Marc Hutchby, Chris E. Houlden, Mairi F. Haddow, Simon N. G. Tyler, Guy C. Lloyd-Jones, and Kevin I. Booker-Milburn Angew. Chem. Int. Ed.
Solvolysis of amide bonds is notoriously difficult under neutral conditions. This is due to conjugation of the nitrogen lone pair with the pi system of the carbonyl group in a planar ground state where the nitrogen is sp2-hydridised. The resulting system displays a stronger C-N bond and a less ‘ketonic’ C=O bond. The reactivity of strained lactams, where the amide lone pair is geometrically constrained out of conjugation with the carbonyl group, has been studied extensively, and these species have been shown to undergo efficient solvolysis under relatively mild conditions. However, due to the lack of pi system conjugation in the ground state, these strained lactams may be considered to be less ‘amide-like’ in character.
Lloyd-Jones and Booker-Milburn report a method of activating simple amides to solvolysis using a combination of electron-withdrawing alpha-substituents and sterically bulky substituents on nitrogen.
The groups have previously reported a similar reaction of ureas where a ‘proton switch’ mechanism allows the expulsion of the hindered amine and the generation of the rapidly quenched isocyanate. By employing an electron-withdrawing group at the alpha position of an amide, a similar mechanism can be promoted allowing the formation and quenching of a ketene intermediate.
Various alpha-substituents are shown to allow this reactivity, a benzenesulfonyl group displaying the greatest reaction rates. Similarly, a number of sterically encumbered substituents on nitrogen can be used with, unsurprisingly, TMP being the most efficient.
The preparation of several esters, thioesters and amides are shown employing a TMP-amide substrate with reaction occurring under exceptionally mild conditions. However, perhaps an interesting use of this chemistry might be in the protection of hindered amines. An amine protecting group that can be removed under mild and neutral conditions would be complementary to most commonly used protections.