Reversal of Fortune - The Amide Umpolung

http://www.nature.com/nature/journal/v465/n7301/abs/nature09125.html

Commentary:
http://www.nature.com/nature/journal/v465/n7301/full/4651020a.html

^o^: Finally, an unconventional solution for the classic problem of amide-bond formation, and an innovative excuse for an alternative exam answer! Instead of the condensation of an carboxylic acid and an amine, Sehn et. al. proposed an 'umpolung' (reversal of polarity) approach which uses the nitroalkane as the NUCLEOPHILIC partner and an [iodine-activated] amine as the ELECTROPHILIC partner, to afford the amide product. It is of no surprise that the use of nitroalkane (-CH2NO2) as an enolate equivalent - only as an umpolung - has seen a fruitful development in the field of Henry reaction, and also because of its unmasking into a carbonyl group via the McMurry Reaction or ouch(!), the Nef Reaction. This novel concept has seen a wide substrate scope and the authors have expanded this methodolgy to some sort of a 3-component reaction (fist a Henry reaction between an imine and nitroalkane, then the coupling) in an attempt to control the formation of a stereogenic center alpha to the resultant amide. The mechanism is intriguing and they have done some control experiments to rule out other possibilities (e.g. a Nef-like mechanism). It is also encouraging to learn that they have started to look into the asymmetric version of this methodology, and given the exciting field in the catalysis of Henry reaction, it should come as no surprise there will be new inpisrations in the form of organocatalsysis / Lewis Acid catalysis for this methodology.

An interesting observation is that the nitro-bromo intermedaite (Figure 3, 10) can be hydrolysed, presumably via the aqueous workup, into the ketone (detach the amide N for the moment) in a rather mild condition. Given that the hydrolytic transformation of a nitro into a ketone is often harsh (see the Nef reaction), it may serve as an implication that the bromide may somehow aid in the hydrolysis of the nitro group. This observation somewhat gives weight to the value of using these bromo-nitro functionalities in synthesis.

by Ed Law
24/06/2010