Those Damn Rearrangements…

Burkhard, J. A.; Tchitchanov, B. H.; Carreira, E. M. Cascade Formation of Isoxazoles: Facile Base-Mediated Rearrangement of Substituted Oxetanes Angew. Chem., Int. Ed. Early View April 28th, 2011

There’s not much I love more (besides my girlfriend…awww….) than a week of chemistry ownage. That really summarizes this week for me. I actually made a count of how many reactions (I did 14), which is roughly 3 a day. I’d call that pretty good considering I had not only teaching to do (and grading) but also going to classes and I was even out for a day because of car troubles! So all and all it was a good week. I even went in for 12 hours Saturday to make up for my missed day. I really enjoy lab on weekends. Its very quiet and peaceful and I can get a lot done. Speaking of getting stuff done, my work with Dr. Fenteany’s group is roughly halfway done! And my work with Professor Tilley is also nearing completion. I can’t believe it! I also got a bunch of new ideas this week that I’ve been dying to try. So my luck continues! I also wanted to send out a special thank you to all my readers. Since I started blogging in January, I already have over 8000 hits! So thanks for reading my reviews! Speaking of which, let’s get to this week’s article!

Until recently, when I was compiling information about impact factors for various journals to be put into our lab’s “organic chemistry bible”, I didn’t realize how high of an impact Angewandte Chemie had. It ranks higher than JACS. Interestingly, however, there is far more organic chemistry published in Angewandte than in its ACS competitor. I don’t know what to make of that. Are more significant findings in organic being sent to Angewandte as compared to JACS? Or is JACS biased against organic chemistry since there are two other sister journals it can be sent to? Who knows. But that’s aside from the point, we are here to talk organic not politics!

This week’s review comes out of some work done by Dr. Erick Carreira at the Laboratory for Organic Chemistry at ETH Zurich. For some time, Carreria’s group has been interested in the development of synthetic methods towards the synthesis of novel heterocyclic compounds. Considering his group is mostly in the business of natural product synthesis, it’s no surprise they often need to be a bit creative and develop some new methodologies. So this particular article starts out by detailing the use and methods to synthesize isoxazoles. Unfortunately, most current methods are harsh and low yielding. Hence, Carreira’s group looked into their own method for synthesis of these sorts of motifs (specifically 3-subsituted isoxazoles-4-carbaldehydes) but not so initially. They were really interested in the product of the Henry reaction of 3-oxetanone and (2-nitroethyl)benzene:

They believed that these moieties could serve as good oxetane donors. When added to larger molecular scaffolds via conjugate addition, oxetanes can modify properties of the scaffold to make it more effective as a drug. Hence their methodology would be highly attractive since the starting material, 3-oxetanone, is commercially available. I wouldn’t tote that fact though. It’s absurdly expensive (5 g is $780 from Synthonix or 0.5 g for $65 from Aldrich) and polymerizes over time. Despite this, the authors hoped to test the feasibility of using this substrate as an oxetene source by performing a 1,4 Michael addition with an amines. The authors chose two representative amines, benzylamine and dibenzylamine. The results they got were quite surprising:

While the primary amine worked as expected, the secondary amine gave an unusual rearrangement to give 3-benzyl isoxazole-4-carbaldehyde. To rationalize this result the authors invoked steric arguments citing that 1,4 addition of dibenzylamine results in a benzyl-benzyl or a benzyl-2x CH2 interaction (depending on the approach). 1,4 addition with benzyl amine give no such interactions (only a benzyl-nitro interaction). They give a nice Newman projection, which explain it visually far better than I can in words. As always, when you find something interesting and unusual in chemistry, pursue it! And that’s exactly what the authors did. Since they only got 48% conversion, the authors therefore decided to optimize the reaction by first examining the base. They found that of the bases examined (and many worked!), tertiary amines worked best, with diisopropylethylamine (DIPEA) being the most superior of these. They found that reaction could be performed as a cascade one-pot reaction by simply adding DIPEA to the crude reaction mixture and stirring for 12 hours (giving 82% yield of the desired isoxazole).

The authors found that this reaction was not limited to just (2-nitroethyl)benzene (otherwise they probably wouldn’t be publishing in a journal with an impact factor of near 12 :P). A variety of nitro compounds, from alkyl to pyridyl, could be used with little determent to the yield. But how are they forming these isoxazoles? Well, after conducting some careful NMR studies, they found that it occurs via the following pathway:

Overall this was some excellent work by Carreira and co-workers! I look forward to reading more from their lab because they seem to do some interesting (and highly strained :P) chemistry. That’s all for this week, Ckellz…Signing off…



  1. There are several things that IMHO increase the IF of ACIE. Probably the major one is the fact that ACIE publishes reviews, minireviews and highlights (I call them nanoreviews). Those papers are being cited often and quite soon after publication. Also, chemists in Germany and Switzerland (and KCN) tend to publish in ACIE which gives the journal a specific character when compared to JACS.

  2. I’m interested in those beautiful pics showing the reactions, could you please tell me what software you are using to produce them? 🙂

  3. @ Hurbert Ah that makes a lot of sense, I had read something to that effect but i didn’t realize how impactful those reviews are. Come to think of it, I used a few in the last talk I gave so yeah that and the kicker that Nicolau tends to publish there certainly helps…off topic but what do you think of Org Lett and JACS as journals in general? I have the sinking feeling that a lot of chemistry in Org Lett shouldn’t be published there, that the journal is slowly going the way of Tet Lett…

    @dofine I use Cambridgesoft’s chemdraw and I use the format file provided in the FAQ on totallysynthetic. Its such a good program and format scheme!

    • Thx, I’ll give it a try 🙂

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