磺酰氯制备磺酸酯和磺酰胺

通过磺酰氯制备磺酸酯

磺酰氯具有较高的反应活性，在碱性条件下，与醇反应生成磺酸酯[1]，所用碱通常为三乙胺，吡啶和DMAP。

实例：

To a suspension of p-TsCl (14.3 g, 75.0 mmol) in pyridine (60 mL) was added slowly 3-methyl-3-oxetanemethanol (5.11 g,50.0 mmol) at 0 °C, and the mixture was stirred under nitrogen atmosphere at 0 °C for 4 h. The mixture was added to ice water and stirred for 1 h. The precipitate was collected by filtration, washed with cold water, and dried to give the target (8.97 g, 70%) as colorless crystals. (Negoro,N et al. J. Med. Chem. 2012, 55,3960.)

当底物同时含有伯羟基和仲羟基时，通过控制磺酰氯的当量，可以选择性地在伯羟基上引入磺酰基[2]。

实例：

To a solution of cis-tert-butyl 1-[4-(hydroxymethyl)piperidin-3-ol-1-yl]carboxylate  (760 mg, 3.28 mmol), Et3N (540 mL, 3.6mmol) and catalytic amount of 4-dimethyl aminopyridine in CH2Cl2(24 mL), was added portionwise 4-nitrobenzene sulfonylchloride (797 mg, 3.6mmol) at -50 oC under nitrogen atmosphere. After 3h, the reaction mixture was warmed up to room temperature and was stirred further overnight. Then, the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (310 mL). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The purification by silica gel chromatography(CH2Cl2:MeOH = 99:1) led to the target as a yellow solid (1.26 g,93%). (Koudih, R et al. Eur. J. Med. Chem. 2012, 53, 408.)

通过磺酰氯制备磺酰胺

磺酰氯与胺在碱性条件下反应生成磺酰胺。所用碱包括三乙胺，吡啶，DMAP等。反应通常以二氯甲烷为溶剂，在0 oC至室温进行。也可以直接以吡啶做碱和溶剂，高产率得到磺酰胺[3]。

实例：

A mixture of amine A (0.84 g, 4 mmol) and methanesulfonyl chloride (0.69 g, 6 mmol) in pyridine (10 mL) was stirredat 0 oC for 10 min. After aqueous workup, the residue was purified by flash column chromatography on silica gel using EtOAc:hexanes (1:2) as eluant togive the desired product (1.05 g,91%) as a white solid. (Kim, Y et al. Bioorg.Med. Chem. 2012, 20, 215.)

对于某些活性较差的底物，如带有吸电子的芳胺或者含氮杂环化合物，其与磺酰氯反应制备磺酰胺时通常需要较强的碱，包括KOH[4]，t-BuOK[5]和NaH[6]等。

实例：

Methyl indole-2-carboxylate (1.86 g,10.6 mmol) was dissolved in a flask by distilled DMF. NaH (0.50 g, 1.1 equiv) and PhSO2Cl(1.6 mL, 1.2 equiv) were slowly added to the flask on a pre-cooled bath of ice. The mixture was stirred overnight at room temperature.The crude product was extracted with ethyl ether/purified water (320 mL), the organic layer was dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure to obtain the desired product(3.3 g, 99%) as a white solid. (Oikawa, M et al. Eur. J. Org. Chem. 2011, 24, 4654.)

【参考文献】

[1] Negoro, N et al. J. Med. Chem. 2012, 55, 3960.

[2] Koudih, R et al. Eur. J. Med. Chem. 2012, 53, 408.

[3] Kim, Y et al. Bioorg. Med. Chem. 2012, 20, 215.

[4] Lai, Met et al. J. Med. Chem. 2012, 55, 3777.

[5] Lai, Metet al. J. Med. Chem. 2012, 55, 3777.

[6] Oikawa,M et al. Eur.J. Org. Chem. 2011, 24, 4654.