六组分一锅法!
常见的有机反应都是两组分反应,可以很轻易地控制选择性,而三组分反应就要求分子的各个亲核亲电位点具有合适的活性以保证三组分按照次序反应,对于四组分反应,则更为苛刻。这类多组分反应已经衍生出了一系列人名反应,包括Ugi反应Passerini反应以及Asinger反应等。
当反应组分扩大到六种,就很难控制其选择性,但是在某些特殊的情况下,这也是可以完成的——猜猜下面这个反应产物是什么样子:
Meldrum's acid是一种酸性非常强的有机化合物,由丙二酸和丙酮在脱水剂存在下制备得到。Meldrum's acid的亚甲基非常活泼,能够迅速与羰基缩合,并得到对应的产物,但是这种产物并不稳定,随着羟基对羟基的亲核进攻,脱去一分子丙酮,得到羧基。
得到了羧基,接下来就是经典的四组分反应——Ugi反应,利用羧酸,异腈,胺与羰基进行协同的缩合过程(胺与羰基首先形成亚胺,再进行三分子过程):
分子中具有一个在上述条件下不活泼的炔基,能够进行经典的点击化学(Click Chemistry)反应,炔-叠氮环加成(Azide-Alkyne Cycloaddition),这是典型的[3+2]环加成,也可以理解为1,3-偶极环加成。
这一反应能够兼容多种底物,因而具有巨大的应用前景。
(ORTEP图像说明得到了目标产物)
从反应操作看,无需进行分离,只需分两次投料,即可得到目标产物7,并且不需要过柱子,这在工业上的应用意义重大。
A mixture of salicylaldehyde (1 mmol) and Meldrum’s acid (1 mmol) in EtOH (5 ml) were stirred for 10 h. Then, amine (1mmol), propargyloxy aldehyde (1mmol) and isocyanide (1mmol) were added and the mixture stirred at ambient temperature for 8 h. After completion of reaction, as indicated by TLC, aryl azide (1.2 mmol), Cu(OAc)2 (0.02 g, 10 mol%) and sodium ascorbate (0.04g, 20 mol%) were added. Then the resulting mixture was stirred for 6 h at room temperature. After completion of the reaction, as indicated by TLC, the product was filtered off. Then it was stirred in a solution of ammonia and water for 30 min. Then the solid was filtered and washed with EtOH and water to give the pure product.