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In a lot of procedures for amide couplings (acid + amine) using PPAA, the coupling agent is added to a cooled solution of the acid, amine, and a non-nucleophilic base such as DIPEA. This is done even when the reaction itself is conducted at a higher temperature (e.g. the reaction might be run at 60 °C). Furthermore, unlike with reagents like oxalyl chloride, there is no separate step form formation of an activated acid prior to adding the amine (everything is just mixed at the same time).

On a process scale, this initial cooling step makes sense as there is a slight exotherm to the addition (avoids thermal runaway), but the method is often also used on small scales (less than 100mg) too , even when conducted in higher boiling solvents like DMF or AcOEt.

Unlike HATU where the side reactions are well known, there is little discussion of what can go ‘wrong’ with PPAA couplings (and whether this is related to the temperature).

  • Is the initial temperature control preventing something from happening before the desired reaction gets going?
  • What are the most common side reactions? I’m not talking about the PPAA by-products (water soluble P containing molecules) but rather things that can form from the starting materials through competing reactions/mechanisms

As a footnote - I often just mix at room temperature and stirr. 90% of the time this causes no problems, however on occasion the reaction profile (judged by UPLC) gives multiple side products in addition to the product.

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