Rapid Cleavage of Unactivated, Unstrained Amide Bonds at Neutral pH

Building upon the discovery of Suggs and Pires that N-(2-hydroxyethyl)glycine amides undergo rapid amide cleavage under mild conditions [ Suggs J. W. ; Pires R. M. Tetrahedron Lett. 1997, 38, 2227–2230], we synthesized the derivatives (4aα,8β,8aα)-1-ethylamido-8-hydroxydecahydroquinoline (4) and (4aα,8α,8aβ)-1-ethylamido-8-hydroxydecahydroquinoline (5). These two species are conformationally constrained, but steric compression is not introduced between the hydroxyl group and the amide functionality it attacks. At 20 °C and slightly basic pH, derivatives 4 and 5 undergo amide cleavage with half-lives of 21 min and 14 h, respectively, which correspond to rate increases of 251- and 6.3-fold relative to the acyclic analogue N-(2-hydroxyethyl)glycine amide (3).