WO2015087352A1 - A process for the synthesis of aryl sulfones - Google Patents
A process for the synthesis of aryl sulfones Download PDFInfo
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- WO2015087352A1 WO2015087352A1 PCT/IN2014/000772 IN2014000772W WO2015087352A1 WO 2015087352 A1 WO2015087352 A1 WO 2015087352A1 IN 2014000772 W IN2014000772 W IN 2014000772W WO 2015087352 A1 WO2015087352 A1 WO 2015087352A1
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- benzene
- phenylsulfonyl
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- alkyl
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- 0 C[C@]1*CCC1 Chemical compound C[C@]1*CCC1 0.000 description 3
- KZTYYGOKRVBIMI-UHFFFAOYSA-N O=S(c1ccccc1)(c1ccccc1)=O Chemical compound O=S(c1ccccc1)(c1ccccc1)=O KZTYYGOKRVBIMI-UHFFFAOYSA-N 0.000 description 2
- RAYKFMBXKZRFBC-UHFFFAOYSA-N COc1cccc(S(c2ccccc2)(=O)=O)c1 Chemical compound COc1cccc(S(c2ccccc2)(=O)=O)c1 RAYKFMBXKZRFBC-UHFFFAOYSA-N 0.000 description 1
- KUJUKTAMPGOZAG-UHFFFAOYSA-N O=S(c([s]1)ccc1Br)(c1ccccc1)=O Chemical compound O=S(c([s]1)ccc1Br)(c1ccccc1)=O KUJUKTAMPGOZAG-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/04—Preparation of sulfones; Preparation of sulfoxides by reactions not involving the formation of sulfone or sulfoxide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/14—Sulfones; Sulfoxides having sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/16—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C317/22—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- 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
- C07D333/30—Hetero atoms other than halogen
- C07D333/34—Sulfur atoms
Definitions
- the present invention relates to a novel, efficient and transition-metal-free process for the preparation of aryl sulfones.
- Arylsulfbnes are important building blocks in organic chemistry and especially in medicinal chemistry.
- the arylsulfone fragment is found in various drugs, such as the COX-2 inhibitor Vioxx or the prostaglandin D 2 antagonist Laropiprant.
- Diarylsulfones have been shown to exhibit antitumor activities or to inhibit HIV-1 reverse transcriptase.
- US 3,250,812 discloses a process for producing alkyl aryl sulfones which comprises reacting an aryl compound having free hydrogen on the ring with a compound having the formula (R1 S02)20, wherein Rl is a lower alkyl radical in a solvent at sufficient temperatures to effect said reaction.
- US 4,386,221 disclose a process for the preparation of aryl alkyl sulfones and aryl vinyl sulfones. The process comprises of reacting an aryl compound with an alkyl sulfonyl fluoride or with a vinyl sulfonyl fluoride in the presence of a catalyst selected from AlC13 and AlBr3.
- US 5,015,775 discloses Alkyl aryl sulfones of the formula R— S0 3 -Ar— Yn, wherein Ar is an aryl compound, Y is a substituent on the aryl compound and R is alkyl or cycloalkyl, and liquid mixtures of positional isomers of the same are prepared by reacting an aryl compound of the formula Ar— Yn, with an alkyl sulfonic acid of the formula — S0 3 H and a phosphorus reagent, preferably under heat.
- US 5 468 903 relates to a process for preparing a compound comprising a monocyclic aromatic ring having at least a first substituent and a substituted sulphonyl group at the position para to the first substituent, the process comprising mixing a reactant comprising the monocyclic aromatic ring with the first substituent and hydrogen in the position of the ring para to the first substituent, with a sulphonic acid halide derivative in the presence of a naturally occurring or synthetic zeolite capable of catalyzing a sulphonylation reaction between the reactant and the sulphonic acid halide.
- US 6,455,738 Bl relates to a process for the sulfonation of an aromatic compound, said process comprising the steps of: a) reacting said aromatic compound with a sulfonating agent, in the presence of a catalytically effective amount of a catalyst which is a mixture of bismuth trihalide and of perfluoroalkanesulfonic acid, with a molar ratio less than the stoichiometry resulting in the complete exchange of the halide by the sulfonic functional group, to obtain a sulfonated aromatic compound, and b) recovering the sulfonated aromatic compound obtained in step (a).
- a catalyst which is a mixture of bismuth trihalide and of perfluoroalkanesulfonic acid
- US 4,950,793 discloses a process of reacting an aromatic hydrocarbon with a halogenated sulfonic acid in the presence of a Lewis acid to obtain an aromatic sulfone compound .
- US 5,276,196 relates to the synthesis of bis(haloarylsulfonyl) aromatic compounds and more specifically, bis(chlorophenylsulfonyl) aromatic compounds.
- a process has been reported wherein product of high purity and minimal iron contamination is produced by reacting haloarylsulfonyl halide with an aromatic compound in the presence of an appropriate catalyst with and without solvent.
- US 2743290 relates to a process for the production of halogenated thioesters of a sulfonic acid.
- the main object of the present invention is to provide a room temperature single step process for synthesis of aryl sulfones and substituted aryl sulfones starting from aryl/aryl substrates.
- the present invention provides a room temperature single step process for synthesis of compound of Formula I
- R is selected from H, alkyl (d-C 6 ), aryl, heteroaryl, 0-, S-, N-, P- alkyl/unsubstituted and substituted aryl;
- R " is selected from alkyl (Ci-C 6 ), aryl, heteroaryl, 0-, S-, N-, P- alkyl/unsubstituted and substituted aryl; comprising the steps of: a. adding benzyne precursor of Formula II to a stirred solution of fluoride ion source and compound of Formula III in the ratio ranging between 1 : 1 to 1 : 1.1 in anhydrous acetonitrile to obtain a reaction mixture;
- R is selected from H, alkyl, aryl, heteroaryl, 0-, S-, N-, P- alkyl/ unsubstituted and substituted aryl;
- R ' is selected from, alkyl, aryl, heteroaryl, 0-, S-, N-, P- alkyl/ unsubstituted and substituted aryl;
- X is selected from H, Li, Na, K, Cs; b. stirring the reaction mixture of step (a) for the period in the range of 1 to 8 hours followed by purification to obtain the desired product t.
- fluoride ion source is selected from the group consisting of TBAF (Tetra-n-butylammonium fluoride), CsF (Cesium fluoride), NaF (Sodium Fluoride), RbF (Rubidium fluoride) or KF (Potassium fluoride).
- the fluoride ion source is selected from TBAF or CsF.
- compound of formula I is selected from the group consisting of:
- compound of formula II is selected from the group consisting df: 2- (trimethylsilyl)phenyl trifluoromethane-sulfonate (1)
- compound of formula III is selected from the group consisting of: sodium benzenesulfinate (2)
- the yield of the compound of formula I is in the range of 45-96%.
- Root temperature means temperature in the range of 20-30°C.
- Present invention provides a transition metal free process for the synthesis of arylsulfones, wherein sulfinic acid/sulfinic acid salt is treated with arynes to obtain arylsulfones under mild reaction condition, in high yields. Further, the present invention provides a process for the synthesis of arylsulfones which works with all kinds of aryl substrates having electron donating or withdrawing functional groups.
- the process of the present invention provides aryl-aryl sulfones as well as aryl-alkyl sulfones.
- Present invention provides a room temperature single step process for synthesis of aryl sulfones and substituted aryl sulfones compound of Formula I
- R is selected from H, alkyl, aryl, heteroaryl, 0-, S-, N-, P- alkyl/unsubstituted and substituted aryl;
- R' is selected from alkyl, aryl, heteroaryl, 0-, S-, N-, P- alkyl/unsubstituted and substituted aryl, starting from compounds of Formula II and Formula III,
- R is selected from H, alkyl, aryl, heteroaryl, 0-, S-, N-, P- alkyl/ unsubstituted and substituted aryl;
- R' is selected from, alkyl, aryl, heteroaryl, 0-, S-, N-, P- alkyl/ unsubstituted and substituted aryl;
- X is selected from H, Li, Na, K, Cs; comprising the steps of: adding benzyne precursor of Formula II to a stirred solution of fluoride ion source and compound of Formula III in anhydrous acetonitrile to obtain a reaction mixture; stirring the reaction mixture of step (a) followed by purification affords a solid or thick oil sulfone I.
- the present invention provides a room temperature single step process for synthesis of aryl sulfones and substituted aryl sulfones compounds of Formula I wherein the fluoride ion source is selected from TBAF, CsF, NaF, RbF, KF and preferably from TBAF or CsF.
- the present invention provides a room temperature single step process for synthesis of sulfones and substituted sulfones compounds of Formula I wherein the yield is more than - 45% and preferably more than 80%.
- 4-Methoxybenzenesulfinic acid sodium salt (26) was prepared by heating of sodium sulfite (2.5 g, 20 mmol), 4-methoxybenzenesulfonyl chloride (2.06 g, 10 mmol) and sodium bicarbonate (1.68 g, 20 mmol) in water (9.6 mL) at 70-80 °C for 4 h. After cooling to room temperature (20-30°C), water was removed under vacuum and the residue was extracted in ethanol. Recrystallization from ethanol furnished sodium sulfmate 26 (1.34 g, 67%) as a white solid.
- the other sodium sulfonates 20, 22, 24, 28, 30, 32 and 34 were prepared similarly from their corresponding sulfonyl chlorides using known methods.
- the process of the invention works with very simple reagents at very mild reaction condition which can be very useful industrially. Also the process can be applied for large scale synthesis.
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Abstract
The present patent discloses a novel, efficient and transition-metal-free room temperature single step process for synthesis of aryl sulfones and substituted aryl sulfones starting from aryl substrates.
Description
A PROCESS FOR THE SYNTHESIS OF ARYL SULFONES
FIELD OF THE INVENTION
The present invention relates to a novel, efficient and transition-metal-free process for the preparation of aryl sulfones.
BACKGROUND AND PRIOR ART OF THE INVENTION
Arylsulfbnes are important building blocks in organic chemistry and especially in medicinal chemistry. The arylsulfone fragment is found in various drugs, such as the COX-2 inhibitor Vioxx or the prostaglandin D2 antagonist Laropiprant. Diarylsulfones have been shown to exhibit antitumor activities or to inhibit HIV-1 reverse transcriptase.
Because of their importance, numerous procedures for the synthesis of arylsulfbnes have been reported, such as the oxidation of sulfides, the sulfonylation of arenes, or Pd- and Cu-catalyzed coupling reactions as well as transition-metal-free synthesis of diarylsulfones from arylsulfinic acid sodium salts and diaryliodonium salts.
Article titled, "Arylation of Lithium Sulfinates with Diaryliodonium Salts: A Direct and Versatile Access to Arylsulfbnes" by Natalie Umierski and Georg Manolikakes in Organic Letters 2013, 15, 188 reports an efficient, transition-metal-free arylation of lithium sulfinates, which are readily accessible from reactions of organolithium reagents with sulfurdioxide. Based on this method, it further reports a practical protocol for the direct transformation of (hetero)arenes and (hetero)aromatic halides into diarylsulfones. US 3,250,812 discloses a process for producing alkyl aryl sulfones which comprises reacting an aryl compound having free hydrogen on the ring with a compound having the formula (R1 S02)20, wherein Rl is a lower alkyl radical in a solvent at sufficient temperatures to effect said reaction. US 4,386,221 disclose a process for the preparation of aryl alkyl sulfones and aryl vinyl sulfones. The process comprises of reacting an aryl compound with an alkyl sulfonyl fluoride or with a vinyl sulfonyl fluoride in the presence of a catalyst selected from AlC13 and AlBr3.
US 5,015,775 discloses Alkyl aryl sulfones of the formula R— S03-Ar— Yn, wherein Ar is an aryl compound, Y is a substituent on the aryl compound and R is alkyl or cycloalkyl, and liquid mixtures of positional isomers of the same are prepared by reacting an aryl compound of the formula Ar— Yn, with an alkyl sulfonic acid of the formula — S03H and a phosphorus reagent, preferably under heat.
Article titled, "One-step synthesis of a, ?-unsaturated arylsulfones by a novel multicomponent reaction of aromatic aldehydes, chloroacetonitrile, benzenesulfinic acid sodium salt" by Lei Zhang, Mao Hua Ding, Hong Yun Guo in Chinese Chemical Letters, Volume 23, Issue 12, December 2012, Pages 1352 1354 reports a new and green method for the synthesis of a, ?-unsaturated arylsulfones through the condensation of aromatic aldehydes, chloroacetonitrile, benzenesulfinic acid sodium salt in the presence of l-butyl-3 -methyl imidazolium hydroxide ([bmimJOH) in EtOH under reflux. The ionic liquid was recovered and recycled for subsequent reactions. The advantages of this protocol were non-toxic, easy work-up and good yields.
Article titled, "A mild and efficient new synthesis of aryl sulfones from boronic acids and sulfinic acid salts" by Christian Beaulieu, Daniel Guay, Zhaoyin Wang and David A. Evans in Tetrahedron Letters 45 (2004) 3233-3236 reports a new efficient and mild preparation of sulfones from boronic acids and sulfinic acid salts. The cross-coupling reaction mediated by cupric acetate gives access to a variety of sulfones in excellent yield.
Article titled, "Synthesis of Aryl Sulfones via 1-Proline-Promoted Cul-Catalyzed Coupling Reaction of Aryl Halides with Sulfinic Acid Salts" by Wei Zhu and Dawei Ma in J. Org. Chem., 2005, 70 (7), pp 2696-2700 reports The Cul/l-proline sodium salt catalyzed coupling reaction of aryl halides with sulfinic acid salts readily occurs at 80-95 °C in DMSO to give the corresponding aryl sulfones in good to excellent yields. This process is well- tolerated by a wide range of functional groups including hydroxyl, amino, acetanilide, ketone, ester, and nitrile. Using this method, 4-phenylsulfonyl- and 4-methanesulfonyl-substituted 1- phenylalanine derivatives are prepared.
US 5 468 903 relates to a process for preparing a compound comprising a monocyclic aromatic ring having at least a first substituent and a substituted sulphonyl group at the position para to the first substituent, the process comprising mixing a reactant comprising the
monocyclic aromatic ring with the first substituent and hydrogen in the position of the ring para to the first substituent, with a sulphonic acid halide derivative in the presence of a naturally occurring or synthetic zeolite capable of catalyzing a sulphonylation reaction between the reactant and the sulphonic acid halide.
US 6,455,738 Bl relates to a process for the sulfonation of an aromatic compound, said process comprising the steps of: a) reacting said aromatic compound with a sulfonating agent, in the presence of a catalytically effective amount of a catalyst which is a mixture of bismuth trihalide and of perfluoroalkanesulfonic acid, with a molar ratio less than the stoichiometry resulting in the complete exchange of the halide by the sulfonic functional group, to obtain a sulfonated aromatic compound, and b) recovering the sulfonated aromatic compound obtained in step (a).
US 4,950,793 discloses a process of reacting an aromatic hydrocarbon with a halogenated sulfonic acid in the presence of a Lewis acid to obtain an aromatic sulfone compound .
US 5,276,196 relates to the synthesis of bis(haloarylsulfonyl) aromatic compounds and more specifically, bis(chlorophenylsulfonyl) aromatic compounds. A process has been reported wherein product of high purity and minimal iron contamination is produced by reacting haloarylsulfonyl halide with an aromatic compound in the presence of an appropriate catalyst with and without solvent.
US 2743290 relates to a process for the production of halogenated thioesters of a sulfonic acid.
However, till date arynes have not been used for such transformation.
OBJECTIVE OF THE INVENTION
The main object of the present invention is to provide a room temperature single step process for synthesis of aryl sulfones and substituted aryl sulfones starting from aryl/aryl substrates.
SUMMARY OF THE INVENTION
The present invention provides a room temperature single step process for synthesis of compound of Formula I
Formula I wherein, R is selected from H, alkyl (d-C6), aryl, heteroaryl, 0-, S-, N-, P- alkyl/unsubstituted and substituted aryl;
R" is selected from alkyl (Ci-C6), aryl, heteroaryl, 0-, S-, N-, P- alkyl/unsubstituted and substituted aryl; comprising the steps of: a. adding benzyne precursor of Formula II to a stirred solution of fluoride ion source and compound of Formula III in the ratio ranging between 1 : 1 to 1 : 1.1 in anhydrous acetonitrile to obtain a reaction mixture;
Formula II Formula III
wherein, R is selected from H, alkyl, aryl, heteroaryl, 0-, S-, N-, P- alkyl/ unsubstituted and substituted aryl; R' is selected from, alkyl, aryl, heteroaryl, 0-, S-, N-, P- alkyl/ unsubstituted and substituted aryl;
X is selected from H, Li, Na, K, Cs;
b. stirring the reaction mixture of step (a) for the period in the range of 1 to 8 hours followed by purification to obtain the desired product t.
In an embodiment of the present invention, fluoride ion source is selected from the group consisting of TBAF (Tetra-n-butylammonium fluoride), CsF (Cesium fluoride), NaF (Sodium Fluoride), RbF (Rubidium fluoride) or KF (Potassium fluoride).
In yet another embodiment of the present invention, the fluoride ion source is selected from TBAF or CsF.
In another embodiment of the present invention, compound of formula I is selected from the group consisting of:
1 -Phenyl (sulfonyl) benzene (3);
l,2-Difluoro-4-(phenylsulfonyl)benzene (5);
1.2- Dimethyl-4-(phenylsulfonyl)benzene (7);
1 ,4-Dimethyl-2-(phenylsulfonyl)benzene (9);
l-Methoxy-3-(phenylsulfonyl)benzene (11);
1.3- Dimethoxy-5-(phenylsulfonyl)benzene (13);
l,2-Dimethoxy-4-(phenylsulfonyl)benzene (15);
5-(Phenylsulfonyl)benzo[d] [1 ,3]dioxole (17);
(Methylsulfonyl)benzene (19);
(Butylsulfonyl)benzene (21);
1 -Methyl-4-(phenylsulfonyl)benzene (23);
l-(Tert-butyl)-4-(phenylsulfonyl)benzene (25);
l-Methoxy-4-(phenylsulfonyl)benzene (27);
l-(4-(phenylsulfonyl)phenyl)ethan-l-one (29);
l-Nitro-4-(phenylsulfonyl)benzene (31);
1 -Fluoro-4-(phenylsulfonyl)benzene 33);
2-bromo-5-(phenylsulfonyl)thiophene (35).
In yet another embodiment of the present invention, compound of formula II is selected from the group consisting df:
2- (trimethylsilyl)phenyl trifluoromethane-sulfonate (1)
4,5-difluoro-2-(trimethylsilyl)phenyl trifluoromethane-sulfonate (4)
4.5- dimethyl-2-(trimethylsilyl)phenyl trifluoromethane-sulfonate (6)
3.6- dimethyl-2-(trimethylsilyl)phenyl trifluoromethane-sulfonate (8)
3- methoxy-2-(trimethylsilyl)phenyl trifluoromethane-sulfonate (10)
3 ,5 -dimethoxy-2-(trimethylsilyl)phenyl trifluoromethane-sulfonate (12)
4,5-dimethoxy-2-(trimethylsilyl)phenyl trifluoromethane-sulfonate (14)
6-(trimethylsilyl)benzo[d] [1 ,3]dioxol-5-yl trifluoromethane-sulfonate (16)
In yet another embodiment of the present invention, compound of formula III is selected from the group consisting of: sodium benzenesulfinate (2)
sodium methanesulfmate (18)
sodium butane-l-sulfinate (20)
sodium 4-methylbenzenesulfmate (22)
sodium 4-(tert-butyl)benzenesulfinate (24)
sodium 4-methoxybenzenesulfinate (26)
sodium 4-acetylbenzenesulfinate (28)
sodium 4-nitrobenzenesulfinate (30)
sodium 4-fluorobenzenesulfmate (32)
Sodium 5-bromothiophene-2-sulfinate (34).
In yet another embodiment of the present invention, the yield of the compound of formula I is in the range of 45-96%.
DETAILED DESCRIPTION OF THE INVENTION
For the purposes of this patent application, "Room temperature" means temperature in the range of 20-30°C.
Present invention provides a transition metal free process for the synthesis of arylsulfones, wherein sulfinic acid/sulfinic acid salt is treated with arynes to obtain arylsulfones under mild reaction condition, in high yields.
Further, the present invention provides a process for the synthesis of arylsulfones which works with all kinds of aryl substrates having electron donating or withdrawing functional groups.
The process of the present invention provides aryl-aryl sulfones as well as aryl-alkyl sulfones.
Present invention provides a room temperature single step process for synthesis of aryl sulfones and substituted aryl sulfones compound of Formula I
Formula I
wherein, R is selected from H, alkyl, aryl, heteroaryl, 0-, S-, N-, P- alkyl/unsubstituted and substituted aryl;
R' is selected from alkyl, aryl, heteroaryl, 0-, S-, N-, P- alkyl/unsubstituted and substituted aryl, starting from compounds of Formula II and Formula III,
Formula II Formula III
Wherein, R is selected from H, alkyl, aryl, heteroaryl, 0-, S-, N-, P- alkyl/ unsubstituted and substituted aryl;
R' is selected from, alkyl, aryl, heteroaryl, 0-, S-, N-, P- alkyl/ unsubstituted and substituted aryl; and
X is selected from H, Li, Na, K, Cs;
comprising the steps of: adding benzyne precursor of Formula II to a stirred solution of fluoride ion source and compound of Formula III in anhydrous acetonitrile to obtain a reaction mixture; stirring the reaction mixture of step (a) followed by purification affords a solid or thick oil sulfone I.
The process is shown below in Scheme A:
Scheme: A
The present invention provides a room temperature single step process for synthesis of aryl sulfones and substituted aryl sulfones compounds of Formula I wherein the fluoride ion source is selected from TBAF, CsF, NaF, RbF, KF and preferably from TBAF or CsF.
The present invention provides a room temperature single step process for synthesis of sulfones and substituted sulfones compounds of Formula I wherein the yield is more than - 45% and preferably more than 80%.
In an aspect, the present invention provides the optimization results of fluoride source, various silyl triflate and sulfinates substrates selected which are summarized below in table 1, 2 and 3: Table 1: O timization studies3
aAll the reactions were performed on 25 mg scale of o-silyl aryl triflate 1. bA = 18- crown-6-ether (5 mol %).
Table 2: Pre aration of sulfones from various silyl triflates1
(1 equiv) 2 (1 equiv)
Table 3: Preparation of sulfones from various sulfinatesa
equiv) (1 equiv)
'All the reactions were performed on 50 mg scale of o-silyl aryl triflate 1. bTBAF (6 equiv). cCsF (4 equiv), 18-crown-6-ether. EXAMPLES
Following examples are given by way of illustration and therefore should not be construed to limit the scope of the invention.
GENERAL INFORMATION
All reagents and solvents were used as received from commercial sources unless and otherwise noted. Acetonitrile was dried and stored over 4 A molecular sieves. All experiments were carried out under an atmosphere of Argon. o-Silyl aryl inflates were synthesized by known procedures. Sodium sulfinates 2 and 18 were purchased from commercial sources and rest of the sodium sulfinates were prepared using known literature procedures. Pre-coated plates (silica gel 60 PF254, 0.25 mm or 0.5 mm) were utilized for Thin Layer Chromatography (TLC). Column chromatographic purifications were carried out on flash silica-gel (240-400 mesh) using petroleum ether and ethyl acetate as eluents. The 1H, 13C, NMR spectra were recorded on 200/400/500 MHz, 50/100/125 MHz NMR spectrometer respectively in CDC13. Chemical shifts were reported as δ values from standard peaks. Melting point was recorded on Buchi instrument. Mass spectra were taken on LC-MS (ESI) mass spectrometer. HRMS were scanned at NCL, Pune.
EXAMPLE 1 EXPERIMENTAL PROCEDURE FOR THE PREPARATION OF SODIUM SULFINATES
4-Methoxybenzenesulfinic acid sodium salt (26) was prepared by heating of sodium sulfite (2.5 g, 20 mmol), 4-methoxybenzenesulfonyl chloride (2.06 g, 10 mmol) and sodium bicarbonate (1.68 g, 20 mmol) in water (9.6 mL) at 70-80 °C for 4 h. After cooling to room temperature (20-30°C), water was removed under vacuum and the residue was extracted in
ethanol. Recrystallization from ethanol furnished sodium sulfmate 26 (1.34 g, 67%) as a white solid.
The other sodium sulfonates 20, 22, 24, 28, 30, 32 and 34 were prepared similarly from their corresponding sulfonyl chlorides using known methods.
GENERAL EXPERIMENTAL PROCEDURE FOR THE SYNTHESIS OF SULFONES
To a round-bottom flask containing TBAF (1.10 equiv) and sodium sulfmate (1.0 equiv) was added o-silylaryl triflate (1.00 equiv) in acetonitrile (1 mL) at room temperature (20-30°C), under Argon atmosphere. The reaction mixture was stirred at roojn temperature (20-30°C) and the progress was monitored by TLiC. After completion of* the reaction, acetonitrile was removed on rotary evaporator and the crude product was purified by flash silica gel column using a gradient of ethyl acetate-petroleum ether to afford the corresponding diaryl/aryl-alkyl/aryl-heteroaryl sulfones in good to excellent yields.
Example 2
Experimental Procedure using CsF: (Butylsulfonyl)benzene (21)
To a round-bottom flask containing CsF (101 mg, 670 mmol) butyl sulfmic acid sodium salt (36.2 mg, 251 mmol) and 18-Crown-6-ether (4.4 mg, 16.7 mmol) was added o- silyl aryl triflate (50 mg, 167.5 mmol) in acetonitrile (2 mL) at room temperature (25°C), under Argon atmosphere. The reaction mixture was stirred at room temperature (25°C) and the progress was monitored by TLC. After completion of the reaction (3 h), acetonitrile was
removed on rotary evaporator and the crude product was purified by flash silica gel column using a gradient of ethyl acetate-petroleum ether (1 :4) to afford the sulfone 21 (29 mg, 86%) as a yellow thick oil. Example 3
Large Scale Experiment (sulfone 3, table 2, entry 1)
equiv) 2 (1 equiv)
To a round-bottom flask containing TBAF (581 mg, 1.84 mol, 1.10 equiv) and aryl sulfinic acid sodium salt (275 mg, 1.67 mol, 1.0 equiv) was added o-silyl aryl triflate (500 mg, 1.67 mol, 1.0 equiv) in acetonitrile (10 mL) at room temperature (30°C), under Argon atmosphere. The reaction mixture was stirred at room temperature (30°C) and the progress was monitored by TLC. After completion of the reaction (3 h), acetonitrile was removed on rotary evaporator and the crude product was purified by flash silica gel column using a gradient of ethyl acetate-petroleum ether (3: 17) to afford the sulfone 3 (260 mg, 95%) as a white solid.
CHARACTERIZATION DATA OF COMPOUNDS
All reactions were performed on 50 mg scale of o-silyl aryl triflates. Representative large scale experiment was performed on 500 mg scale of o-silyl aryl triflates.
EXAMPLE 4
1-Phenyl (sulfonyl) benzene (3)
Reaction Time: 3 h; Rf: 0.3 (1 :4 EtOAc: Pet Ether); White solid; 34 mg, 94%; mp 120 °C; Ή NMR (400 MHz, CDC13) δ 7.88 (d, J= 8.0 Hz, 4H), 7.50 (t, J= 8.0 Hz, 2H), 7.44 (t, J
= 8.0 Hz, 4H); 1JC NMR (125 MHz, CDC13) δ 141.6, 133.2, 129.3, 127.7; HRMS-ESI (m/z) calcd [Ci2Hio02S+ H]+: 219.0474, found : 219.0474.
EXAMPLE 5 l,2-Difluoro-4-(phenyIsulfonyl)benzene 5)
Reaction Time: 6 h; Rf. 0.3 (1 :4 EtOAc:Pet Ether); White solid; 28.9 mg, 76%; mp 179-181 °C 1H NMR (400 MHz, CDC13) δ 7.86 (d, J = 8.2 Hz, 2H), 7.75-7.65 (m, 2H), 7.54 (t, J= 8.0 Hz, 1H), 7.47 (t, J= 8.0 Hz, 2H), 7.18-7.28 (m, 1H); 13C NMR (100 MHz, CDC13) δ 153.6 (dd, J= 257.8, 12.4 Hz), 150.3 (dd, J= 255.9, 17.2 Hz) , 140.8, 138.5 (t, J= 7.6 Hz), 133.7, 129.5, 127.7, 124.8 (q, J = 3.84 Hz), 118.4 (d, J = 18.2 Hz), 11 1.7 (d, J = 18.2 Hz); HRMS-ESI (m/z) calcd [Ci2H802SF2Na]+: 277.0105 found: 277.0100
EXAMPLE 6 l,2-Dimethyl-4-(phenylsulfonyl)benzene
Reaction Time: 4 h; Rf. 0.3 (1 :4 EtOAc:Pet Ether); White solid; 34.7 mg, 92%; mp 114-1 16 °C; 1H NMR (400 MHz, CDC13) δ 7.86 (d, J= 7.3 Hz, 2H), 7.63-7.58 (m, 2H), 7.50- 7.38 (m, 3H), 7.17 (s, 1H), 2.23 (s, 3H), 2.22 (s, 3H); 13C NMR (100 MHz, CDC13) δ 142.9, 142.1 , 138.7, 138.1, 132.9, 130.4, 129.2, 128.4, 127.5, 125.2, 20.0, 19.8; HRMS-ESI (m/z) calcd [C14H1402S+ H]+: 247.0787, found : 247.0786.
Example 7
l,4-DimethyI-2-(phenylsulfonyl)benzene (9)
Reaction Time: 8 h; R i 0.3 (1 :4 EtOAc:Pet Ether); White solid; 20.7 mg, 55%; mp 1 1 1-1 13 °C;
1H NMR (500 MHz, CDC13) δ 7.98 (s, 1H), 7.79 (d, J = 7.6 Hz,2H), 7.52-7.38 (m, 3H), 7.21 (d, J = 7.6 Hz, 1H),7.04 (d, J= 7.6 Hz, 1H), 2.35 (s, 3H), 2.30 (s, 3H); 13C NMR (125 MHz, CDC13) δ 141.5, 138.4, 136.5, 134.8, 134.3, 132.9, 132.6, 129.7, 128.9, 127.6, 20.9, 19.7; HRMS-ESI (m/z) calcd [C14H1402S+ H]+: 247.0787, found: 247.0786. Example 8 l-Methoxy-3-(phenylsulfonyl)benzene (11)
Reaction Time: 4 h; R i 0.3 (1 :4 EtOAc:Pet Ether); White solid; 24.2 mg, 64%; mp 82 °C; 1H NMR (500 MHz, CDC13) δ 7.88 (d, J = 7.6 Hz, 2H), 7.50 (t, J = 7.6 Hz, 1H), 7.46- 7.40 (m,3H), 7.38 (t, J = 2.2 Hz, 1H), 7.34 (t, J = 8.0 Hz, 1H), 7.01 (dd, J = 2.2, 2.2 Hz, 1H), 3.77 (s, 3H); 13CNMR (125 MHz, CDC13) δ 160.0, 142.7, 141.5, 133.2, 130.4, 129.5, 127.6, 119.9, 119.5, 112.2, 55.7; HRMS-ESI (m/z) calcd [C13H1203S + H]+ : 249.0580, found: 249.0579.
Example 9 l,3-Dimethoxy-5-(phenylsulfonyl)benzene (13)
Reaction Time: 4 h; R/i 0.2 (1 :4 EtOAc:Pet E
3.4 mg, 86%; mp 92-94 °C; 1H NMR (500 MHz, CDC13) δ 7.87 (d, J = 7.3 Hz, 2H), 7.49 (t, J = 7.6 Hz, 1H),
7.44 (t, J = 7.9 Hz, 2H), 6.99 (d, J = 2.8 Hz, 2H ), 6.52 (t, J = 2.5 Hz, 1H), 3.74 (s, 6H); C NMR (100 MHz, CDC13) δ 161.2, 143.3, 141.5, 133.2, 129.2, 127.6, 105.5, 105.4, 55.80; HRMS-ESI (m/z) calcd [C14H1404S+ H]+: 279.0686, found : 279.0682. Example 10 l,2-Dimethoxy-4-(phenylsulfonyI)benze
Reaction Time: 3 h; Rf. 0.4 (3 :7 EtOAc:Pet Ether); Red solid; 23.3 mg, 60%; mp 1 18- 1 19 °C; 1H NMR (400 MHz, CDC13) δ 7.85 (d, J = 7.3 Hz, 2H), 7.54-7.40 (m, 4H), 7.32 (s, 1H), 6.86 (d, J = 8.5 Hz, 1H ), 3.85 (s, 3H), 3.84 (s, 3H); 13C NMR (100 MHz, CDC13) δ 153.0, 149.3, 142.2, 133.0, 132.9, 129.2, 127.3, 121.9, 110.8, 109.9, 56.3, 56.2; ESI-Mass (M + Na) 301. HRMS-ESI (m/z) calcd [C14H1404S+ H]+: 279.0686, found : 279.0678.
Example 11 5-(Phenylsulfonyl)benzo[d] [l,3]dioxole (17)
104 °C; 1H NMR (500 MHz, CDC13) δ 7.84 (d, J= 7.3 Hz, 2H), 7.51-7.40 (m, 4H), 7.24 (d, J = 1.8 Hz, 1H), 6.80 (d, J = 8.2 Hz, 1H), 5.97 (s, 2H); 13C NMR (125 MHz, CDC13) δ 151.9, 148.4, 142.0, 134.9, 133.0, 129.2, 127.4, 123.6, 108.5, 107.8, 102.4; HRMS-ESI (m/z) calcd [Ci3H10O4S +H]+: 263.0373, found: 263.0371.
Example 12
(Methylsulfonyl)benzene (19)
Reaction Time: 4 h; Rfi 0.2 (1 :4 EtOAc:Pet Ether); Yellow solid; 19.6 mg, 75%; mp 256-258 °C;'H NMR (500 MHz, CDC13) δ 7.89 (d, J= 7.6 Hz, 2H), 7.60 (t, J= 7.6 Hz, 1H), 7.52 (t, J = 7.6 Hz, 2H), 2.99 (s, 3H); 13C NMR (125 MHz, CDC13) δ 140.6, 133.7, 129.4, 127.3, 44.5; HRMS-ESI (m/z) calcd [C7H802S + H]+: 157.0318 found: 157.0319.
Example 13
(Butylsulfonyl)benzene (21)
Reaction Time: 3 h; R i 0.5 (1 :4 EtOAc:Pet Ether); thick oil; 28.9 mg, 86%; ]H NMR (400 MHz, CDC13) δ 7.84 (d, J = 7.5 Hz, 2H), 7.59 (t, J = 7.5 Hz, 1H), 7.50 (t, J = 7.8 Hz, 2H), 3.02 (t, J = 8.0 Hz, 2H), 1.67-1.58 (m, 2H), 1.38-1.27 (m, 2H), 0.82 (t, J= 7.3 Hz, 3H); 13C NMR (100 MHz, CDC13) δ 139.2, 133.6, 129.2, 128.1, 56.1, 24.6, 21.5, 13.5; HRMS-ESI (m/z) calcd [C10H14O2S + H]+: 199.0787 found: 199.0788.
Example 14 l-Methyl-4-(phenylsulfonyl)benzene (23)
Reaction Time: 3 h; R/i 0.5 (l :4EtOAc:Pet Ether); White solid; 26.5 mg, 68%; mp 198-200 °C; 1H NMR (500 MHz, CDC13) δ 7.86 (d, J = 7.3 Hz, 2H), 7.47 (d, J = 7.9 Hz, 2H), 7.47 (t, J= 7.3 Hz, 1H), 7.42 (t, J= 7.6 Hz, 2H), 7.23 (d, J= 7.9 Hz, 2H), 2.32 (s, 3H); 13C NMR (100 MHz, CDC13) δ 144.1, 141.9, 138.6, 133.0, 129.9, 129.2, 127.7, 127.5, 21.5; HRMS-ESI (m/z) calcd [C]3H,202S + H]+: 233.0631 found: 233.0630.
Example 15 l-(Tert-butyl)-4-(phenylsulfonyl)benzene (25)
Reaction Time: 4 h; Rf. 0.5 (1 :4 EtOAc:Pet Ether); White solid; 38.7 mg, 85%; mp 129-130 °C; 1H NMR (400 MHz, CDC13) δ 7.88 (d, J= 7.0 Hz, 2H), 7.79 (d, J= 8.8 Hz, 2H), 7.52-7.40 (m, 5H), 1.24 (s, 9H); 13C NMR (100 MHz, CDC13) δ 157.1, 141.9, 138.5, 133.0, 129.2, 127.6, 127.5, 126.3, 35.2, 31.0; HRMS-ESI (m/z) calcd [C16Hi802S + H]+: 275.1100 found: 275.1099.
Example 16 l-Methoxy-4-(phenylsulfonyl)benzene (27)
Reaction Time: 1 h; Rf. 0.2 (1 :4 EtOAc:Pet Ether); White solid; 25.4 mg, 61%; mp 90-91 °C; 1H NMR (400 MHz, CDC13) δ 7.87-7.78 (m, 4H), 7.50-7.38 (m, 3H), 6.92-6.87 (m, 2H), 3.77 (s, 3H); 13C NMR (100 MHz, CDC13) δ 163.3, 142.3, 133.1, 132.8, 129.9, 129.2, 127.3, 1 14.5, 55.6; HRMS-ESI (m/z) calcd [C13H1203S + H]+: 249.0580 found: 249.0579.
Example 17 l-(4-(phenylsulfonyl)phenyl)ethan-l-one (29)
Reaction Time: 4 h; Rf. 0.2 (1 :4 EtOAc:Pet Ether); Yellow solid; 22.5 mg, 54%; mp 132-134 °C; 1H NMR (400 MHz, CDC13) δ 7.98 (s, 4H), 7.89 (d, J = 8.5 Hz, 2H), 7.53 (t, J = 8.5 Hz, 1H), 7.46 (t, J = 8.5 Hz, 2H), 2.55 (s, 3H); 13C NMR (100 MHz, CDC13) δ 196.7, 145.4, 140.7, 140.3, 133.6, 129.5, 129.0, 128.0, 127.8, 26.9; ESI-Mass (M + 1) 261. HRMS- ESI (m/z) calcd [C14H1203S+ H]+: 261.0580, found : 261.0573. Example 18 l-Nitro-4-(phenylsulfonyl)benzene (31)
Reaction Time: 3 h; Rf. 0.5 (1 :4 EtOAc:Pet Ether); White solid; 32.6 mg, 74%; mp 144-145 °c 1H NMR (400 MHz, CDC13) δ 8.28 (d, J = 9 Hz, 2H), 8.07 (d, J = 9 Hz, 2H), 7.90 (d, J = 7.3 Hz, 2H), 7.57 (t, J = 7.3 Hz, 1H), 7.49 (t, J = 7.3 Hz, 2H); 13C NMR (100 MHz, CDClj) δ 150.3, 147.3, 140.0, 134.1, 129.7, 129.0, 128.0, 124.5; ESI-Mass (M + Na) 209;
Example 19 l-Fluoro-4-(phenylsulfonyl)benzene (33)
Reaction Time: 3 h; Rf. 0.5 (1 :4 EtOAc:Pet Ether); White solid; 34 mg, 86%; mp 113- 115 °C; 1H NMR (500 MHz, CDC13) δ 7.93-7.83, (m, 4H), 7.55-7.41 (m, 3H), 7.22-7.08 (m, 2H); 13C NMR (100 MHz, CDC13) δ 165.4 (d, J = 255.8 Hz), 141.5, 137.7, 133.3, 130.5 (d, J= 9.2 Hz), 129.4, 127.6, 116.6 (d, J= 32.1 Hz); HRMS-ESI (m/z) calcd [C12H902SF + H]+: 237.0380 found: 237.0379.
Example 20
2-bromo-5-(phenyIsuIfonyI)thiophen
Reaction Time: 3 h; Rf. 0.5 (1 :4 EtOAc:Pet Ether); White solid; 37.09 mg, 73%; mp
105-107 °C; Ή NMR (400 MHz, CDC13) δ 7.90 (d, J= 6.8 Hz, 2H), 7.54 (t, J= 7.7 Hz, 1H), 7.46 (t, J = 7.5 Hz, 2H), 7.39 (d, J = 4.1 Hz, 1H), 6.99 (d, J = 4.1 Hz, 1H); 13C NMR (100 MHz, CDC13) δ 143.8, 141.5, 133.6, 133.4, 130.8, 129.5, 127.3, 122.1; HRMS-ESI (m/z) calcd C10H7O2S2 81Br+Na]+ : 326.8943, found: 326.8936.
ADVANTAGES OF THE INVENTION
The process of the invention works with very simple reagents at very mild reaction condition which can be very useful industrially. Also the process can be applied for large scale synthesis.
Claims
1. A room temperature single step process for synthesis of compound of Formula I
Formula I wherein, R is selected from H, alkyl (Q-C6), aryl, heteroaryl, 0-, S-, N-, P- alkyl/unsubstituted and substituted aryl;
R" is selected from alkyl (Ci-C6), aryl, heteroaryl, 0-, S-, N-, P- alkyl/unsubstituted and substituted aryl; comprising the steps of: a. adding benzyne precursor of Formula II to a stirred solution of fluoride ion source and compound of Formula III in the ratio ranging between 1 : 1 to 1 : 1.1 in anhydrous acetonitrile to obtain a reaction mixture;
Formula II Formula III wherein, R is selected from H, alkyl, aryl, heteroaryl, 0-, S-, N-, P- alkyl/ unsubstituted and substituted aryl;
R' is selected from, alkyl, aryl, heteroaryl, 0-, S-, N-, P- alkyl/ unsubstituted and substituted aryl;
X is selected from H, Li, Na, K, Cs;
b. stirring the reaction mixture of step (a) for the period in the range of 1 to 8 hours followed by purification to obtain the desired product I.
The process according to claim 1 , wherein the fluoride ion source is selected from the group consisting of TBAF (Tetra-n-butylammonium fluoride), CsF (Cesium fluoride), NaF (Sodium Fluoride), RbF (Rubidium fluoride) or KF (Potassium fluoride).
The process according to claim 1, wherein the fluoride ion source is selected from TBAF or CsF.
The process according to claim 1 , wherein the compound of formula I is selected from the group consisting of:
1 -Phenyl (sulfonyl) benzene (3);
1 ,2-Difluoro-4-(phenylsulfonyl)benzene (5);
1.2- Dimethyl-4-(phenylsulfonyl)benzene (7);
1 ,4-Dimethyl-2-(phenylsulfonyl)benzene (9);
l-Methoxy-3-(phenylsulfonyl)benzene (11);
1.3- Dimethoxy-5-(phenylsulfonyl)benzene (13);
1 ,
2-Dimethoxy-4-(phenylsulfonyl)benzene (15);
5 -(Phenylsulfonyl)benzo [d] [ 1 ,
3 ] dioxole (17);
(Methylsulfonyl)benzene (19);
(Butylsulfonyl)benzene (21);
1 -Methyl-4-(phenylsulfonyl)benzene (23);
l-(Tert-butyl)-4-(phenylsulfonyl)benzene (25);
1 -Methoxy-4-(phenylsulfonyl)benzene (27);
1 -(4-(phenylsulfonyl)phenyl)ethan- 1 -one (29);
1- Nitro-4-(phenylsulfonyl)benzene (31);
1 -Fluoro-4-(phenylsulfonyl)benzene (33);
2- bromo-5-(phenylsulfonyl)thiophene (35).
The process according to claim 1, wherein the compound of formula II is selected from the group consisting of:
2- (trimethylsilyl)phenyl trifluoromethane-sulfonate (1)
4,5-difluoro-2-(trimethylsilyl)phenyl trifluoromethane-sulfonate (4)
4.5- dimethyl-2-(trimethylsilyl)phenyl trifluoromethane-sulfonate (6)
3.6- dimethyl-2-(trimethylsilyl)phenyl trifluoromethane-sulfonate (8)
3- methoxy-2-(trimethylsilyl)phenyl trifluoromethane-sulfonate (10)
3,5-dimethoxy-2-(trimethylsilyl)phenyl trifluoromethane-sulfonate (12)
4,5 -dimethoxy-2-(trimethylsilyl)phenyl trifluoromethane-sulfonate (14)
6-(trimethylsilyl)benzo[d] [1 ,3]dioxol-5-yl trifluoromethane-sulfonate (16)
The process according to claim 1, wherein the compound of formula III is selected from the group consisting of: sodium benzenesulfinate (2)
sodium methanesulfinate (18)
sodium butane- l-sulfinate (20)
sodium 4-methylbenzenesulfinate (22)
sodium 4-(tert-butyl)benzenesulfmate (24)
sodium 4-methoxybenzenesulfinate (26)
sodium 4-acetylbenzenesulfinate (28)
sodium 4-nitrobenzenesulfinate (30)
sodium 4-fluorobenzenesulfinate (32)
Sodium 5-bromothiophene-2-sulfinate (34).
The process according to claim 1 , wherein the yield of the compound of formula I is in the range of 45-96%.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105693567A (en) * | 2016-01-06 | 2016-06-22 | 四川大学 | Method for preparing aryl sulfinate |
| CN111068776A (en) * | 2020-01-16 | 2020-04-28 | 苏州大学 | Application of HEH in preparation of sulfone compound by catalyzing reaction of aryl halogen and aryl sulfinate |
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| JP7769365B2 (en) * | 2021-09-22 | 2025-11-13 | 日本メナード化粧品株式会社 | Skin stem cell proliferation promoter and skin regeneration promoter |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105693567A (en) * | 2016-01-06 | 2016-06-22 | 四川大学 | Method for preparing aryl sulfinate |
| CN111068776A (en) * | 2020-01-16 | 2020-04-28 | 苏州大学 | Application of HEH in preparation of sulfone compound by catalyzing reaction of aryl halogen and aryl sulfinate |
| CN111068776B (en) * | 2020-01-16 | 2022-09-23 | 苏州大学 | Application of HEH in preparation of sulfone compound by catalyzing reaction of aryl halogen and aryl sulfinate |
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| US20160304447A1 (en) | 2016-10-20 |
| US9650330B2 (en) | 2017-05-16 |
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