Got my mind on rearrangements lately. Thought this recent article (ChemInform 2013) served both to help remind us of appropriately positioned functionality can provide the right recipe…..and chiral to boot (I’m telling you that we have only scratched the surface of enantioselective microwave work — just who is going to do it.

First thing — Smiles rearrangment:

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Smiles Rearrangements

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Mechanistic: The arrows at work

The group was interesting in testing substituted benzoxazinones and benzothiazinones and needed an efficient method for obtaining a chiral substituent alpha to the carbonyl, but also something easily accessible from cheap starting materials. By starting with (S)-2-chloroproprionic acid, it was easy to form the desired N-Benzyl-(S)-2-chloroproprianamide by direct coupling from DCC activation. Following this, any appropriately substituted phenol or thiophenol could be added to the starting material to provide the desired final compounds following — chloro displacement and rearrangement from internal attack of the impending N forming the requisite spirocycle and finishing with the loss of HCl to complete the aromatization.

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Displacement and a Smile

Checking over the reaction benefits — this was either performed conventionally at 130C — overnight (sounds like someone had to be at the bar ;)). Using microwave irradiation, the reactions were finished within 20 min at 130C. The Table indicates several examples in a small library. For me, because the reaction sequence contains so few steps — would be nice to see some additional substitutions. With the activity this is preliminary or a subsequent paper will flash out the SAR. Enjoy the article.

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Conventional v. MW