Imidoyl Cyanides via Piperidines

I spent a good part of my weekend at the library researching fragmentation reactions (hours of fun, I know).  One of the several older papers I read came from Norbert De Kimpe's lab at Ghent University (Belgium).  Apart from contributing to organofluorine, cyclopropane and medicinal chemistry, De Kimpe has also dabbled a bit in heterocyclic synthesis.  The paper in question reports an interesting method for preparing imidoyl cyanide from a piperidine intermediate (Tetrahedron Lett. 2001, 42, 3921).  Here’s the general reaction scheme:

The electron pushing for this transformation was rather interesting, so apart from submitting the mechanism to our Department’s weekly problem set, I figured I’d cover it on the blog.  Bromination with elemental bromine results in 5-exo-tet cyclization to give the corresponding 1-pyrroldinium salt (a transformation previously reported by De Kimpe: Tetrahedron Lett. 1994, 35, 1925-1928).  Treatment of the pyrroldinium species with KCN quenches the positive charge, which ends up causing an intramolecular C-N bond formation, followed by SN2 attack from the bromide ultimately giving the piperidine system.

Finally, treatment of the piperidine with a strong base (i.e. NaH) results in deprotonation at the reasonably acidic methine. 

Here’s the challenging part to rationalize: proper orbital alignment in the transition state.  Grob fragmentations fall into that category of “elimination-type” transformations.  Because Grob reactions are notoriously E1cb-like, orbital alignment is critical for the reaction to proceed.  In the chair diagram below, electron density between the C-N bond is aligned with the adjacent sp³-hybrid, which forms the C-Br bond.  As the C-N bond breaks, the electron density flows into the proximal, “empty” lobe (more accurately called the sigma*-orbital) giving the double bond in the product. 

From a purely utilitarian standpoint, the chemistry in the paper is great for a few reasons: good yields, high diastereoselectivity (in the piperidine synthesis) and use of commonly available chemicals found in most synthetic labs.  The necessary evil, however, is the use of potassium cyanide, which, judging by its once notorious use in several state correctional systems, can pose serious health risks.  But, as Chris Rock once said, "You can't be happy that fire cooks your food and be mad it burns your fingertips."