In-line quenching and scavenging under continuous flow conditions

While there are a number of publications illustrating these techniques in action, I am going to talk about two of them: 1) handing the formation of organic azides and their transformations and 2) the total synthesis of oxomaritidine using in-line techniques.

For the first topic, there are different approaches to handling organic azides formed in flow reactor. For example, an aniline starting material can be diazotized in the presence of a stream of tert-butyl nitrate. Substitution using an azide nucleophile (generated in situ from TMS-N3 provides the requisite azide with loss of N2. However, improvements to the sequence can be made by using an in-line packed bed of sulfonic acid resin, followed by a trialkylamine base resin before the azide leaves the reactor (same bed flow reactor). The SO3H resin will sequester any unreacted aniline – and also functions to degrade and deprotonate any TMS-N3 forming hydrazoic acid. Although dangerous in its’ own right, the hydrazoic acid is scavenged by the presence of the amine resin in the same cartridge, leaving a purified stream of organic azide flowing through the reactor for the next transformation (an example of this utility in the formation of a series of triazoles, (Org Biomol Chem 2011). As illustrated below:

Screen Shot 2014-10-30 at 4.34.36 PM

An alternate strategy, making use of azide ion-exhange polymers to displace more reactive alkyl halides under continuous flow, shows an in-line azide resin with a stream of substrate flowing through in the formation of an organic azide under the appropriate flow and heating conditions. In an illustration below, you see this is the initial step in a synthesis (followed by a key aza-Staudinger-Wittig reaction, Org Biomol Chem 2011), where nearly all of the steps contain an in-line trapping technique or reactive resin in the total synthesis of oxomaritidine (Chem Comm 2006). Happy Reading!

Screen Shot 2014-10-30 at 4.46.36 PM

 

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