The first installment of cool methods for indole construction seemed to be well received so I thought I would try another (one which I had done in my past). With the ability to C-C triple bonds to aromatic rings, the set-up up for a cycloisomerization reaction of an ortho amine seems like a great way to construct the requisite indole. Looking at the scheme below, there are a few approaches to the connection. For this story we are going to look at route a, but concentrating on the ring formation.

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Disconnection approaches to cyclizations

The general idea for the reaction can be shown from the scheme below (shown from another good book [Catalyzed Carbon Heteroatom Bond Construction late 2010] to get your hands on since it provides strategies for carbon catalyzed heteroatom bond construction, with all the big players). Isn’t that high on your list of needs in synthetic strategies?

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Cu-catalyzed Indole cyclization

Ok without drawing arrows all over the place – the accepted mechanism is generally described as a 5-exo-dig intramolecular cyclization of the amine onto a transition-metal activated C-C multiple bond. Given the simplicity of the reaction and the number of possibilities as starting materials I would say this is a great way to construct the heterocycle late in a scheme if needed. But what I typically look for are the conditions — DMF 110C for 8 h is just way too long nowadays when we have new tools. So let’s blow this up and look at expanding the scope a bit, perhaps a variety of ring substitutions or substituted pyridines for making azaindoles. Ready?

A recent publication from the chemistry development group at GlaxoSmithKline in Italy (Tetrahedron 2010) developed an approach to a variety of the aforementioned varieties from 2-alkynylanilines as well as some pyridine analogs. Now you will have to do some work and read through the paper a bit, but the schemes below indicate a variety of substitutions on the aromatic ring as well as R group at the 2-position of the indole if you will can be varied to include a hydrogen or alkyl functionality — so you are not bound by aromatic groups to get the reaction to go [alkyl and the unsubstituted alkyne will cyclize nicely.

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Cyclization in a closed-vessel with a variety of bases

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Aryl subst – albeit fixed for the closure

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So you can see this group utilized NaHCO3, pyrrolidine and Na2CO3 at 200C for 15-90 minutes to provide the indoles in good to high yields (water based in nearly all cases). There are several additional examples that will help satisfy curiosities and  to look at other examples. One thing to note is that looking back at our initial mechanism of an activated multiple bond by a transition metal — doesn’t look like that is a requisite for constructing the ring and perhaps that gives some thought on additional things to try. Certainly from a development route perspective, I would opt for the non-metal based approach. But I am also certain the metal chemists would give me plenty of reasons they can find a better way. If properly positioned in a total synthesis with the need for an indole ring, at least it can be placed at many different timepoints. Happy Reading!