and R 2 are independently any one of aryl; furthermore, R 1 is preferably phenyl, and R 2 is preferably 4-methylphenyl.

[0035] In the present invention, by controlling the equivalent ratio of N-bromosuccinimide and potassium hydroxide and the reaction time, the selective synthesis of α-bromo sulfone compounds such as α-bromo-β-carbonyl sulfone, α,α-dibromo sulfone, and α,α,α-tribromo sulfone compounds is achieved. The structural general formulas of α-bromo-β-carbonyl sulfone, α,α-dibromo sulfone, and α,α,α-tribromo sulfone are shown in Formula I, Formula II, and Formula III respectively:

[0036]

[0037] The method of the present invention further includes the separation and purification of the products obtained in each step of the reaction. The separation and purification process can refer to the conventional purification and separation methods in the art, such as column chromatography, thin layer chromatography, recrystallization method, etc.

[0038] Compared with the existing technology, the method of the present invention has mild reaction conditions, simple operation, excellent yield, and good functional group tolerance, and is an effective method for constructing α-bromo sulfone compounds. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1 1H NMR spectrum of the product of Example 1;

[0040] Figure 213C NMR spectrum of the product of Example 1;

[0041] Figure 3 1H NMR spectrum of the product of Example 2;

[0042] Figure 4 13C NMR spectrum of the product of Example 2;

[0043] Figure 5 1H NMR spectrum of the product of Example 3;

[0044] Figure 6 13C NMR spectrum of the product of Example 3. Detailed implementation mode

[0045] The technical solution of the present invention will be described in detail below through examples.

[0046] Example 1:

[0047] 1-Phenyl-2-(p-toluenesulfonyl)acetylene (0.2 mmol, 51 mg), NBS (0.2 mmol, 36 mg), NaOH (0.3 mmol, 12 mg), 1 mL DMSO, and 0.3 mL H2O were added to a reaction tube. The reaction was stirred at 25 °C for 1.5 h. After the reaction was completed, it was quenched with saturated ammonium chloride and extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous Na2SO4, allowed to stand, filtered, concentrated, and the crude product was separated by flash column chromatography (petroleum ether / ethyl acetate 15 / 1) to obtain the target product 2-bromo-1-phenyl-2-p-toluenesulfonylacetone. The reaction route of this step is shown in the following formula:

[0048]

[0049] The data test results of the product were: White solid; mp 149-150 °C.

[0050] 1 1H NMR (300 MHz, CDCl3): δ 8.00 (d, J = 7.6 Hz, 2H), 7.85 (d, J = 8.2 Hz, 2H), 7.66 (t, J = 7.2 Hz, 1H), 7.51 (t, J = 7.7, 2H), 7.37 (d, J = 8.0 Hz, 2H), 6.22 (s, 1H), 2.47 (s, 3H). 13 13C NMR (75 MHz, CDCl3): δ 186.7, 146.4, 134.7, 134.3, 131.8, 130.9, 129.6, 129.5, 129.0, 60.1, 21.8. IR (KBr): v (cm -1)3002,1686,1594,1329,1155.HRMS(ESI)m / z calculated for C 15 H 14 BrO3S[M+H] + :352.9847,found 352.9842.

[0051] Example 2:

[0052] 1-Phenyl-2-(p-toluenesulfonyl)acetylene (0.2 mmol, 51 mg), NBS (0.6 mmol, 72 mg), NaOH (0.6 mmol, 24 mg), 1 mL of DMSO, and 0.3 mL of H2O were added to a reaction tube. The mixture was stirred at 25 °C for 1 h. After the reaction was completed, the reaction was quenched with saturated ammonium chloride, and the product was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous Na2SO4, allowed to stand, filtered, concentrated, and the crude product was separated by flash column chromatography (petroleum ether / ethyl acetate 15 / 1) to obtain the target product 1-methyl-4-tribromomethylsulfonylbenzene. The reaction route for this step is shown in the following formula:

[0053]

[0054] The data test results of the product were as follows: White solid; mp 138 - 139 °C.

[0055] 1 H NMR(300MHz,CDCl3):δ8.12(d,J=8.1Hz,4H),7.42(d,J=8.0Hz,2H),2.51(s,3H). 13 C NMR(75MHz,CDCl3):δ147.4,133.7,129.9,129.5,51.1,21.9.IR(KBr):v(cm -1 )1592,1336,1152.HRMS(ESI)m / z calculated for C8H8Br3O2S[M+H] + :406.7769,found406.7764.

[0056] Example 3:

[0057] 1-Phenyl-2-(p-toluenesulfonyl)acetylene (0.2 mmol, 51 mg), NBS (0.6 mmol, 72 mg), NaOH (0.6 mmol, 24 mg), 1 mL DMSO, and 0.3 mL H2O were added to a reaction tube. The reaction was stirred at 25 °C for 12 h. After the reaction was completed, it was quenched with saturated ammonium chloride and extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous Na2SO4, allowed to stand, filtered, concentrated, and the crude product was separated by flash column chromatography (petroleum ether / ethyl acetate 15 / 1) to obtain the target product, methyl 4-dibromomethylsulfonylbenzene. The reaction route for this step is shown in the following formula:

[0058]

[0059] The data test results of the product were as follows: White solid; mp 95 - 96 °C; yield: 75%.

[0060] 1 1H NMR (300 MHz, CDCl3): δ 7.93 (d, J = 8.3 Hz, 2H), 7.42 (d, J = 8.1 Hz, 2H), 6.23 (s, 1H), 2.50 (s, 3H). 13 13C NMR (125 MHz, CDCl3): δ 147.3, 131.6, 130.3, 129.4, 51.1, 22.3. IR (KBr): v (cm -1 ) 3002, 1686, 1329, 1155. HRMS (ESI) m / z calculated for C8H9Br2O2S [M + H] + : 328.8664, found 328.8660.

[0061] The preferred embodiments of the present invention have been described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solutions of the present invention, and these simple modifications all fall within the protection scope of the present invention.

[0062] In addition, it should be noted that, in the case of no contradiction, the various specific technical features described in the above specific embodiments can be combined in any appropriate manner. To avoid unnecessary repetition, the present invention will not describe various possible combination methods separately.

Claims

1. A method for synthesizing α-bromosulfone compounds, characterized in that: A mixed solvent is used, and N-bromosuccinimide is used as a brominating reagent. Under alkaline conditions, alkynyl sulfone compounds are converted into corresponding α-bromosulfone compounds. The reaction is controlled by the equivalent ratio of N-bromosuccinimide and base and the reaction time to achieve the selective synthesis of α-bromosulfone compounds. The specific steps are as follows: Route 1: Dissolve alkynyl sulfone compounds and N-bromosuccinimide in a mixed solvent, then add a base, and react at 25 °C for 1.5 hours to obtain the target product α-bromo-β-carbonyl sulfone; the molar ratio of alkynyl sulfone compounds, N-bromosuccinimide, and base is 1:1:1.5; Route 2: Dissolve alkynyl sulfone compounds and N-bromosuccinimide in a mixed solvent, then add a base, and react at 25 °C for 1 hour to obtain the target product α,α,α-tribromosulfone; the molar ratio of alkynyl sulfone compounds, N-bromosuccinimide, and base is 1:3:3; Route 3: Dissolve alkynyl sulfone compounds and N-bromosuccinimide in a mixed solvent, then add a base, and react at 25 °C for 12 hours to obtain the target product α,α-dibromosulfone; the molar ratio of alkynyl sulfone compounds, N-bromosuccinimide, and base is 1:3:3; The mixed solvent is composed of a mixture of dimethyl sulfoxide and water; The structure of the alkynyl sulfone compounds is as follows: ； The general structural formulas of the target products α-bromo-β-carbonyl sulfone, α,α-dibromosulfone, and α,α,α-tribromosulfone are shown as Formula I, Formula II, and Formula III respectively as follows: 。 2. The synthesis method according to claim 1, characterized in that: The base is selected from one of potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, sodium ethoxide, sodium acetate, and potassium acetate.

3. The synthesis method according to claim 1, characterized in that: The volume ratio of water to dimethyl sulfoxide is 1:0.3.

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