I thought I saw it…

Aromatic heterocycles form the backbone of drug discovery. It is difficult to deny this statement for two simple reasons: a. the relative resistance of aromatic heterocycles to oxidation and b. their capacity to partake in a gamut of interactions with protein targets (hydrogen bonds, hydrophobic interactions, etc). While linking heterocycles into oligomeric chains is best done by way of cross-coupling reactions, there is no better alternative to condensations when it comes to making heterocycles themselves. Copper-catalyzed azide/alkyne cycloaddition is an exception to this rule. If you are thinking about a pyrrole, a pyridine, or a pyrimidine (the list can go on and on), nothing comes close to gaining aromaticity by kicking out water molecule(s) from a carbonyl precursor. Aromatic heterocycles that contain N-N or N-O bonds belong to a particularly vast class of useful molecules. Some time ago, I wondered about reactions that provide access to pyrazoles or isoxazoles by building a heteroatom-heteroatom bond as part of the process. For the life of me, I could not think of an example. You might say: why bother? As a matter of fact, I would agree because hydrazines and hydroxylamines are some of the most versatile and readily accessible nucleophiles. However, if I put my basic scientist hat on, I want to see reactions of this kind. Until we get there, my claim stays put: there are no examples where heteroatom-heteroatom bonds are made in the course of aromatic heterocycle synthesis.



I was reading a cool paper by the Swedish group led by F. Almquist and, upon a cursory look at one of the schemes, I said to myself:  “Darn, this must be it! The N-N bond construction…”. Take a look above. On a sober glance, however, the reaction amounts to a Sandmeyer process gone “haywire”. In this reaction, the targeted diazonium intermediate activates the proximal methyl group. The reaction is rather unusual, which is why I like it. Still, this does not affect my assertion that there are no useful ways of making aromatic heterocycles by building heteroatom-heteroatom bonds. There might be something I am missing, of course. But I do not mean an obscure example, ladies and gentlemen. Please give me something synthetically useful.

Apart from the interesting pyrazole-forming reaction, this paper provides a neat example of peptidomimetic design. The tricyclic pyrazole-2-pyridone-thiazoline structures accessible with the Almquist method incorporate a dipeptide sequence within a rigid framework. Importantly, the two substituents that correspond to amino acid side chains may be varied, enabling construction of compounds libraries.

2 thoughts on “I thought I saw it…

    • Thanks a lot, Mike! This is a great one (and a very recent one too!). I think this work builds very nicely on what Narasaka taught us all (in terms of nucleophilic reactions at nitrogen). It will be interesting to see how nice methods such as this are going to compete with condensation reactions in terms of enabling features… This reminds to to discuss Narasaka’s work at some point as well.

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