A pleasant surprise

Here is a pleasant surprise. For the life of me, I cannot believe that this has never been tried before. The venerable Passerini reaction, one of the cornerstones of multicomponent reactivity, hinges upon the union of a carboxylic acid, an isocyanide, and an aldehyde. Now Soeta and Ukaji are telling us that sulfinic acids are also competent participants in this process. While the report triggers that classic response “Why didn’t I try this?”, finding the right sulfur-containing participant was probably not that straightforward. After all, readily accessable and infinitely more stable sulfonic acids would have probably been the first choice. Alas, the stars in the pKa universe are not aligned in that case and the reaction does not work (Or does it? Maybe someone should give another kick in that can!). The good news is that synthetically meaningful sulfonates in the Soeta/Ukaji method can be generated through in situ oxidation, giving rise to substrates that undergo straightforward nucleophilic displacement reactions.

This chemistry is nicely set up for a lot of divergent possibilities and lends itself really well to library synthesis. As far as the mechanism – the “sulfono-version” of the familiar acyl transfer is taking place here. Still, with all the effort spent in the area of multicomponent reactivity I am somewhat puzzled by this report that just appeared two weeks ago… But then again – this only underscores the notion that the most obvious things have not been attempted. This is the golden rule of research in my view (and a rather ironic one).

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http://pubs.acs.org/doi/abs/10.1021/acs.joc.5b00131

2 thoughts on “A pleasant surprise

  1. My colorblind grandfather had fondness for wild mushrooms, but it was difficult for him to find them in the woods, and he always said he would rather have all those he missed than those he found…

    It would be interesting to try a phosphite diester in Passerini, to see if the product is a phosphite triester (that can be oxidized with tBuOOH to a phosphate triester), or if the reaction produces a phosphonate instead, it could be quite valuable too.

  2. Thanks for this. I agree with you – as far as P version, Ivan Natchev (Bulgaria) did some work at the end of 80’s in this regard. I was actually looking into it last week for our macrocyclization project.

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