芳香磺酰氯的制备

chem 有机方法 1.5W+ 0
芳香磺酰氯的制备一般分为以下几种方法, 直接用氯磺化法制备芳香磺酰氯。 芳香磺酸或盐经氯化制备芳香磺酰氯。 芳香硫醇及相关衍生物氯化,氧化合成芳香磺酰氯。 Sandermeyer反应由芳胺合成芳香磺酰氯。




直接氯磺化法制备芳香磺酰氯


氯磺酸是一类比较常用的直接氯磺化试剂,氯磺酸的活性比浓硫酸大,反应温度较低,同时可以直接得磺酰氯。氯磺化也是亲电反应,选择性也遵循芳环取代基定位效应及其规则。有规律可循。如果希望反应比较缓和,可以用氯仿或其它卤代烷烃作为稀释剂。反应温度一般都控制在020℃。


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如果芳环上存在至钝基团,像羧基等,直接氯磺化的温度要提的比较高,要达到100多度。


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当体系因为位阻,取代基定位效应劣势等等不能直接完成氯磺化时,就可以选择分两步走,先引入磺酸基团。再转变为磺酰氯。


1.1

芳香环磺化反应示例


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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.




芳香磺酸或盐氯化制备芳香磺酰氯


芳香磺酸或盐可以用氯气或者某些氯化试剂比如五氯化磷,三氯氧磷,二氯化砜等处理得到芳香磺酰氯。这几种氯磺化试剂各有优缺点,五氯化磷,三氯氧磷反应效果较好,但是后处理比较繁琐,反应温度要求较高。而二氯化砜后处理方便,往往蒸掉溶剂就可以直接投入下一步反应。因此,芳香磺酸作为引入芳香磺酰氯基团重要的前体得到非常大的重视。


2.1

芳香磺酸的制备


芳香磺酸的制备有几种办法,磺化,有机金属试剂同三氧化硫加成,Sandermeyer法合成芳香磺酸。这几种合成芳香磺酸的方法也是各有特色,针对不同的底物也可有不同的选择。磺化是对芳环体系直接的引入磺酸基团。想把芳卤转变成芳香磺酰基团时,就可以考虑用有机金属试剂置换卤素后用三氧化硫处理即可以得到芳香磺酸。Sandermeyer法则提供了由芳胺基团转变为芳香磺酸的一条途径。

 

    2. 1. 1磺化




芳烃的磺化通常采用浓硫酸或含有5%-20%三氧化硫的发烟硫酸。磺化反应是一可逆反应,欲得良好产率的磺酸,必须使用过量的磺化剂或者不断移去生成的水。对于较难磺化的芳烃可采用三氟化硼,锰盐,汞盐,矾盐做催化剂。苯在室温下可用浓硫酸磺化生成苯磺酸2;而在70-90oC磺化则生成间苯二磺酸,产率为90% 3;间苯二磺酸钠在汞盐的催化下,与15%的发烟硫酸于275oC反应,则以73%产率生成135-苯三磺酸 4。由于磺化反应是一可逆反应,磺酸基位置随反应温度不同而改变5

例:甲苯的磺化与反应温度的关系6


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例:萘的磺化也有类似情况。低温,小于80磺化,主要生成α-萘磺酸,这时由动力学控制,一旦达到160的反应温度,主要产生β-萘磺酸。这时由热力学控制7


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例:磺化反应的可逆性的一个重要应用是将磺酸基先临时占据芳环某特定位置,然后再进行其他的反应,待反应完成后,再在稀硫酸中加热,以移去磺酸基。例如β-溴代萘的合成8


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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


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    2. 1. 2有机金属试剂与三氧化硫的加成




三氧化硫对碳-金属键的插入反应,提供了由芳卤或烯卤制备磺酸的又一条途径。有机锂是较为典型的试剂。由于三氧化硫在操作中较为不便,而使用三氧化硫-吡啶或三氧化硫-三甲胺复合试剂能使反应在更为温和,便利的条件下进行。
以三氧化硫-三甲胺复合物为起始剂,在无水乙醚或四氢呋喃中与有机锂化合物反应,控制反应温度由-78到室温,得到磺酸盐,酸化后即得磺酸10

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    2. 1. 3芳香硫醇合成方法示例2




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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.

 

    2. 1. 4 Sandermeyer反应合成芳香磺酸




Sandermeyer反应的应用之一就是将芳香化重氮盐转化为芳香磺酸。这是一类很经典的反应。具体操作是将芳胺经重氮盐在二价金属离子催化下(一般是二价铜)用液态二氧化硫处理,就可以得到芳香磺酸。


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2.2

芳香磺酸或盐氯化制备芳香磺酰氯示例



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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.


2.3

芳香环磺化反应示例


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2-Nitro-phenylamine (13.8 g) are dissolved in conc. H2SO4(75 mL), H3PO(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 CH2Cl (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.) .





芳香硫醇及相关衍生物氯代、氧化合成芳香磺酰氯


芳香硫醇及相关衍生物,比如硫醚,二硫化物在氧化性氯化试剂存在下,均能够较容易的转变成磺酰氯。因此,芳香硫醇及其衍生物也是合成芳香磺酰氯的一类重要前体。
文献报道:对硝基硫酚在以下两种条件下都可以很容易的转变成对硝基苯磺酰氯11


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AndrewsStephen P. 报道:将如下底物悬浮于醋酸水中,导入氯气,就能以76%的收率得到磺酰氯12


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二硫化物也是一类可以通过氯气处理转化成磺酰氯的重要前体。如Berryman, K. A. 13


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3.1

硫酚变磺酰氯合成方法示例


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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.

 

3.2

芳香硫醇相关衍生物氯代、氧化合成芳香磺酰氯举例


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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%).


3.3

应用硝酸钾-SO2Cl2的反应示例


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To above compound (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. 

  



芳香硫醇的制备

 

有机镁与有机锂试剂与硫发生插入反应,生成物进一步水解,则生成硫醇或硫酚。由于硫醇可由多种其他方法制得。因此,本法合成硫酚更具有实用价值。
例:苯基锂与硫发生放热反应,生成物进一步水解则生成苯硫酚14


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二硫化物很容易被多种还原试剂还原成硫醇。二硫化物本身也能被氯化试剂作用直接得到磺酰氯。锌-乙酸15,氢化铝锂16 等均为常用的还原试剂。若为硝基取代的二芳基二硫化物被锌-乙酸还原时,硝基亦被还原成氨基。但用二硫化钠做还原剂时,硝基不受影响。铝-二氯化镍,四叔丁基硼氢化物也能还原二硫醚成硫酚。作为Sandermeyer直接芳磺化的一种替代方法,在某些二氧化硫不适宜的情况下,成为了一种变通的选择。
邻氨基苯甲酸形成的重氮盐与二硫化钠反应,生成相应的二硫化物。它与锌-乙酸共回流,则被还原生成邻巯基苯甲酸15。经过氯气处理,即可生成相应的磺酰氯。


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4.1

芳香硫醇合成方法示例


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2,4-Dibromo-6-methyl-benzothiazole3.1 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.

 

 



Sandermeyer 反应由芳胺合成芳香磺酰氯



Sandermeyer反应的另一个应用是直接得到芳香磺酰氯。这种反应对催化剂,反应条件的要求及控制都比成磺酸高。市场上有二氧化硫醋酸溶液出售。将芳胺做成重氮盐,以亚铜盐作为催化剂,醋酸做溶剂,再用二氧化硫处理就能够以较好的收率得到芳香磺酰氯。17


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5.1

芳香环磺化反应示例


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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.

 

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