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Nicolette M. Fernandes, Fabienne Fache, Mari Rosen, Phuong-Lan Nguyen, and David E. Hansen. 2008. Rapid Cleavage of Unactivated, Unstrained Amide Bonds at Neutral pH. Journal of Organic Chemistry 73: 64136416. Full Article

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, 22272230], 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).

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