OK I have to go back to my earlier med chem days at Abbott (oh sorry, Abbvie now) to think of reactions that you usually don’t see in microwave reports……how about the Mitsunobu Reaction. Let me tell you…..I think I have probably run a thousand of these so I have a pretty good handle on all of the things that have been done using this nice little reaction. Just to get everyone up to date — the scheme is below — the easy chalkboard version:

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General Mitsunobu Rxn

Before talking about this reaction under microwave conditions, David Hughes (Merck) wrote an excellent review and the application of this reaction — some key points, The acid can be substituted with phenols or heteroaromatic-OH functionalities — and if acidic enough, specific amides or imides can also be used to replace the alcohol with a nitrogen (notice the inversion of steriochemistry in the reaction –well some of mine ended under a different mechanism so tread carefully). The simplistic version of the mechanism:

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Mechanism

OK — let’s move forward to the microwave thing — what you don’t see in these schemes. The reaction itself is generally not heated — and if you use DEAD — you should even keep the reaction cool and add the reagent dropwise (you can even see each orange drop dissipate). Having said that, ADDP and DIAD are much easier to work with. I found a couple of examples that were noteworthy, a combined Mitsunobu-Claisen combined scheme from Moody and a couple of examples found in Kappe’s Angewandte Microwave Review in 2004. The examples illustrated, needed the heat compared with the standard conditions. In the first example below –(S)-Sulcatol could be converted to the (R)-Sulcatol acetate in high yield in the microwave at 180C over 5 min. High transfer of selectivity was transfered without any decomposition, whereas the conventional conditions were sluggish at best.

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Mitsunobu Claisen

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(S)-Sulcatol Mitsunobu Inversion

The second example shows a peptidomimetic approach to 1,4-diazapan-2,5-diones. The hydroxy hydroxamate dipeptide underwent an intramolecular Mitsunobu reaction at 210C over 10 min to provide the desired material in 75% isolated yield…..much faster and much higher yield compared to their conventional approach.

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Intramolecular Mitsunobu

There are a few more examples out there — using activated Sulfamides and phthalimides applied in a microwave. Although I think there is some development to be done for this reaction to show some utility under irradiation, it requires thinking about the substrates in a little more depth…..maybe with the peptide world coming back to drug discovery we will see some insights.

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