磺酰氯的制备方法的汇总

脂肪磺酰氯大部分是由相应的硫醇及其衍生物用氯磺化试剂（比如氯气）作用得来。因此，硫醇及其衍生物的引入是合成脂肪族磺酰氯的重要手段。硫类得衍生物有多种，包括硫脲，异硫氰酸酯，硫代乙酸酯，磺原酸酯等等。

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3-[4-(4-chlorophenoxy)phenyl]-7-iodo-hept-2-enoate (59.8 g) and thiourea (9.39 g) in ethanol (123 ml) was refluxed for 24 hours. The resulting mixture was cooled and evaporated to give ethyl 7-amidinothio-3-[4-(4-chlorophenoxy)phenyl]hept-2-enoate hydroiodide (70.2 g) (E:Z = 1:1 mixture) as slightly yellow oil. This sample was then dissolved in AcOH (1000 mL), chlorine gas was bubbled into the mixture at 0-10℃, TLC indicate the reaction completed.  The precipitate was collected by filtration, washed with water.  Re-dissolved in CH2Cl2 (1000 mL).  Dried upon anhydrous MgSO4, filtered, concentrated to afford the target sulfonyl chloride (52 g, 65 %).

A mixture of 1-iodo-3-methylbutane (12 g) and potassium thiocyanate (5.9 g) in acetone (110 ml) was refluxed for 4 hours. After precipitate was filtered off, the filtrate was evaporated in vacuo. Water was added to the residue followed by extraction with chloroform. The extract was dried over magnesium sulfate and evaporated under reduced pressure to give the thiocyanate (8.3 g). A solution of above thiocyanate was bubbled with chlorine gas for 1 hour under ice-cooling (below 0.deg. C.) with stirring followed by extraction with diisopropyl ether. After extract was dried over sodium sulfate, the solvent was evaporated in vacuo to give sulfonyl chloride (9.0 g). To a 28percent ammonium hydroxide (50 ml) was added dropwise crude sulfonyl chloride in dichloromethane (15 ml) over 20 minutes at approximately 0.deg. C. The reaction mixture was stirred vigorously overnight at ambient temperature. The phases were separated. The aqueous phase was extracted with chloroform/methanol (5/1). The combined organic extracts were washed with half-brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column (chloroform/methanol=95/5) to give 3-methyl-1-butanesulfonamide (4.3 g).

In a three necked 500 mL round flask equipped with mechanical stirring, was placed with ClSO3H (290g, 2.49mol).  The system was cooled to 12-15℃ using ice water.  N-Phenyl-acetamide (67.5 g, 0.5 mol) was added dropwise.  The temperature was maintained at 15 oC.  After addition, the reaction mixture was heated at 60oC for two hours. The reaction was cooled down to room temperature and poured slowly into 1000 mL of water under finely stirring.  The precipitate was collected by filtration, washed with water, dried to afford desired 4-Acetylamino-benzenesulfonyl chloride (90 g, 77% yield).  This sample could be used in next step without further purification.

例：甲苯的磺化与反应温度的关系6

芳香族化合物磺化时，芳环上存在的羟基，烷氧基，羧基，卤素等取代基均无影响。芳胺与硫酸反应，首先生成胺盐，继而受热重排成对胺基苯磺酸9。

To 4-bromotoluene (518 mg, 3.1 mmol) was added n-BuLi (2.3 M in hexane, 1.35 mL, 3 mmol) over 10 min with cooling (ice bath). After 6 hours, the supernatant solution used in the next stage. To a stirred suspension of crystalline STTAC (sulfur trioxide-trimethylamine complex, commercially available) (431 mg, 3.1 mmol) in dry THF (15 mL) at –78 oC was added the preformed hexane solution of p-tolyllithium dropwise over 15 min. The reaction mixture was stirred for 2 hours at – 78 oC and then allowed to warm to room temperature over 18 hours. After removal of solvent, H2O (10 mL) and KOH (3M, 1 mL, 3 mmol) were added to the mixture, which was then extracted with Et2O to remove unreacted 4-bromotoluene. The aqueous solution was evaporated to a white solid. HCl(6 M, 4 mL, 24 mmol) was added. The mixture was extracted with EtOAc (4×20 mL), and the combined organic extract was dried (MgSO4) and evaporated to give a moist solid. Et2O (15 mL) was added and some white solid precipitated. This was washed with further Et2O (2×10 mL). The combined Et2O extracts were concentrated to give white crystals (383 mg, 62%) of the monohydrate.

A mixture of sodium 4'-cyanobiphenyl-4-sulfonate (251 g) and phosphorous oxychloride was refluxed for 16 h. The reaction mixture was poured into a large quantity of ice/water and the resulting slurry was extracted with dichloromethane (1*1.8 L).The organic extract was washed with brine, dried over magnesium sulfate, filtered, and concentrated to approximately 200 mL. Hexanes (200 mL) was added. The slurry was stirred for 30 min, filtered, washed with 1:1 dichloromethane/hexanes, and dried to give product (82.1 g).The mother liquor was concentrated and further purified by flash chromatography on silica gel (40-->70percent dichloromethane/hexanes) to give an additional 16.2 g of white solid.

2-Nitro-phenylamine (13.8 g) are dissolved in conc. H2SO4(75 mL), H3PO4 (100 mL) and water (50 mL).  The solution of NaNO2 (8.3 g) in water (25 mL) was slowly added dropwise under ice-water cooling.  The temperature was maintained at 10-15 oC.  NH3-SO3H was added in batches to remove the extra formed HNO2.  The reaction was cooled down to -10 oC, liquid SO2 (50 mL) was added dropwise.  The reaction mixture was poured into another mixture of FeSO4.7H2O (55.7 g) and Cu (1 g).  Half an hour later, the reaction was filtered, the residue cake was washed with mixture of ether (750 mL) and CH2Cl2  (750 mL).  The combined filtrate and washings were washed with brine, dried and concentrated.  The residue was precipitated in water (50 mL), then diluted ammonia was used to adjust pH equal 9 under stirring.  Filtered, the filtrate was acidified with HCl (6 N), the precipitate was collected by filtration and dried to afford desired 2-Nitro-benzenesulfonic acid, (9.4 g, 65% yield.) .

4-Nitro-3-trifluoromethyl-benzenethiol 47g was dissolved in AcOH (100 mL), chlorine gas was bubbled into the mixture at 0-10 oC, TLC indicate the reaction completed.  The precipitate was collected by filtration, washed with water.  Taken into CH2Cl2 (200 mL).  Dried upon anhydrous MgSO4, filtered, concentrated to afford the desired sulfonyl chloride (22.3 g) as an yellow oil, this sample could be used in next step without further purification.

Chlorine gas was bubbled through a suspension of methyl 4-benzylsulfanyl-3-nitrobenzoate (25.4 g, 83.7 mmol) in acetic acid/water (2:3, 500 mL) for 1.5 h. The mixture was stirred under the chlorine atmosphere for 19 h when the system was purged with nitrogen and the solvent was concentrated in vacuo. The resulting yellow precipitate was collected by filtration, washed with hexane (2 × 50 mL), and recrystallized from chloroform/hexane to afford the sulfonyl chloride as a white crystal (17.8 g, 76%).

To above compound 1 (6.55 g, 14.4 mmol) and potassium nitrate (4.37 g, 43.0 mmol) in acetonitrile (45 mL) was added sulfuryl chloride (3.45 mL, 43.0 mmol) dropwise over 7 min and the reaction mixture was stirred at room temperature. After 5 h sodium bicarbonate (500 mL, aq satd) was added and the solution extracted with ethyl acetate (600 mL). The organic phase was washed with brine (400 mL), dried with magnesium sulfate, and evaporated in vacuo to give the title compound (6.6 g, 78%) as an oil. Used without further purification. 

2,4-Dibromo-6-methyl-benzothiazole（3.1 g） and NaHS (1.0 g) in methanol (30 mL) was heated to reflux for 1 hour.  TLC indicated the reaction completed.  The solvent was removed under reduced pressure.  Water (30 mL) was added.  The water layer was extracted with CH2Cl2 (100 mL) three times.  Combined organic layer was washed with brine.  Dried upon anhydrous Na2SO4, concentrated to afford desired product.

To a suspension of 4-amino-2-chloro-3-methyl-benzonitrile (500 mg, 3.00 mmol) in 1.8 mL of 6 N HCl at room temperature was added 2 mL of water followed by a solution of NaNO2 (220 mg, 3.13 mmol) in 1 mL of water dropwise and the suspension stirred at room temperature for 20 min. The suspension was added to a solution of SO2 in acetic acid (prepared by bubbling SO2 gas into acetic acid until saturation at room temperature) and copper(II) chloride dihydrate (60 mg, 3.52 mmol) in 0.15 mL of water. The suspension was stirred at room temperature for 1.25 h and extracted with EtOAc. The organic layer was washed with water and brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, CH2Cl2/Hexanes, 50:50, 75:25 and 100:0) to afford the title compound (305 mg) as a white solid。