In the introductory section of this chapter, we explored the retrosynthetic analysis of Cardura (doxazosin), a clinically significant alpha-adrenergic blocker. Recall that a key disconnection involved the formation of a benzodioxin ring system. This motif can be elegantly constructed through a sequence of two successive SN2 reactions, demonstrating the power of these transformations in complex molecule synthesis. Below is the overall transformation to form benzodioxin.
We begin with catechol (1,2-dihydroxybenzene), a readily available starting material. To initiate the first SN2 reaction, catechol is treated with a strong base, such as sodium hydroxide (NaOH). This deprotonation generates the corresponding phenoxide anion, a potent nucleophile. This phenoxide anion then attacks an appropriate electrophile, an α,β-dihaloalkane (ethyl 2,3-dibromopropanoate). Following the first SN2 reaction, the resulting intermediate still possesses a free hydroxyl group, which can be similarly deprotonated with a base (NaOH or potassium tert-butoxide, for instance) to generate another nucleophilic alkoxide. This alkoxide then undergoes a second intramolecular SN2 reaction, attacking the remaining halide on the dihaloalkane chain, closing the benzodioxin ring.
This two-step sequence highlights the utility of the SN2 reaction in creating cyclic ethers. The reaction is particularly effective when the geometry of the starting materials favors intramolecular ring closure, as seen in this example. This strategy provides a concise and efficient route to benzodioxin derivatives, which are found in a variety of pharmaceuticals and natural products.