Maybe it’s just me, but I like the idea of having a functionality that can be used and replaced with another functionality in a reaction. Many rearrangements offer just that and the Curtius rearrangemnt is no exception. Just think about having a nice carboxylic acid on a heterocycle that needs to be a nitrogen — and OK I’m stretching here but a coupling just isn’t cutting it….or maybe you want to replace the acid with a urea moiety. I also like reactions that run downhill so to speak….you know they give up energy easily and in this case nitrogen. Now that I sped ahead, let’s back up and show the scheme below:

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Curtius Rearrangement: Acyl azide to isocyante

So depending on what you want and where you started, it can be a urethane (carbamate), urea or amine. What is most popular is the use of DPPA (diphenylphosphorylazide) to convert the acid to acyl azide.

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Curtius rearrangement from acid to urethane

A recent paper (Tetrahedron 2012) illustrates the utility of a Curtius rearrangement in the synthesis of isocryptolepine (below) using microwave irradiation. The novelty in this approach is that the impending isocyanate is trapped at the 3-position on an indole — wish I had thought of that — tandem Curtius, aza 6(pi) electrocyclization. If you read this blog regularly it should be obvious that the 2-aryl indoles would be a perfect set-up for setting this up….now that’s two microwave steps to generate analogs of this indolo[3,2-c]quinoline alkaloid (folk antimalarial).

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Taking a look at the scheme starting from indole 2, N-MOM protection and hydrolysis set up the requisite carboxylic acid, 3. The acid is simply reacted with DPPA in toluene under microwave irradiation to deliver the desired fused lactam in 97% yield.

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Setting up the Curtius starting material

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Curtius/electrocylization microwave reaction

Although I would probably find use for these as well, protecting groups play a big role in this working. If the protecting group falls off (as is the case with N-BOC) or the indole nitrogen is unprotected, a competing mechanism with formation of the urea on the indole nitrogen takes place. Haha! I love reading papers where the research group has to figure that out — doesn’t it sound like how we really work?

Happy Reading!