CN114933556B - Preparation method of thioether compound - Google Patents
Preparation method of thioether compound Download PDFInfo
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- CN114933556B CN114933556B CN202210884300.5A CN202210884300A CN114933556B CN 114933556 B CN114933556 B CN 114933556B CN 202210884300 A CN202210884300 A CN 202210884300A CN 114933556 B CN114933556 B CN 114933556B
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- B01J31/0222—Sulfur-containing compounds comprising sulfonyl groups
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- B01J31/181—Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine
- B01J31/1815—Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine with more than one complexing nitrogen atom, e.g. bipyridyl, 2-aminopyridine
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- B01J31/181—Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine
- B01J31/1825—Ligands comprising condensed ring systems, e.g. acridine, carbazole
- B01J31/183—Ligands comprising condensed ring systems, e.g. acridine, carbazole with more than one complexing nitrogen atom, e.g. phenanthroline
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- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
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- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- B01J2231/42—Catalytic cross-coupling, i.e. connection of previously not connected C-atoms or C- and X-atoms without rearrangement
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Abstract
The invention relates to a preparation method of a thioether compound, and relates to the technical field of organic synthesis. The preparation method of the invention comprises the following steps of preparing the compound R 1 ‑B(OH) 2 And with
Reacting in a solvent I under the action of a copper salt catalyst I to obtain a thiosulfonate intermediate;
reacting with the thiosulfonate intermediate in a solvent II under the action of a catalyst II and a ligand to obtain the thioether compound
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a preparation method of a thioether compound.
Background
Organic sulfides are in a wide variety and are widely present in natural products. Sulfur-containing organic compounds are widely used in pesticides, medicines, materials, and the like because of their special structural properties. In view of the important value of organosulfur compounds, chemists are constantly developing efficient methods for preparing multifunctional sulfides.
Thioethers, especially asymmetric diaryl sulfides, are important core structural motifs that have been widely used in ligand chemistry, pharmaceutical chemistry, and material science. In addition, thioethers can be converted into a range of related functionalized scaffolds, such as sulfones, sulfoximines, and thioylides, greatly expanding the complexity and diversity of the molecule. The traditional synthetic method has harsh conditions and large substrate limitation. Therefore, the development of a new thioether synthetic route and the expansion of the substrate range of thioether are very important.
Disclosure of Invention
Therefore, the technical problem to be solved by the invention is to overcome the problems of harsh synthetic method and large substrate limitation of the thioether compound in the prior art.
In order to solve the technical problems, the invention provides a preparation method of a thioether compound. In order to develop thioether compounds with wide substrate range, the thioether compounds which can be used as functional intermediates are synthesized by adopting suzuki coupled raw materials through molecular design and optimization, and the synthetic route has the advantages of mild conditions, high yield and wide substrate range.
An object of the present invention is to provide a method for preparing a thioether compound, comprising the steps of,
s1, compound R 1 -B(OH) 2 Reacting with a compound with a structure shown in a formula (II) in a solvent I under the action of a copper salt catalyst I to obtain a thiosulfonate intermediate;
s2, reacting the compound with the structure of the formula (III) with the thiosulfonate intermediate of the S1 in a solvent II under the action of a catalyst II and a ligand to obtain a thioether compound with the structure of the formula (IV); the catalyst II is one or more of nickel salt, zinc powder and manganese powder; the ligand is 1, 10-phenanthroline or bipyridine ligand;
wherein the structures of formulas (II) - (IV) are as follows:
wherein X is selected from I or Br;
R 1 selected from substituted or unsubstituted aryl groups, substituted or unsubstituted heterocyclic groups; the substituted group is selected from C 1 -C 18 Alkyl, methoxy, cyano, nitro, carbonyl or halogen;
when X = I, R 2 Is selected from C 1 -C 18 An alkyl, aryl or heterocyclic group;
when X = Br, R 2 Selected from substituted or unsubstituted C 1 -C 18 An alkyl group; the substituted group is cyano;
R 3 selected from hydrogen, methyl, methoxy, tert-butyl, halogen or heterocyclic groups.
In one embodiment of the present invention, in S1, the preparation method of the compound having the structure of formula (II) comprises the following steps: reacting a compound with a structure shown in a formula (V) with an acylating reagent in a solvent to obtain a compound with a structure shown in a formula (II);
R 3 selected from hydrogen, methyl, methoxy, tert-butylA group, a halogen or a heterocyclic group.
In one embodiment of the invention, the acylating agent is an acid anhydride and/or acyl halide.
In one embodiment of the invention, the acyl halide is acetyl chloride and/or acetyl bromide; the acid anhydride is one or more of acetic anhydride, butyric anhydride, benzoic anhydride and phthalic anhydride.
In one embodiment of the invention, the solvent is one or more of chloroform, acetonitrile and dichloromethane.
In one embodiment of the present invention, in S1, the copper salt catalyst I is one or more of copper sulfate, copper trifluoromethanesulfonate, copper bromide and copper iodide.
In one embodiment of the present invention, in S1, the solvent I is methanol and/or ethanol.
In one embodiment of the invention, in S1, the reaction temperature is 60-100 ℃ and the reaction time is 10-12h.
In one embodiment of the invention, in S1, the compound R 1 -B(OH) 2 The molar ratio of the compound having the structure of formula (II) to the copper salt catalyst I is (20.
In one embodiment of the invention, in S2, the catalyst II is one or more of nickel salt, zinc powder and manganese powder; the nickel salt is one or more of nickel bromide, bis (triphenylphosphine) nickel chloride and nickel acetate.
In one embodiment of the invention, in S2, the ligand is a 1, 10-phenanthroline or bipyridine-based ligand.
In one embodiment of the invention, the bipyridine-based ligand is one or more of 6,6' -dimethyl-2, 2' -bipyridine, 2' -bipyridine and 4,4' -di-tert-butyl-2, 2' -bipyridine.
In one embodiment of the present invention, in S2, the solvent II is one or more of N, N-dimethylformamide, N-dimethylacetamide and acetonitrile.
In one embodiment of the invention, in S2, the reaction is carried out at a temperature of 30 to 50 ℃ for a time of 5 to 6 hours.
In one embodiment of the present invention, in S2, the molar ratio of the compound of the structure of formula (III), the thiosulfonate intermediate, the mixture is (40; the mixture is catalyst II and a ligand.
In one embodiment of the present invention, the specific reaction formula is as follows:
the principle of the invention is as follows: generating aryl copper active species by using a boric acid (ester) compound which is a raw material of Suzuki coupling reaction under the action of a copper salt catalyst I, and further reacting the aryl copper active species with an electrophilic polysulfide compound (II) to obtain a thiosulfonate intermediate; the thiosulfonate intermediate can realize reduction coupling with halogenated compounds under the catalysis of a catalyst II so as to obtain thioether compounds,
compared with the prior art, the technical scheme of the invention has the following advantages:
(1) The preparation method adopts the commercialized suzuki coupled raw materials, and the raw materials are cheap and easy to obtain.
(2) The preparation method of the invention greatly widens the substrate range of the thioether compound.
(3) The preparation method can obtain more thioether compounds with complex structures, and is an important synthetic intermediate or a drug intermediate.
Detailed Description
The present invention is further described below in conjunction with specific examples to enable those skilled in the art to better understand the present invention and to practice it, but the examples are not intended to limit the present invention.
In the present invention, mol% represents a molar ratio unless otherwise specified.
Example 1
A thioether compound 01 and a preparation method thereof specifically comprise the following steps:
step 1: intermediate PhSO 2 Synthesis of SNa (a-1)
Sodium benzenesulfinate (10g, 61mmol) and sulfur (1.95g, 61mmol) were dissolved in anhydrous pyridine (60 mL) to give a yellow solution. The reaction was stirred under argon to give a white suspension after 1 h. Ether was added to the suspension and the reaction was filtered and washed with anhydrous ether to give intermediate PhSO 2 SNa (a-1) as a white crystalline solid.
Step 2: synthesis of intermediate (a-2)
1.97g (10 mmol) of intermediate PhSO 2 SNa (a-1) was dissolved in chloroform (10 mL), and 0.5mL of acetyl chloride (7.2 mmol) was slowly added thereto, followed by stirring at room temperature (25 ℃ C.) for 12 hours. After the reaction is finished, extracting by using ethyl acetate and water, removing a water layer, drying by using anhydrous sodium sulfate, removing an organic solvent by rotary evaporation, and purifying by using column chromatography to obtain a light yellow solid, namely the intermediate (a-2).
And 3, step 3: synthesis of intermediate (a-3)
In a glove box, 80.1mg (0.4 mmol) of intermediate (a-2), 27.4mg (0.2 mmol) of p-methylphenylboronic acid, cu (OSO) 2 CF 3 ) 2 (1 eq.) to a dry 8mL reaction vial, 2mL of anhydrous methanol was added, the reaction vial was capped, and the reaction was carried out at 60 ℃ for 12h. After the reaction is finished, removing the organic solvent by rotary evaporation, and purifying by column chromatography to obtain a transparent oily product, namely the intermediate (a-3), wherein the reaction yield is 95%.
And 4, step 4: synthesis of Compound 01
In a glove box, 42.0mg (0.2 mmol) of 3-iodothiophene, 106mg (0.4 mmol) of intermediate (a-3), niBr (2.5 mol%), 1, 10-phenanthroline (3.0 mol%), zinc powder (2.5 eq) were weighed into a dry 8mL reaction vial, and 1mLN, N-dimethylformamide was added, the reaction vial cap was closed, and the reaction was carried out at 50 ℃ for 6 hours. After the reaction is finished, ethyl acetate (20 mL multiplied by 2) is used for extraction twice, a water layer is removed, the mixture is dried by anhydrous sodium sulfate, organic solvent is removed by rotary evaporation, and a transparent oily product, namely the compound 01, is obtained after column chromatography purification, and the reaction yield is 74%.
Example 2
A thioether compound 02 and a preparation method thereof specifically comprise the following steps:
step 1: intermediate PhSO 2 Synthesis of SNa (a-1)
Sodium benzenesulfinate (10g, 61mmol) and sulfur (1.95g, 61mmol) were dissolved in anhydrous pyridine (60 mL) to obtain a yellow solution. The reaction was stirred under argon to give a white suspension after 1 h. Diethyl ether was added to the suspension, and the reaction was filtered and washed with anhydrous diethyl ether. Obtaining an intermediate PhSO 2 SNa (a-1) as a white crystalline solid.
And 2, step: synthesis of intermediate (a-2)
1.97g (10 mmol) of intermediate PhSO 2 SNa (a-1) was dissolved in chloroform (10 mL), and 0.5mL of acetyl chloride (7.2 mmol) was slowly added thereto and stirred at room temperature (25 ℃) for 12 hours. After the reaction, the mixture was extracted with ethyl acetate and water, and the aqueous layer was removedDrying with sodium sulfate, removing organic solvent by rotary evaporation, and purifying by column chromatography to obtain light yellow solid, namely the intermediate (a-2).
And 3, step 3: synthesis of intermediate (a-4)
In a glove box, 80.1mg (0.4 mmol) of intermediate (a-2), 24.4mg (0.2 mmol) of phenylboronic acid, cu (OSO) 2 CF 3 ) 2 (1 eq.) to a dry 8mL reaction vial, 2mL of anhydrous methanol was added, the reaction vial was capped, and the reaction was carried out at 60 ℃ for 12h. After the reaction is finished, removing the organic solvent by rotary evaporation, and purifying by column chromatography to obtain a transparent oily product, namely the intermediate (a-4), wherein the reaction yield is 96%.
And 4, step 4: synthesis of Compound 02
In a glove box, 46.8mg (0.2 mmol) of 4-iodoanisole, 106mg (0.4 mmol) of intermediate (a-4), niBr (2.5 mol%), 1, 10-phenanthroline (3.0 mol%), zinc powder (2.5 eq) were weighed into a dry 8mL reaction vial, and 1mLN, N-dimethylformamide was added, the reaction vial cap was closed, and the reaction was carried out at 50 ℃ for 6 hours. After the reaction is finished, ethyl acetate (20 mL multiplied by 2) is used for extracting twice, a water layer is removed, anhydrous sodium sulfate is used for drying, organic solvent is removed by rotary evaporation, and a transparent oily product, namely the compound 02 is obtained after column chromatography purification, and the reaction yield is 86%.
Example 3
A thioether compound 03 and a preparation method thereof comprise the following steps:
step 1: intermediate PhSO 2 Synthesis of SNa (a-1)
Sodium benzenesulfinate (10 g,61 mmol) and sulfur (1.95g, 61mmol) were dissolved in anhydrous pyridine (60 mL) to give a yellow solution. The reaction was stirred under argon to give a white suspension after 1 h. Diethyl ether was added to the suspension, and the reaction was filtered and washed with anhydrous diethyl ether. Obtaining an intermediate PhSO 2 SNa (a-1) as a white crystalline solid.
And 2, step: synthesis of intermediate (a-2)
1.97g (10 mmol) of intermediate PhSO 2 SNa (a-1) was dissolved in chloroform (10 mL), and 0.5mL of acetyl chloride (7.2 mmol) was slowly added thereto, followed by stirring at room temperature (25 ℃ C.) for 12 hours. After the reaction is finished, ethyl acetate and water are used for extraction, a water layer is removed, anhydrous sodium sulfate is used for drying, organic solvent is removed through rotary evaporation, and light yellow solid, namely the intermediate (a-2), is obtained through column chromatography purification.
And 3, step 3: synthesis of intermediate (a-4)
In a glove box, 80.1mg (0.4 mmol) of intermediate (a-2), 24.4mg (0.2 mmol) of phenylboronic acid, cu (OSO) 2 CF 3 ) 2 (1 eq.) to a dry 8mL reaction vial, 2mL of anhydrous methanol was added, the reaction vial was capped and allowed to react at 60 ℃ for 12h. After the reaction is finished, removing the organic solvent by rotary evaporation, and purifying by column chromatography to obtain a transparent oily product, namely the intermediate (a-4), wherein the reaction yield is 96%.
And 4, step 4: synthesis of Compound 03
In a glove box, 39.2mg (0.2 mmol) of iodocyclopentane, 106mg (0.4 mmol) of intermediate (a-4), niBr (2.5 mol%), 1, 10-phenanthroline (3.0 mol%), zinc powder (2.5 eq) were weighed into a dry 8mL reaction vial, 1mLN, N-dimethylformamide was added, the reaction vial cap was closed, and the reaction was allowed to react at 50 ℃ for 6h. After the reaction is finished, ethyl acetate (20 mL multiplied by 2) is used for extraction twice, a water layer is removed, the mixture is dried by anhydrous sodium sulfate, organic solvent is removed by rotary evaporation, and a transparent oily product, namely the compound 03, is obtained after column chromatography purification, and the reaction yield is 76%.
Example 4
A thioether compound 04 and a preparation method thereof specifically comprise the following steps:
step 1: intermediate PhSO 2 Synthesis of SNa (a-1)
Sodium benzenesulfinate (10g, 61mmol) and sulfur (1.95g, 61mmol) were dissolved in anhydrous pyridine (60 mL) to obtain a yellow solution. The reaction was stirred under argon to give a white suspension after 1 h. Diethyl ether was added to the suspension, and the reaction was filtered and washed with anhydrous diethyl ether. To obtain an intermediate PhSO 2 SNa (a-1) as a white crystalline solid.
Step 2: synthesis of intermediate (a-2)
1.97g (10 mmol) of intermediate PhSO 2 SNa (a-1) was dissolved in chloroform (10 mL), and 0.5mL of acetyl chloride (7.2 mmol) was slowly added thereto, followed by stirring at room temperature (25 ℃ C.) for 12 hours. After the reaction is finished, ethyl acetate and water are used for extraction, a water layer is removed, anhydrous sodium sulfate is used for drying, organic solvent is removed through rotary evaporation, and light yellow solid, namely the intermediate (a-2), is obtained through column chromatography purification.
And step 3: synthesis of intermediate (a-4)
In a glove box, 80.1mg (0.4 mmol) of intermediate (a) were weighed-2), 24.4mg (0.2 mmol) of phenylboronic acid, cu (OSO) 2 CF 3 ) 2 (1 eq.) to a dry 8mL reaction vial, 2mL of anhydrous methanol was added, the reaction vial was capped, and the reaction was carried out at 60 ℃ for 12h. After the reaction is finished, removing the organic solvent by rotary evaporation, and purifying by column chromatography to obtain a transparent oily product, namely the intermediate (a-4), wherein the reaction yield is 96%.
And 4, step 4: synthesis of Compound 04
In a glove box, a microsyringe was used to weigh 24 microliters (0.2 mmol) of 5-bromovaleronitrile and 106mg (0.4 mmol) of intermediate (a-4), niCl (PPh) 3 ) 2 (2.5 mol%), 6 '-dimethyl-2, 2' -bipyridine (7.5 mol%), manganese powder (1.5 eq) in a dry 8mL reaction vial, 2mL of N, N-dimethylformamide was added, the reaction vial was capped, and the reaction was carried out at 30 ℃ for 6h. After the reaction is finished, ethyl acetate (20 mL multiplied by 2) is used for extraction twice, a water layer is removed, the mixture is dried by anhydrous sodium sulfate, organic solvent is removed by rotary evaporation, and a light yellow oily product, namely the compound 04, is obtained after column chromatography purification, wherein the reaction yield is 81%.
Example 5
A thioether compound 05 and a preparation method thereof specifically comprise the following steps:
step 1: intermediate PhSO 2 Synthesis of SNa (a-1)
Sodium benzenesulfinate (10g, 61mmol) and sulfur (1.95g, 61mmol) were dissolved in anhydrous pyridine (60 mL) to obtain a yellow solution. The reaction was stirred under argon to give a white suspension after 1 h. Ether was added to the suspension and the reaction was filtered and washed with anhydrous ether to give intermediate PhSO 2 SNa (a-1) as a white crystalline solid.
And 2, step: synthesis of intermediate (a-2)
1.97g (10 mmol) of intermediate PhSO 2 SNa (a-1) was dissolved in chloroform (10 mL), and 0.5mL of acetyl chloride (7.2 mmol) was slowly added thereto, followed by stirring at room temperature (25 ℃ C.) for 12 hours. After the reaction is finished, ethyl acetate and water are used for extraction, a water layer is removed, anhydrous sodium sulfate is used for drying, organic solvent is removed through rotary evaporation, and light yellow solid, namely the intermediate (a-2), is obtained through column chromatography purification.
And 3, step 3: synthesis of intermediate (a-4)
In a glove box, 80.1mg (0.4 mmol) of intermediate (a-2), 24.4mg (0.2 mmol) of phenylboronic acid, cu (OSO) 2 CF 3 ) 2 (1 eq.) to a dry 8mL reaction vial, 2mL of anhydrous methanol was added, the reaction vial was capped, and the reaction was carried out at 60 ℃ for 12h. After the reaction is finished, removing the organic solvent by rotary evaporation, and purifying by column chromatography to obtain a transparent oily product, namely the intermediate (a-4), wherein the reaction yield is 96%.
And 4, step 4: synthesis of Compound 05
In a glove box, 40.2mg (0.2 mmol) of 2-phenoxyethyl bromide, 106mg (0.4 mmol) of intermediate (a-4), and NiCl (PPh) 3 ) 2 (2.5 mol%), 6 '-dimethyl-2, 2' -bipyridine (7.5 mol%), manganese powder (1.5 eq) in a dry 8mL reaction vial, 2mLN, N-dimethylformamide were added, the reaction vial was capped, and the reaction was carried out at 30 ℃ for 6h. After the reaction is finished, ethyl acetate (20 mL multiplied by 2) is used for extracting twice, a water layer is removed, anhydrous sodium sulfate is used for drying, organic solvent is removed by rotary evaporation, and an off-white solid product, namely the compound 05, is obtained after column chromatography purification, and the reaction yield is 92%.
Test example 1
The thioether compounds 01 to 05 synthesized in examples 1 to 5 of the present invention were subjected to nuclear magnetic resonance testing.
Table 1 shows the structures of the compounds and 1 h NMR test results:
TABLE 1
It should be understood that the above examples are only for clarity of illustration and are not intended to limit the embodiments. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither required nor exhaustive of all embodiments. And obvious variations or modifications of the invention may be made without departing from the scope of the invention.
Claims (9)
1. A process for producing a thioether compound, comprising the steps of,
s1, compound R 1 -B(OH) 2 Reacting with a compound with a structure shown in a formula (II) in a solvent I under the action of a copper salt catalyst I to obtain a thiosulfonate intermediate;
s2, reacting the compound with the structure of the formula (III) with the thiosulfonate intermediate of the S1 in a solvent II under the action of a catalyst II and a ligand to obtain a thioether compound with the structure of the formula (IV); the catalyst II is one or more of nickel salt, zinc powder and manganese powder; the ligand is 1, 10-phenanthroline or bipyridine ligand;
wherein the structures of formulas (II) - (IV) are as follows:
wherein X is selected from I or Br;
R 1 selected from substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic group; the substituted group is selected from C 1 -C 18 Alkyl, methoxy, cyano, nitro, carbonyl or halogen;
when X = I, R 2 Is selected from C 1 -C 18 An alkyl, aryl or heterocyclic group;
when X = Br, R 2 Selected from substituted or unsubstituted C 1 -C 18 An alkyl group; the substituted group is cyano;
R 3 selected from hydrogen, methyl, methoxy, tert-butyl, halogen or heterocyclic groups.
2. The method for preparing a thioether compound according to claim 1, wherein in S1, the copper salt catalyst I is one or more of copper sulfate, copper trifluoromethanesulfonate, copper bromide and copper iodide.
3. The method for producing a thioether compound according to claim 1, wherein in S1, the solvent I is methanol and/or ethanol.
4. The method for preparing a thioether compound according to claim 1, wherein the reaction is carried out at a temperature of 60-100 ℃ for 10-12h in S1.
5. The process for producing a thioether compound according to claim 1, wherein in S1, the compound R 1 -B(OH) 2 The molar ratio of the compound having the structure of formula (II) to the copper salt catalyst I is (20.
6. The method according to claim 1, wherein in S2, the nickel salt is one or more of nickel bromide, nickel bis (triphenylphosphine) chloride, and nickel acetate.
7. The method for preparing a thioether compound according to claim 1, wherein in S2, the solvent II is one or more of N, N-dimethylformamide, N-dimethylacetamide and acetonitrile.
8. The method for preparing a thioether compound according to claim 1, wherein the reaction is carried out at a temperature of 30-50 ℃ for 5-6h in S2.
9. The method for preparing a thioether compound according to claim 1, wherein, in S2, the molar ratio of the compound of the structure of formula (III), the thiosulfonate intermediate, the mixture is (40; the mixture is catalyst II and a ligand.
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| CN112812046A (en) * | 2020-12-29 | 2021-05-18 | 中国科学院西北高原生物研究所 | Preparation method of thiosulfonate compound |
| CN114181122A (en) * | 2021-11-27 | 2022-03-15 | 苏州照固新材料科技有限公司 | Benzyl thioether compound and preparation method thereof |
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| CN112812046A (en) * | 2020-12-29 | 2021-05-18 | 中国科学院西北高原生物研究所 | Preparation method of thiosulfonate compound |
| CN114181122A (en) * | 2021-11-27 | 2022-03-15 | 苏州照固新材料科技有限公司 | Benzyl thioether compound and preparation method thereof |
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| Reactions of p-toluenesulfinic acid with dialkoxy or diamino sulfides and disulfides;Okawara, Tadashi 等;《Chemical & Pharmaceutical Bulletin》;19851231;5225-30 * |
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