还原Weinreb酰胺制备醛

Weinreb酰胺用氢化铝锂、Red-Al、DIBAL等还原可得到醛。

反应机理

Weinreb酰胺和金属还原试剂的加成物由于甲氧基的存在形成一个五元环的螯合物相对稳定，使反应不再继续。

反应实例

装备有温度计、搅拌子、滴液漏斗、空气冷凝回流管的5L圆底瓶中，通入氩气保护气后，加入LiAlH4(0.44 mol)以及无水乙醚(1.5L)。室温下搅拌一小时后，冷却到-45℃。将Boc-亮氨酸Weinreb酰胺(～100g, 約0.4mol)的无水乙醚溶液(300mL)、保持反应温度在-35℃以下缓慢滴加。加完后移去冷却槽，搅拌下让温度缓慢回复到5℃。再一次冷却降温到-35℃，将KHSO4(96.4g, 0.71mol)的水溶液(265mL)缓慢滴加，这时保持温度不要超过零度。去掉冷却槽，继续搅拌一小时。用硅藻土过滤反应液，用五百毫升乙醚洗净固体残渣。得到的有机溶液用1N盐酸(350mL)在5℃下洗净三次，再用饱和小苏打溶液(350mL)和饱和食盐水(350mL)先后分别洗净三次，用无水硫酸镁干燥除水。蒸干溶剂后，得到油状的Boc-L-Leucinal(69-70g,产率87-88%)。生成物放在冰柜(-17℃)保存。

【 Goel, O. P.; Krolls, U.; Stier, M.; Kesten, S. Org. Synth. 1989, 67, 69.】

【Tetrahedron 2008, 64(40), 9384-9387】

【Angew. Chem. Int. Ed. 2007, 119(45), 8862-8865】

4-[4-(methanesulfonamido)phenyl]butyraldehyde

A mixture of 4.20 g (14 mmol) of4-[4-(methanesulfonamido)phenyl]butyric acid, N-methoxy-N-methylamide and 100 mLof anhydrous tetrahydrofuran was stirred under nitrogen with cooling in an icebath as 17.5 mL (17.5 mmol) of 1Mlithium aluminum hydride in tetrahydrofuran was added gradually by syringe. After 0.75 hours, 70 mL of 5percent potassiumhydrogen sulfate solution (aqueous) was added cautiously by syringe. Themixture was then removed from the ice bath, diluted with 150 ML of water, andshaken with 150 mL of ethyl acetate. The milky aqueous phase was extracted withan additional 50 mL of ethyl acetate. The combined organic fractions werewashed successively with 2*100 mL of 1N hydrochloric acid, then 50 ML ofsaturated aqueous sodium bicarbonate solution, and finally 50 ML of saturatedaqueous sodium chloride solution. The organic phase was dried over magnesiumsulfate, filtered, and concentrated in vacuo. Flash chromatography of theresidue on silica gel (elution with 3:2 hexane-EtOAc) yielded 2.47 g (73%) of an oil; homogeneous by TLC in1:1 hexane-EtOAc).Upon storage in the freezer, solidification occurred (mp 41~44oC.).

【US5756507】