CN110698391A - Preparation method of heterocycle substituted alkyl sulfone or heterocycle substituted alkyl sulfonamide compound - Google Patents
Preparation method of heterocycle substituted alkyl sulfone or heterocycle substituted alkyl sulfonamide compound Download PDFInfo
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
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- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/12—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
Abstract
The invention relates to the technical field of organic synthesis. The invention provides a preparation method of heterocycle substituted alkyl sulfone or heterocycle substituted alkyl sulfonamide. Under the condition of visible light irradiation, the heterocycle substituted olefin derivative, thiourea dioxide and sodium hydroxide are subjected to free radical addition reaction under the action of a catalyst PDI to obtain heterocycle substituted sodium alkyl sulfinate; the heterocycle-substituted alkyl sodium sulfinate and the group donor compound are subjected to alkylation reaction or amidation reaction to obtain heterocycle-substituted alkyl sulfone or heterocycle-substituted alkyl sulfonamide; the group donor compound is a halogenated compound or an amine organic matter. The method provided by the invention can obtain the heterocycle substituted alkyl sulfone or heterocycle substituted alkyl sulfonamide only by two steps of reaction, does not need to use strong corrosive substances, and has few byproducts and high yield.
Description
Technical Field
The invention relates to the technical field of organic synthesis, and relates to a preparation method of a heterocycle substituted alkyl sulfone or heterocycle substituted alkyl sulfonamide compound.
Background
The sulfone and sulfonamide compounds are important organic synthesis intermediates and are widely applied to the field of chemical industry such as dyes. Meanwhile, the compound molecules often have good biological activity, such as good effects in the aspects of antivirus, anti-tumor, disinsection and weeding, and the sulfone and sulfonamide compounds are also commonly used as effective medicines for treating diabetes, cardiovascular diseases and the like, for example: viagra is a specific drug for the treatment of male erectile dysfunction, which was sold in the US market in 2010 in excess of 10 billion dollars; glimepiride is a third-generation oral medicament for treating diabetes, and the medicament has the advantages of quick response, small side effect and the like; torasemide has good diuretic effect, and can be used as a medicine for treating edematous diseases, such as heart failure and kidney diseases.
Although the sulfones and sulfonamides compounds are widely used in the fields of medicine and pesticides, the methods for synthesizing these compounds, especially the alkyl-substituted sulfones or sulfonamides, have been relatively few and have many drawbacks. For example, the traditional synthetic sulfones and sulfonamides are mainly prepared by oxidizing sulfur compounds with strong oxidants or nucleophilic substitution reaction of sulfonyl chloride and amine, and these synthetic methods have the problems of complicated steps, need of using sulfonyl chloride reagents with strong corrosivity and sulfuration reagents with irritability, and in the oxidation process, functional groups which are not resistant to oxidation are easily oxidized to generate byproducts.
Disclosure of Invention
The invention aims to solve the defects of the prior art and provides a preparation method of a heterocycle substituted alkyl sulfone or heterocycle substituted alkyl sulfonamide compound.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a preparation method of a heterocycle substituted alkyl sulfone or heterocycle substituted alkyl sulfonamide compound, which comprises the following steps:
(1) in a protective atmosphere, under the condition of visible light irradiation, the heterocyclic substituted olefin compound, thiourea dioxide and sodium hydroxide undergo a free radical addition reaction to obtain heterocyclic substituted sodium alkyl sulfinate; the catalyst of the free radical addition reaction is PDI;
(2) maintaining a protective atmosphere, and carrying out alkylation reaction or amidation reaction on the heterocycle substituted alkyl sulfinate and a group donor compound to obtain a heterocycle substituted alkyl sulfone or heterocycle substituted alkyl sulfonamide compound; the group donor compound is a halogenated compound or an amine organic matter.
Preferably, the heterocyclic substituted olefinic compound is
Wherein the heterocyclic substituent is a pyridine ring, a pyrazine ring or a pyrimidine ring; r1Or R2Is an electron-withdrawing aromatic ring or an electron-rich aromatic ring; the electron-withdrawing aromatic ring is an aromatic ring substituted by fluorine, chlorine, bromine or trifluoromethyl; the electron-rich aromatic ring is an aromatic ring containing methyl or methoxy substitution.
Preferably, the mole ratio of the heterocyclic substituted olefin compound, thiourea dioxide, sodium hydroxide and PDI is 1 (2.0-2.2): (4.0-4.2): 0.01-0.02), more preferably 1:2:4: 0.01.
Preferably, the light source of the visible light is a fluorescent lamp, the power of the fluorescent lamp is 30-40W, more preferably 35W, the reaction temperature is 30-40 ℃, more preferably 35 ℃, and the reaction time is 16-24 h.
Preferably, the halogenated compound is halogenated alkane, halogenated aromatic hydrocarbon, halogenated acetate or benzyl halogen compound, and the halogenated alkane is preferably brominated alkane or iodoalkane; the halogenated aromatic hydrocarbon (the halogenated aromatic hydrocarbon is a halogenated aromatic hydrocarbon containing a substituent or not containing a substituent) is preferably brominated aromatic hydrocarbon or iodo aromatic hydrocarbon, and is more preferably (E) - (3-bromopropenyl) benzene; the benzyl halide compound is preferably benzyl bromide and substituted benzyl bromide; the substituent of the substituted benzyl bromide is preferably at least one of methoxy, tert-butyl, methyl, fluoro, chloro, bromo, trifluoromethyl, ethoxycarbonyl, cyano and ester group, and more preferably 4-methylbenzyl bromide or 4-ethyl formate benzyl bromide; the haloacetate is preferably tert-butyl bromoacetate.
Preferably, when the group donor compound is a halogenated compound, the reaction in the step (2) is an alkylation reaction, the alkylation reaction is carried out by using tetrabutylammonium iodide and potassium iodide as catalysts, and the molar ratio of the heterocycle-substituted olefin compound, the halogenated compound, the tetrabutylammonium iodide and the potassium iodide is 1 (2-2.2): (0.1-0.2): 1.2-1.4), more preferably 1:2:0.1: 1.2.
Preferably, when the group donor compound is a halogenated compound, the reaction temperature of the alkylation reaction is room temperature; the time of the alkylation reaction is preferably 8-15 hours, and more preferably 10-12 hours.
Preferably, the amine organic compound has the formula
The structure shown, the R4And R5Is independently alkyl, or R4And R5Looping; more preferably, the amine organic compound is morpholine or thiomorpholine.
Preferably, when the group donor compound is an amine organic compound, the reaction in the step (2) is an amidation reaction, and the catalyst of the amidation reaction is N-chlorosuccinimide; the mol ratio of the heterocycle substituted olefin compound, the amine compound and the N-chlorosuccinimide is 1 (2-2.2) to (2-2.2), and the preferable mol ratio is 1:2: 2.
Preferably, when the group donor compound is an amine organic compound, the amidation reaction comprises a first-stage reaction and a second-stage reaction, and the temperature of the first-stage reaction is-5 ℃; the temperature of the second stage reaction is room temperature.
The method takes PDI as a catalyst, and generates free radical addition reaction on the heterocyclic substituted olefin compound, thiourea dioxide and sodium hydroxide under the conditions of irradiation of visible light and 30-40 ℃ to generate heterocyclic substituted alkyl sodium sulfinate; when the group donor compound is a halogenated compound, carrying out alkylation reaction on the heterocycle-substituted sodium alkylsulfinate and the group donor compound to obtain heterocycle-substituted alkyl sulfone; when the group donor compound is an amine organic matter, the heterocycle-substituted sodium alkylsulfinate and the group donor compound are subjected to amidation reaction to obtain the heterocycle-substituted alkylsulfonamide.
The invention has the beneficial effects that: the method provided by the invention can obtain the heterocycle substituted alkyl sulfone or heterocycle substituted alkyl sulfonamide compound only by two steps of reaction, does not need to use strong corrosive substances, and has few byproducts and high yield.
Detailed Description
The invention provides a preparation method of a heterocycle substituted alkyl sulfone or heterocycle substituted alkyl sulfonamide compound, which comprises the following steps:
(1) in a protective atmosphere, under the condition of visible light irradiation, the heterocyclic substituted olefin compound, thiourea dioxide and sodium hydroxide undergo a free radical addition reaction to obtain heterocyclic substituted sodium alkyl sulfinate; the catalyst of the free radical addition reaction is PDI;
(2) maintaining a protective atmosphere, and carrying out alkylation reaction or amidation reaction on the heterocycle substituted alkyl sulfinate and a group donor compound to obtain heterocycle substituted alkyl sulfone or heterocycle substituted alkyl sulfonamide; the group donor compound is a halogenated compound or an amine organic matter.
In the invention, under the irradiation of visible light, thiourea dioxide reacts with sodium hydroxide to generate reductive sulfur dioxide anions, then the sulfur dioxide anions and excited PDI undergo single electron transfer to generate reduced PDI and sulfur dioxide negative charge free radicals, then heterocyclic substituted olefin is subjected to free radical addition to generate alkyl free radicals, the alkyl free radicals and the reduced PDI undergo single electron transfer to obtain carbanions, and then the carbanions are protonated to obtain heterocyclic substituted sodium alkylsulfinate.
In the present invention, the protective atmosphere is preferably a nitrogen or inert gas atmosphere.
In the present invention, the solvent used for the radical addition reaction is preferably anhydrous dimethyl sulfoxide.
In the present invention, the order of addition of the raw materials and the solvent required for the radical addition reaction is not particularly limited, and may be any order of mixing.
In the embodiment of the present invention, it is preferable that the heterocyclic substituted olefin compound, thiourea dioxide, sodium hydroxide and PDI are mixed in the reactor, then the gas in the reactor is replaced with nitrogen or an inert gas, and then dimethyl sulfoxide is added to perform a radical addition reaction under visible light.
After the radical addition reaction is completed, the mixed solution obtained by the radical addition reaction, which contains the heterocycle-substituted sodium alkylsulfinate, is preferably directly used in the subsequent step.
After the heterocycle substituted alkyl sodium sulfinate is obtained, the invention maintains the protective atmosphere, and the heterocycle substituted alkyl sodium sulfinate and the group donor compound are subjected to alkylation reaction or amidation reaction to obtain the heterocycle substituted alkyl sulfone or the heterocycle substituted alkyl sulfonamide.
In the present invention, when the group donor compound is a halogenated compound, it is preferable that the halogenated compound, tetrabutylammonium iodide and potassium iodide are added to the mixed solution obtained by the radical addition reaction, and then the alkylation reaction is carried out by replacing the gas in the reactor with nitrogen or an inert gas.
In the invention, when the group donor compound is an amine organic compound, the mixed solution obtained by the free radical addition reaction is preferably cooled to the temperature required by the first-stage reaction, then tetrahydrofuran is added, the temperature is kept unchanged, the tetrahydrofuran solution of N-chlorosuccinimide is dropwise added into the reaction solution, after the dropwise addition is finished, the constant-temperature reaction is continued for 0.5-1 h, then the temperature is raised to the room temperature, the second-stage reaction is continued for 1.5-2.5 h, and the amidation reaction is finished; the time of the second-stage reaction is preferably recorded from the time of warming up to room temperature; the rate of the temperature rise is not particularly limited in the present invention. In the invention, in the first stage reaction process, N-chlorosuccinimide reacts with heterocycle substituted sodium alkylsulfinate to generate heterocycle substituted alkyl sulfonyl chloride, and in the second stage reaction process, heterocycle substituted alkyl sulfonyl chloride reacts with amine organic matters to generate heterocycle substituted alkyl sulfonamide.
In the present invention, the volume ratio of dimethyl sulfoxide to tetrahydrofuran is preferably 1: 2. In the invention, the mixed solution of dimethyl sulfoxide and tetrahydrofuran is used as the medium of amidation reaction, so that the reaction can be ensured to be carried out in a homogeneous phase.
In the invention, the dropping speed of the tetrahydrofuran solution of the N-chlorosuccinimide is based on the temperature of the reaction system.
In the present invention, the radical addition reaction, the alkylation reaction or the amidation reaction is preferably performed under stirring conditions.
After the alkylation reaction or amidation reaction is finished, the present invention preferably uses saturated salt solution to quench the reaction, and then the mixed solution obtained by the reaction is subjected to post-treatment to obtain the heterocycle substituted alkyl sulfone or heterocycle substituted alkyl sulfonamide.
In the present invention, the post-treatment preferably comprises extraction, drying, concentration, column chromatography and solvent removal in this order.
In the present invention, the extractant for extraction is preferably ethyl acetate. The extraction method is not particularly limited in the invention, and the extraction method commonly used in the field can be adopted, for example, the extraction agent and the reaction product are mixed and then are kept stand for layering to obtain an organic phase.
After the extraction is completed, the organic phase obtained by the extraction is preferably dried in the invention.
The drying mode is not particularly limited in the invention, and the organic phase drying mode commonly used in the field, such as drying agent drying mode, can be adopted.
After drying of the organic phase is complete, the present invention preferably concentrates the dried organic phase, followed by column chromatography to provide a solution of the heterocycle substituted alkyl sulfone or heterocycle substituted alkyl sulfonamide.
The degree of concentration of the organic phase is not particularly limited in the present invention, and can be determined empirically by those skilled in the art.
The column chromatography method is not particularly limited in the present invention, and those skilled in the art can select a conventional developing solvent to perform column chromatography according to the technical knowledge in the art.
After obtaining a solution of the heterocycle-substituted alkyl sulfone or heterocycle-substituted alkyl sulfonamide, the present invention preferably subjects the solution to solvent removal to obtain the heterocycle-substituted alkyl sulfone or heterocycle-substituted alkyl sulfonamide.
The solvent removal mode is not particularly limited in the invention, and the solvent removal mode commonly used in the field, such as rotary evaporation, reduced pressure distillation and the like, can be adopted.
The following examples are provided to illustrate the preparation of several heterocyclic substituted alkyl sulfone or heterocyclic substituted alkyl sulfonamide compounds of the present invention, but should not be construed as limiting the scope of the present invention.
Example 1
2-vinylpyridine (0.2mmol,1.0 equivalent), thiourea dioxide (0.4mmol,2.0 equivalents), sodium hydroxide (0.8mmol,4.0 equivalents) and PDI (0.002mmol,0.01 equivalents) were charged into a reaction tube, the air in the tube was replaced with high-purity nitrogen gas, 3mL of dimethyl sulfoxide was added as a solvent, and the reaction was stirred at a constant temperature of 30 ℃ for 24 hours under irradiation of a 30W fluorescent lamp.
After the reaction was cooled, tetrabutylammonium iodide (0.02mmol,0.1 equiv.), potassium iodide (0.24mmol,1.2 equiv.) and 4-methylbenzyl bromide (0.4mmol,2.0 equiv.) were added to the reaction solution, and the atmosphere in the test tube was replaced with high-purity nitrogen gas and stirred at room temperature for 8 hours.
The reaction was quenched with saturated brine, extracted with ethyl acetate, and the organic phases were combined, dried, concentrated, and separated by column chromatography. The target product Ia was obtained in 75% yield.
1H NMR(400MHz,CDCl3)δ8.52(d,J＝4.4Hz,1H),7.62(t,J＝7.6Hz,1H),7.28(d,J＝7.7Hz,2H),7.21–7.15(m,4H),4.16(s,2H),3.42–3.36(m,2H),3.30–3.24(m,2H),2.35(s,3H).；13C NMR(101MHz,CDCl3)δ157.3,149.4,139.0,136.7,130.5,129.7,124.7,123.4,122.0,59.7,50.2,29.9,21.2；HRMS calcd for C15H18NO2S+(M+H+):276.1053,found:276.1058。
Example 2
2-vinylpyrazine (0.2mmol,1.0 equivalent), thiourea dioxide (0.44mmol,2.2 equivalents), sodium hydroxide (0.84mmol,4.2 equivalents), and PDI (0.004mmol,0.02 equivalents) were charged into a reaction tube, air in the tube was replaced with high-purity nitrogen gas, 3mL of dimethyl sulfoxide was added as a solvent, and the reaction was stirred at a constant temperature of 40 ℃ for 16 hours under irradiation of a 40W fluorescent lamp.
After the reaction was cooled, tetrabutylammonium iodide (0.04mmol,0.2 equiv.), potassium iodide (0.28mmol,1.4 equiv.) and 4-methylbenzyl bromide (0.44mmol,2.2 equiv.) were added to the reaction solution, and the atmosphere in the test tube was replaced with high-purity nitrogen gas and stirred at room temperature for 10 hours.
The reaction was quenched with saturated brine, extracted with ethyl acetate, and the organic phases were combined, dried, concentrated, and separated by column chromatography. The target product Ib was obtained in 68% yield.
1H NMR(400MHz,CDCl3)δ8.49(s,1H),8.47(d,J＝11.8Hz,2H),7.30(d,J＝7.6Hz,2H),7.21(d,J＝7.7Hz,2H),4.23(s,2H),3.39–3.35(m,2H),3.30–3.25(m,2H),2.36(s,3H)；13C NMR(101MHz,CDCl3)δ153.1,144.7,144.0,143.1,139.2,130.4,129.8,124.6,114.9,59.9,49.3,26.9,21.2。
Example 3
(E) -2- (4-methoxystyryl) pyridine (0.2mmol,1.0 equivalent), thiourea dioxide (0.4mmol,2.0 equivalent), sodium hydroxide (0.8mmol,4.0 equivalent), and PDI (0.002mmol,0.01 equivalent) were charged into a reaction tube, the air in the tube was replaced with high-purity nitrogen gas, 3mL of dimethyl sulfoxide was added as a solvent, and the reaction was stirred under irradiation of a fluorescent lamp for 24 hours.
After the reaction was cooled, tetrabutylammonium iodide (0.02mmol,0.1 equiv.), potassium iodide (0.24mmol,1.2 equiv.) and 4-methylbenzyl bromide (0.4mmol,2.0 equiv.) were added to the reaction solution, and the atmosphere in the test tube was replaced with high-purity nitrogen gas, followed by stirring at room temperature for 15 hours.
The reaction was quenched with saturated brine, extracted with ethyl acetate, and the organic phases were combined, dried, concentrated, and separated by column chromatography. The desired product Ic was obtained in 84% yield.
1H NMR(400MHz,CDCl3)δ8.45(dd,J＝4.8,0.8Hz,1H),7.43(td,J＝7.7,1.8Hz,1H),7.32–7.27(m,2H),7.19–7.13(m,4H),7.05–7.00(m,1H),6.91(d,J＝7.8Hz,1H),6.83(d,J＝8.8Hz,2H),4.72(dd,J＝10.7,4.4Hz,1H),3.95(d,J＝2.7Hz,2H),3.88(dd,J＝14.0,4.4Hz,1H),3.78(s,3H),3.40(dd,J＝14.0,10.7Hz,1H),2.35(s,3H)；13C NMR(101MHz,CDCl3)δ13C NMR(101MHz,CDCl3)δ159.8,156.7,149.2,138.6,136.2,130.9,130.8,129.3,124.2,124.0,123.9,121.5,114.1,66.1,56.7,55.1,36.5,21.1。
Example 4
2-vinylpyridine (0.2mmol,1.0 equivalent), thiourea dioxide (0.4mmol,2.0 equivalents), sodium hydroxide (0.8mmol,4.0 equivalents) and PDI (0.002mmol,0.01 equivalents) were charged into a reaction tube, the air in the tube was replaced with high-purity nitrogen gas, 3mL of dimethyl sulfoxide was added as a solvent, and the reaction was stirred under irradiation of a fluorescent lamp for 24 hours.
After the reaction was cooled, tetrabutylammonium iodide (0.02mmol,0.1 equivalent), potassium iodide (0.24mmol,1.2 equivalents) and 4-trifluoromethylbenzyl bromide (0.4mmol,2.0 equivalents) were added to the reaction solution, and the air in the test tube was replaced with high-purity nitrogen gas and the mixture was stirred at room temperature for 10 hours.
The reaction was quenched with saturated brine, extracted with ethyl acetate, and the organic phases were combined, dried, concentrated, and separated by column chromatography. The target product Id was obtained in 66% yield.
1H NMR(400MHz,CDCl3)δ8.54(d,J＝4.6Hz,1H),7.87–7.82(m,3H),7.54(d,J＝7.9Hz,2H),7.24–7.18(m,2H),4.24(s,2H),3.51–3.45(m,2H),3.34–3.29(m,2H)；19F NMR(376MHz,CDCl3)δ-62.81；13C NMR(101MHz,CDCl3)δ156.9,149.48(s),136.9,131.6,131.2,125.9(q,J＝3.8Hz),123.8(q,J＝272.4Hz),123.5,122.2,59.3,50.8,29.9。
Example 5
2-vinylpyridine (0.2mmol,1.0 equivalent), thiourea dioxide (0.4mmol,2.0 equivalents), sodium hydroxide (0.8mmol,4.0 equivalents) and PDI (0.002mmol,0.01 equivalents) were charged into a reaction tube, the air in the tube was replaced with high-purity nitrogen gas, 3mL of dimethyl sulfoxide was added as a solvent, and the reaction was stirred under irradiation of a fluorescent lamp for 24 hours.
After the reaction was cooled, tetrabutylammonium iodide (0.02mmol,0.1 equiv.), potassium iodide (0.24mmol,1.2 equiv.) and tert-butyl bromoacetate (0.4mmol,2.0 equiv.) were added to the reaction solution, and the air in the test tube was replaced with high-purity nitrogen gas and stirred at room temperature for 10 hours.
The reaction was quenched with saturated brine, extracted with ethyl acetate, and the organic phases were combined, dried, concentrated, and separated by column chromatography. The target product Ie was obtained in 65% yield.
1H NMR(400MHz,CDCl3)δ8.53(d,J＝4.3Hz,1H),7.63(t,J＝7.6Hz,1H),7.23(d,J＝7.7Hz,1H),7.19–7.15(m,1H),3.90(s,2H),3.80–3.76(m,2H),3.37–3.32(m,2H),1.50(s,9H)；13C NMR(101MHz,CDCl3)δ161.9,157.0,149.5,136.8,123.3,122.0,84.1,59.0,52.6,29.9,27.8。
Example 6
2-vinylpyridine (0.2mmol,1.0 equivalent), thiourea dioxide (0.4mmol,2.0 equivalents), sodium hydroxide (0.4mmol,4.0 equivalents) and fluorescein (0.002mmol,0.01 equivalents) were charged into a reaction tube, the air in the tube was replaced with high-purity nitrogen gas, 3mL of dimethyl sulfoxide was added as a solvent, and the reaction was stirred under irradiation of a fluorescent lamp for 24 hours.
After the reaction is cooled, adding 5mL of tetrahydrofuran solvent into the reaction solution, then adding morpholine (0.4mmol,2.0 equivalents), putting the reaction solution into an ice-water bath, maintaining the temperature of the ice-water bath at-5 ℃, then dropwise adding a tetrahydrofuran (2mL) solution of N-chlorosuccinimide (0.4mmol,2.0 equivalents), continuing to react at 0 ℃ for half an hour after the solution is added, and reacting at normal temperature for 1.5 hours.
The reaction was quenched with saturated brine, extracted with ethyl acetate, and the organic phases were combined, dried, concentrated, and separated by column chromatography. The desired product IIa was obtained in 62% yield.
1H NMR(400MHz,CDCl3)δ8.54(d,J＝4.7Hz,1H),7.64(t,J＝7.7Hz,1H),7.22(d,J＝7.8Hz,1H),7.20–7.16(m,1H),3.73–3.68(m,4H),3.48–3.43(m,2H),3.32–3.27(m,2H),3.27–3.23(m,4H)；13C NMR(101MHz,CDCl3)δ157.5,149.4,136.8,123.4,122.0,66.5,47.8,45.6,31.1。
Example 7
2-vinylpyridine (0.2mmol,1.0 equivalent), thiourea dioxide (0.4mmol,2.0 equivalents), sodium hydroxide (0.4mmol,4.0 equivalents) and fluorescein (0.002mmol,0.01 equivalents) were charged into a reaction tube, the air in the tube was replaced with high-purity nitrogen gas, 3mL of dimethyl sulfoxide was added as a solvent, and the reaction was stirred under irradiation of a fluorescent lamp for 24 hours.
After the reaction is cooled, adding 5mL of tetrahydrofuran solvent into the reaction solution, then adding N-ethyl-N-propylamine (0.44mmol,2.2 equivalents), putting the reaction solution into an ice-water bath, maintaining the temperature of the ice-water bath at-5 ℃, then dropwise adding a tetrahydrofuran (2mL) solution of N-chlorosuccinimide (0.44mmol,2.2 equivalents), continuing to react for half an hour at 0 ℃ after the solution is added, and reacting for 1.5 hours at normal temperature.
The reaction was quenched with saturated brine, extracted with ethyl acetate, and the organic phases were combined, dried, concentrated, and separated by column chromatography. The target product IIb was obtained in 46% yield.
1H NMR(400MHz,CDCl3)δ8.53(d,J＝4.7Hz,1H),7.63(t,J＝7.7Hz,1H),7.21(d,J＝7.8Hz,1H),7.18–7.14(m,1H),3.45–3.40(m,2H),3.33–3.25(m,4H),3.19–3.14(m,2H),1.67–1.56(m,2H),1.21(t,J＝7.1Hz,3H),0.92(t,J＝7.4Hz,3H)；13C NMR(101MHz,CDCl3)δ157.9,149.4,136.7,123.3,121.8,50.9,48.8,42.2,31.7,22.2,14.5,11.1。
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (10)
1. A process for preparing a heterocycle-substituted alkyl sulfone or heterocycle-substituted alkyl sulfonamide compound comprising the steps of:
(1) in a protective atmosphere, under the condition of visible light irradiation, the heterocyclic substituted olefin compound, thiourea dioxide and sodium hydroxide undergo a free radical addition reaction to obtain heterocyclic substituted sodium alkyl sulfinate; the catalyst of the free radical addition reaction is PDI;
(2) maintaining a protective atmosphere, and carrying out alkylation reaction or amination reaction on the heterocycle substituted alkyl sulfinate and the group donor compound to obtain heterocycle substituted alkyl sulfone or heterocycle substituted alkyl sulfonamide; the group donor compound is a halogenated compound or an amine organic matter;
the reaction formula of each step is as follows:
2. the method of claim 1, wherein the heterocycle-substituted olefin compound is
Wherein the heterocyclic substituent is a pyridine ring, a pyrazine ring or a pyrimidine ring; r1Or R2Is an electron-withdrawing aromatic ring or an electron-rich aromatic ring; the electron-withdrawing aromatic ring is an aromatic ring substituted by fluorine, chlorine, bromine or trifluoromethyl; the electron-rich aromatic ring is an aromatic ring containing methyl or methoxy substitution.
3. The method of claim 1 or 2, wherein the molar ratio of the heterocycle-substituted olefin compound, thiourea dioxide, sodium hydroxide and catalyst PDI is 1 (2.0-2.2): (4.0-4.2): 0.01-0.02).
4. The method of claim 1, wherein the light source of visible light is a fluorescent lamp, the power of the fluorescent lamp is 30-40W, and the reaction temperature is 30-40 ℃.
5. The method of claim 1, wherein the halogenated compound is a halogenated alkane, a halogenated arene, a halogenated acetate or a benzyl halide.
6. The method of claim 5, wherein the alkyl halide is alkyl bromide or alkyl iodide; the halogenated aromatic hydrocarbon is brominated aromatic hydrocarbon or iodo aromatic hydrocarbon; the benzyl halogen compound is benzyl bromide or substituted benzyl bromide, and the substituted benzyl bromide is methoxy, tert-butyl, methyl, fluoro, chloro, bromo, trifluoromethyl, ethoxycarbonyl, cyano or ester; the halogenated acetate is tert-butyl bromoacetate.
7. The method of claim 1 or 5, wherein the step (2) is an alkylation reaction in which tetrabutylammonium iodide and potassium iodide are used as catalysts, and the molar ratio of the heterocyclic substituted olefin compound, the halogenated compound, the tetrabutylammonium iodide and the potassium iodide is 1 (2-2.2): 0.1-0.2: 1.2-1.4.
8. The method of claim 1, wherein the amine-type organic compound is represented by formula (la)
The structure shown, the R4And R5Is independently alkyl, or R4And R5Looping.
9. The method of claim 1 or 8, wherein when the group donor compound is an amine-type organic compound, the reaction of step (2) is an amidation reaction in which a catalyst is N-chlorosuccinimide; the mol ratio of the heterocycle substituted olefin compound, the amine compound and the N-chlorosuccinimide is 1 (2-2.2) to 2-2.2.
10. The method of claim 9, wherein the amidation reaction comprises a first-stage reaction and a second-stage reaction when the group donor compound is an amine organic compound, and the temperature of the first-stage reaction is-5 to 5 ℃; the temperature of the second stage reaction is room temperature.
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| CN114934287A (en) * | 2022-06-16 | 2022-08-23 | 浙江师范大学 | Method for synthesizing fluoroalkyl-substituted sulfamino polycyclic compound by electrooxidation |
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| CN109180572A (en) * | 2018-10-12 | 2019-01-11 | 嘉兴学院 | A kind of preparation method of heterocycle sulfone or heterocyclic sulfonamide compound |
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